Marie Standl

In a rapidly urbanizing world, many people have little contact with natural environments, which may affect health and well-being. Existing reviews generally conclude that residential greenspace is beneficial to health. However, the processes generating these benefits and how they can be best promoted remain unclear. During an Expert Workshop held in September 2016, the evidence linking greenspace and health was reviewed from a transdisciplinary standpoint, with a particular focus on potential underlying biopsychosocial pathways and how these can be explored and organized to support policy-relevant population health research. Potential pathways linking greenspace to health are here presented in three domains, which emphasize three general functions of greenspace: reducing harm (e.g. reducing exposure to air pollution, noise and heat), restoring capacities (e.g. attention restoration and physiological stress recovery) and building capacities (e.g. encouraging physical activity and facilitating social cohesion). Interrelations between among the three domains are also noted. Among several recommendations, future studies should: use greenspace and behavioural measures that are relevant to hypothesized pathways; include assessment of presence, access and use of greenspace; use longitudinal, interventional and (quasi)experimental study designs to assess causation; and include low and middle income countries given their absence in the existing literature. Cultural, climatic, geographic and other contextual factors also need further consideration. While the existing evidence affirms beneficial impacts of greenspace on health, much remains to be learned about the specific pathways and functional form of such relationships, and how these may vary by context, population groups and health outcomes. This Report provides guidance for further epidemiological research with the goal of creating new evidence upon which to develop policy recommendations.

Genetic association studies have identified 21 loci associated with atopic dermatitis risk predominantly in populations of European ancestry. To identify further susceptibility loci for this common, complex skin disease, we performed a meta-analysis of >15 million genetic variants in 21,399 cases and 95,464 controls from populations of European, African, Japanese and Latino ancestry, followed by replication in 32,059 cases and 228,628 controls from 18 studies. We identified ten new risk loci, bringing the total number of known atopic dermatitis risk loci to 31 (with new secondary signals at four of these loci). Notably, the new loci include candidate genes with roles in the regulation of innate host defenses and T cell function, underscoring the important contribution of (auto)immune mechanisms to atopic dermatitis pathogenesis.

Birth weight variation is influenced by fetal and maternal genetic and non-genetic factors, and has been reproducibly associated with future cardio-metabolic health outcomes. In expanded genome-wide association analyses of own birth weight (n = 321,223) and offspring birth weight (n = 230,069 mothers), we identified 190 independent association signals (129 of which are novel). We used structural equation modeling to decompose the contributions of direct fetal and indirect maternal genetic effects, then applied Mendelian randomization to illuminate causal pathways. For example, both indirect maternal and direct fetal genetic effects drive the observational relationship between lower birth weight and higher later blood pressure: maternal blood pressure-raising alleles reduce offspring birth weight, but only direct fetal effects of these alleles, once inherited, increase later offspring blood pressure. Using maternal birth weight-lowering genotypes to proxy for an adverse intrauterine environment provided no evidence that it causally raises offspring blood pressure, indicating that the inverse birth weight-blood pressure association is attributable to genetic effects, and not to intrauterine programming.

Birth weight (BW) has been shown to be influenced by both fetal and maternal factors and in observational studies is reproducibly associated with future risk of adult metabolic diseases including type 2 diabetes (T2D) and cardiovascular disease. These life-course associations have often been attributed to the impact of an adverse early life environment. Here, we performed a multi-ancestry genome-wide association study (GWAS) meta-analysis of BW in 153,781 individuals, identifying 60 loci where fetal genotype was associated with BW (P < 5 × 10-8). Overall, approximately 15% of variance in BW was captured by assays of fetal genetic variation. Using genetic association alone, we found strong inverse genetic correlations between BW and systolic blood pressure (Rg = -0.22, P = 5.5 × 10-13), T2D (Rg = -0.27, P = 1.1 × 10-6) and coronary artery disease (Rg = -0.30, P = 6.5 × 10-9). In addition, using large -cohort datasets, we demonstrated that genetic factors were the major contributor to the negative covariance between BW and future cardiometabolic risk. Pathway analyses indicated that the protein products of genes within BW-associated regions were enriched for diverse processes including insulin signalling, glucose homeostasis, glycogen biosynthesis and chromatin remodelling. There was also enrichment of associations with BW in known imprinted regions (P = 1.9 × 10-4). We demonstrate that life-course associations between early growth phenotypes and adult cardiometabolic disease are in part the result of shared genetic effects and identify some of the pathways through which these causal genetic effects are mediated.

Both low and high gestational weight gain have been associated with adverse maternal and infant outcomes, but optimal gestational weight gain remains uncertain and not well defined for all prepregnancy weight ranges.To examine the association of ranges of gestational weight gain with risk of adverse maternal and infant outcomes and estimate optimal gestational weight gain ranges across prepregnancy body mass index categories.Individual participant-level meta-analysis using data from 196 670 participants within 25 cohort studies from Europe and North America (main study sample). Optimal gestational weight gain ranges were estimated for each prepregnancy body mass index (BMI) category by selecting the range of gestational weight gain that was associated with lower risk for any adverse outcome. Individual participant-level data from 3505 participants within 4 separate hospital-based cohorts were used as a validation sample. Data were collected between 1989 and 2015. The final date of follow-up was December 2015.Gestational weight gain.The main outcome termed any adverse outcome was defined as the presence of 1 or more of the following outcomes: preeclampsia, gestational hypertension, gestational diabetes, cesarean delivery, preterm birth, and small or large size for gestational age at birth.Of the 196 670 women (median age, 30.0 years [quartile 1 and 3, 27.0 and 33.0 years] and 40 937 were white) included in the main sample, 7809 (4.0%) were categorized at baseline as underweight (BMI <18.5); 133 788 (68.0%), normal weight (BMI, 18.5-24.9); 38 828 (19.7%), overweight (BMI, 25.0-29.9); 11 992 (6.1%), obesity grade 1 (BMI, 30.0-34.9); 3284 (1.7%), obesity grade 2 (BMI, 35.0-39.9); and 969 (0.5%), obesity grade 3 (BMI, ≥40.0). Overall, any adverse outcome occurred in 37.2% (n = 73 161) of women, ranging from 34.7% (2706 of 7809) among women categorized as underweight to 61.1% (592 of 969) among women categorized as obesity grade 3. Optimal gestational weight gain ranges were 14.0 kg to less than 16.0 kg for women categorized as underweight; 10.0 kg to less than 18.0 kg for normal weight; 2.0 kg to less than 16.0 kg for overweight; 2.0 kg to less than 6.0 kg for obesity grade 1; weight loss or gain of 0 kg to less than 4.0 kg for obesity grade 2; and weight gain of 0 kg to less than 6.0 kg for obesity grade 3. These gestational weight gain ranges were associated with low to moderate discrimination between those with and those without adverse outcomes (range for area under the receiver operating characteristic curve, 0.55-0.76). Results for discriminative performance in the validation sample were similar to the corresponding results in the main study sample (range for area under the receiver operating characteristic curve, 0.51-0.79).In this meta-analysis of pooled individual participant data from 25 cohort studies, the risk for adverse maternal and infant outcomes varied by gestational weight gain and across the range of prepregnancy weights. The estimates of optimal gestational weight gain may inform prenatal counseling; however, the optimal gestational weight gain ranges had limited predictive value for the outcomes assessed.

Objective To assess the separate and combined associations of maternal pre‐pregnancy body mass index (BMI) and gestational weight gain with the risks of pregnancy complications and their population impact. Design Individual participant data meta‐analysis of 39 cohorts. Setting Europe, North America, and Oceania. Population 265 270 births. Methods Information on maternal pre‐pregnancy BMI , gestational weight gain, and pregnancy complications was obtained. Multilevel binary logistic regression models were used. Main outcome measures Gestational hypertension, pre‐eclampsia, gestational diabetes, preterm birth, small and large for gestational age at birth. Results Higher maternal pre‐pregnancy BMI and gestational weight gain were, across their full ranges, associated with higher risks of gestational hypertensive disorders, gestational diabetes, and large for gestational age at birth. Preterm birth risk was higher at lower and higher BMI and weight gain. Compared with normal weight mothers with medium gestational weight gain, obese mothers with high gestational weight gain had the highest risk of any pregnancy complication (odds ratio 2.51, 95% CI 2.31– 2.74). We estimated that 23.9% of any pregnancy complication was attributable to maternal overweight/obesity and 31.6% of large for gestational age infants was attributable to excessive gestational weight gain. Conclusions Maternal pre‐pregnancy BMI and gestational weight gain are, across their full ranges, associated with risks of pregnancy complications. Obese mothers with high gestational weight gain are at the highest risk of pregnancy complications. Promoting a healthy pre‐pregnancy BMI and gestational weight gain may reduce the burden of pregnancy complications and ultimately the risk of maternal and neonatal morbidity. Tweetable abstract Promoting a healthy body mass index and gestational weight gain might reduce the population burden of pregnancy complications.

The causal direction and magnitude of the association between telomere length and incidence of cancer and non-neoplastic diseases is uncertain owing to the susceptibility of observational studies to confounding and reverse causation.To conduct a Mendelian randomization study, using germline genetic variants as instrumental variables, to appraise the causal relevance of telomere length for risk of cancer and non-neoplastic diseases.Genomewide association studies (GWAS) published up to January 15, 2015.GWAS of noncommunicable diseases that assayed germline genetic variation and did not select cohort or control participants on the basis of preexisting diseases. Of 163 GWAS of noncommunicable diseases identified, summary data from 103 were available.Summary association statistics for single nucleotide polymorphisms (SNPs) that are strongly associated with telomere length in the general population.Odds ratios (ORs) and 95% confidence intervals (CIs) for disease per standard deviation (SD) higher telomere length due to germline genetic variation.Summary data were available for 35 cancers and 48 non-neoplastic diseases, corresponding to 420 081 cases (median cases, 2526 per disease) and 1 093 105 controls (median, 6789 per disease). Increased telomere length due to germline genetic variation was generally associated with increased risk for site-specific cancers. The strongest associations (ORs [95% CIs] per 1-SD change in genetically increased telomere length) were observed for glioma, 5.27 (3.15-8.81); serous low-malignant-potential ovarian cancer, 4.35 (2.39-7.94); lung adenocarcinoma, 3.19 (2.40-4.22); neuroblastoma, 2.98 (1.92-4.62); bladder cancer, 2.19 (1.32-3.66); melanoma, 1.87 (1.55-2.26); testicular cancer, 1.76 (1.02-3.04); kidney cancer, 1.55 (1.08-2.23); and endometrial cancer, 1.31 (1.07-1.61). Associations were stronger for rarer cancers and at tissue sites with lower rates of stem cell division. There was generally little evidence of association between genetically increased telomere length and risk of psychiatric, autoimmune, inflammatory, diabetic, and other non-neoplastic diseases, except for coronary heart disease (OR, 0.78 [95% CI, 0.67-0.90]), abdominal aortic aneurysm (OR, 0.63 [95% CI, 0.49-0.81]), celiac disease (OR, 0.42 [95% CI, 0.28-0.61]) and interstitial lung disease (OR, 0.09 [95% CI, 0.05-0.15]).It is likely that longer telomeres increase risk for several cancers but reduce risk for some non-neoplastic diseases, including cardiovascular diseases.

Lavinia Paternoster and colleagues report a meta-analysis of genome-wide association studies of atopic dermatitis. They report three newly identified associated loci near OVOL1 and ACTL9 and in KIF3A. Atopic dermatitis (AD) is a commonly occurring chronic skin disease with high heritability. Apart from filaggrin (FLG), the genes influencing atopic dermatitis are largely unknown. We conducted a genome-wide association meta-analysis of 5,606 affected individuals and 20,565 controls from 16 population-based cohorts and then examined the ten most strongly associated new susceptibility loci in an additional 5,419 affected individuals and 19,833 controls from 14 studies. Three SNPs reached genome-wide significance in the discovery and replication cohorts combined, including rs479844 upstream of OVOL1 (odds ratio (OR) = 0.88, P = 1.1 × 10−13) and rs2164983 near ACTL9 (OR = 1.16, P = 7.1 × 10−9), both of which are near genes that have been implicated in epidermal proliferation and differentiation, as well as rs2897442 in KIF3A within the cytokine cluster at 5q31.1 (OR = 1.11, P = 3.8 × 10−8). We also replicated association with the FLG locus and with two recently identified association signals at 11q13.5 (rs7927894; P = 0.008) and 20q13.33 (rs6010620; P = 0.002). Our results underline the importance of both epidermal barrier function and immune dysregulation in atopic dermatitis pathogenesis.

Background Maternal obesity and excessive gestational weight gain may have persistent effects on offspring fat development. However, it remains unclear whether these effects differ by severity of obesity, and whether these effects are restricted to the extremes of maternal body mass index (BMI) and gestational weight gain. We aimed to assess the separate and combined associations of maternal BMI and gestational weight gain with the risk of overweight/obesity throughout childhood, and their population impact. Methods and findings We conducted an individual participant data meta-analysis of data from 162,129 mothers and their children from 37 pregnancy and birth cohort studies from Europe, North America, and Australia. We assessed the individual and combined associations of maternal pre-pregnancy BMI and gestational weight gain, both in clinical categories and across their full ranges, with the risks of overweight/obesity in early (2.0–5.0 years), mid (5.0–10.0 years) and late childhood (10.0–18.0 years), using multilevel binary logistic regression models with a random intercept at cohort level adjusted for maternal sociodemographic and lifestyle-related characteristics. We observed that higher maternal pre-pregnancy BMI and gestational weight gain both in clinical categories and across their full ranges were associated with higher risks of childhood overweight/obesity, with the strongest effects in late childhood (odds ratios [ORs] for overweight/obesity in early, mid, and late childhood, respectively: OR 1.66 [95% CI: 1.56, 1.78], OR 1.91 [95% CI: 1.85, 1.98], and OR 2.28 [95% CI: 2.08, 2.50] for maternal overweight; OR 2.43 [95% CI: 2.24, 2.64], OR 3.12 [95% CI: 2.98, 3.27], and OR 4.47 [95% CI: 3.99, 5.23] for maternal obesity; and OR 1.39 [95% CI: 1.30, 1.49], OR 1.55 [95% CI: 1.49, 1.60], and OR 1.72 [95% CI: 1.56, 1.91] for excessive gestational weight gain). The proportions of childhood overweight/obesity prevalence attributable to maternal overweight, maternal obesity, and excessive gestational weight gain ranged from 10.2% to 21.6%. Relative to the effect of maternal BMI, excessive gestational weight gain only slightly increased the risk of childhood overweight/obesity within each clinical BMI category (p-values for interactions of maternal BMI with gestational weight gain: p = 0.038, p < 0.001, and p = 0.637 in early, mid, and late childhood, respectively). Limitations of this study include the self-report of maternal BMI and gestational weight gain for some of the cohorts, and the potential of residual confounding. Also, as this study only included participants from Europe, North America, and Australia, results need to be interpreted with caution with respect to other populations. Conclusions In this study, higher maternal pre-pregnancy BMI and gestational weight gain were associated with an increased risk of childhood overweight/obesity, with the strongest effects at later ages. The additional effect of gestational weight gain in women who are overweight or obese before pregnancy is small. Given the large population impact, future intervention trials aiming to reduce the prevalence of childhood overweight and obesity should focus on maternal weight status before pregnancy, in addition to weight gain during pregnancy.

Summary Understanding the complexity of aging is of utmost importance. This can now be addressed by the novel and powerful approach of metabolomics. However, to date, only a few metabolic studies based on large samples are available. Here, we provide novel and specific information on age‐related metabolite concentration changes in human homeostasis. We report results from two population‐based studies: the KORA F4 study from Germany as a discovery cohort, with 1038 female and 1124 male participants (32–81 years), and the TwinsUK study as replication, with 724 female participants. Targeted metabolomics of fasting serum samples quantified 131 metabolites by FIA‐MS/MS. Among these, 71/34 metabolites were significantly associated with age in women/men (BMI adjusted). We further identified a set of 13 independent metabolites in women (with P values ranging from 4.6 × 10 −04 to 7.8 × 10 −42 , α corr = 0.004). Eleven of these 13 metabolites were replicated in the TwinsUK study, including seven metabolite concentrations that increased with age (C0, C10:1, C12:1, C18:1, SM C16:1, SM C18:1, and PC aa C28:1), while histidine decreased. These results indicate that metabolic profiles are age dependent and might reflect different aging processes, such as incomplete mitochondrial fatty acid oxidation. The use of metabolomics will increase our understanding of aging networks and may lead to discoveries that help enhance healthy aging.

Allergen-specific immunoglobulin E (present in allergic sensitization) has a central role in the pathogenesis of allergic disease. We performed the first large-scale genome-wide association study (GWAS) of allergic sensitization in 5,789 affected individuals and 10,056 controls and followed up the top SNP at each of 26 loci in 6,114 affected individuals and 9,920 controls. We increased the number of susceptibility loci with genome-wide significant association with allergic sensitization from three to ten, including SNPs in or near TLR6, C11orf30, STAT6, SLC25A46, HLA-DQB1, IL1RL1, LPP, MYC, IL2 and HLA-B. All the top SNPs were associated with allergic symptoms in an independent study. Risk-associated variants at these ten loci were estimated to account for at least 25% of allergic sensitization and allergic rhinitis. Understanding the molecular mechanisms underlying these associations may provide new insights into the etiology of allergic disease.

Abstract Background Levels of physical activity and variation in physical activity and sedentary time by place and person in European children and adolescents are largely unknown. The objective of the study was to assess the variations in objectively measured physical activity and sedentary time in children and adolescents across Europe. Methods Six databases were systematically searched to identify pan-European and national data sets on physical activity and sedentary time assessed by the same accelerometer in children (2 to 9.9 years) and adolescents (≥10 to 18 years). We harmonized individual-level data by reprocessing hip-worn raw accelerometer data files from 30 different studies conducted between 1997 and 2014, representing 47,497 individuals (2–18 years) from 18 different European countries. Results Overall, a maximum of 29% (95% CI: 25, 33) of children and 29% (95% CI: 25, 32) of adolescents were categorized as sufficiently physically active. We observed substantial country- and region-specific differences in physical activity and sedentary time, with lower physical activity levels and prevalence estimates in Southern European countries. Boys were more active and less sedentary in all age-categories. The onset of age-related lowering or leveling-off of physical activity and increase in sedentary time seems to become apparent at around 6 to 7 years of age. Conclusions Two third of European children and adolescents are not sufficiently active. Our findings suggest substantial gender-, country- and region-specific differences in physical activity. These results should encourage policymakers, governments, and local and national stakeholders to take action to facilitate an increase in the physical activity levels of young people across Europe.

Previous published analyses have focused on the effect of air pollution on asthma and rhinoconjunctivitis throughout early and middle childhood. However, the role of exposure to air pollution in the development of childhood and adolescent asthma and rhinoconjunctivitis remains unclear. We aimed to assess the longitudinal associations between exposure to air pollution and development of asthma and rhinoconjunctivitis throughout childhood and adolescence.We did a population-based birth cohort study of 14 126 participants from four prospective birth cohort studies from Germany, Sweden, and the Netherlands with 14–16 years of follow-up. We linked repeated questionnaire reports of asthma and rhinoconjunctivitis with annual average air pollution concentrations (nitrogen dioxide [NO2], particulate matter [PM] with a diameter of less than 2·5 μm [PM2·5], less than 10 μm [PM10], and between 2·5 μm and 10 μm [PMcoarse], and PM2·5 absorbance [indicator of soot]) at the participants' home addresses. We analysed longitudinal associations of air pollution exposure at participants' birth addresses and addresses at the time of follow-up with asthma and rhinoconjunctivitis incidence and prevalence in cohort-specific analyses, with subsequent meta-analysis and pooled analyses.Overall, the risk of incident asthma up to age 14–16 years increased with increasing exposure to NO2 (adjusted meta-analysis odds ratio [OR] 1·13 per 10 μg/m3 [95% CI 1·02–1·25]) and PM2·5 absorbance (1·29 per 1 unit [1·00–1·66]) at the birth address. A similar, albeit non-significant, trend was shown for PM2·5 and incident asthma (meta-analysis OR 1·25 per 5 μg/m3 [95% CI 0·94–1·66]). These associations with asthma were more consistent after age 4 years than before that age. There was no indication of an adverse effect of air pollution on rhinoconjunctivitis.Exposure to air pollution early in life might contribute to the development of asthma throughout childhood and adolescence, particularly after age 4 years, when asthma can be more reliably diagnosed. Reductions in levels of air pollution could help to prevent the development of asthma in children.The European Union.

Individual differences in aggressive behavior emerge in early childhood and predict persisting behavioral problems and disorders. Studies of antisocial and severe aggression in adulthood indicate substantial underlying biology. However, little attention has been given to genome-wide approaches of aggressive behavior in children. We analyzed data from nine population-based studies and assessed aggressive behavior using well-validated parent-reported questionnaires. This is the largest sample exploring children's aggressive behavior to date (N = 18,988), with measures in two developmental stages (N = 15,668 early childhood and N = 16,311 middle childhood/early adolescence). First, we estimated the additive genetic variance of children's aggressive behavior based on genome-wide SNP information, using genome-wide complex trait analysis (GCTA). Second, genetic associations within each study were assessed using a quasi-Poisson regression approach, capturing the highly right-skewed distribution of aggressive behavior. Third, we performed meta-analyses of genome-wide associations for both the total age-mixed sample and the two developmental stages. Finally, we performed a gene-based test using the summary statistics of the total sample. GCTA quantified variance tagged by common SNPs (10-54%). The meta-analysis of the total sample identified one region in chromosome 2 (2p12) at near genome-wide significance (top SNP rs11126630, P = 5.30 × 10(-8) ). The separate meta-analyses of the two developmental stages revealed suggestive evidence of association at the same locus. The gene-based analysis indicated association of variation within AVPR1A with aggressive behavior. We conclude that common variants at 2p12 show suggestive evidence for association with childhood aggression. Replication of these initial findings is needed, and further studies should clarify its biological meaning. © 2015 Wiley Periodicals, Inc.

Asthma, rhinitis, and eczema are complex diseases with multiple genetic and environmental factors interlinked through IgE-associated and non-IgE-associated mechanisms. Mechanisms of the Development of ALLergy (MeDALL; EU FP7-CP-IP; project no: 261357; 2010-2015) studied the complex links of allergic diseases at the clinical and mechanistic levels by linking epidemiologic, clinical, and mechanistic research, including in vivo and in vitro models. MeDALL integrated 14 European birth cohorts, including 44,010 participants and 160 cohort follow-ups between pregnancy and age 20 years. Thirteen thousand children were prospectively followed after puberty by using a newly standardized MeDALL Core Questionnaire. A microarray developed for allergen molecules with increased IgE sensitivity was obtained for 3,292 children. Estimates of air pollution exposure from previous studies were available for 10,000 children. Omics data included those from historical genome-wide association studies (23,000 children) and DNA methylation (2,173), targeted multiplex biomarker (1,427), and transcriptomic (723) studies. Using classical epidemiology and machine-learning methods in 16,147 children aged 4 years and 11,080 children aged 8 years, MeDALL showed the multimorbidity of eczema, rhinitis, and asthma and estimated that only 38% of multimorbidity was attributable to IgE sensitization. MeDALL has proposed a new vision of multimorbidity independent of IgE sensitization, and has shown that monosensitization and polysensitization represent 2 distinct phenotypes. The translational component of MeDALL is shown by the identification of a novel allergic phenotype characterized by polysensitization and multimorbidity, which is associated with the frequency, persistence, and severity of allergic symptoms. The results of MeDALL will help integrate personalized, predictive, preventative, and participatory approaches in allergic diseases.

Understanding differences in sensitization profiles at the molecular allergen level is important for diagnosis, personalized treatment and prevention strategies in allergy.Immunoglobulin E (IgE) sensitization profiles were determined in more than 2800 sera from children in nine population-based cohorts in different geographical regions of Europe; north [BAMSE (Sweden), ECA (Norway)], west/central [PIAMA (the Netherlands), BiB (the United Kingdom), GINIplus (Germany)], and south [INMA Sabadell and Gipuzkoa (Spain) and ROBBIC Rome and Bologna (Italy)] using the MeDALL-allergen chip.Sensitization to grass pollen allergen, Phl p 1, and to major cat allergen, Fel d 1, dominated in most European regions whereas sensitization to house dust mite allergens Der p 1, 2 and 23 varied considerably between regions and were lowest in the north. Less than half of children from Sabadell which has a hot and dry climate were sensitized to respiratory allergens, in particular house dust mite allergens as compared to Gipuzkoa nearby with a more humid climate. Peanut allergen Ara h 1 was the most frequently recognized class 1 food allergen in Northern/Western Europe, while the fruit allergens Pru p 3, Act d 1 and 2 were prominent in Southern and Western/Central Europe. Ves v 5-sensitization dominated in North and West/Central Europe.We show regional, exposome- and climate-dependent differences in molecular IgE-reactivity profiles in Northern, Western/Central and Southern Europe which may form a molecular basis for precision medicine-based approaches for treatment and prevention of allergy.

Vincent Jaddoe and colleagues report a genome-wide association study for infant head circumference. They identify variants in SBNO1 and near HMGA2 that are associated with this phenotype. To identify genetic variants associated with head circumference in infancy, we performed a meta-analysis of seven genome-wide association studies (GWAS) (N = 10,768 individuals of European ancestry enrolled in pregnancy and/or birth cohorts) and followed up three lead signals in six replication studies (combined N = 19,089). rs7980687 on chromosome 12q24 (P = 8.1 × 10−9) and rs1042725 on chromosome 12q15 (P = 2.8 × 10−10) were robustly associated with head circumference in infancy. Although these loci have previously been associated with adult height1, their effects on infant head circumference were largely independent of height (P = 3.8 × 10−7 for rs7980687 and P = 1.3 × 10−7 for rs1042725 after adjustment for infant height). A third signal, rs11655470 on chromosome 17q21, showed suggestive evidence of association with head circumference (P = 3.9 × 10−6). SNPs correlated to the 17q21 signal have shown genome-wide association with adult intracranial volume2, Parkinson's disease and other neurodegenerative diseases3,4,5, indicating that a common genetic variant in this region might link early brain growth with neurological disease in later life.

Objective The aims of this study were to elucidate the influence of common genetic variants on childhood attention-deficit/hyperactivity disorder (ADHD) symptoms, to identify genetic variants that explain its high heritability, and to investigate the genetic overlap of ADHD symptom scores with ADHD diagnosis. Method Within the EArly Genetics and Lifecourse Epidemiology (EAGLE) consortium, genome-wide single nucleotide polymorphisms (SNPs) and ADHD symptom scores were available for 17,666 children (<13 years of age) from nine population-based cohorts. SNP-based heritability was estimated in data from the three largest cohorts. Meta-analysis based on genome-wide association (GWA) analyses with SNPs was followed by gene-based association tests, and the overlap in results with a meta-analysis in the Psychiatric Genomics Consortium (PGC) case-control ADHD study was investigated. Results SNP-based heritability ranged from 5% to 34%, indicating that variation in common genetic variants influences ADHD symptom scores. The meta-analysis did not detect genome-wide significant SNPs, but three genes, lying close to each other with SNPs in high linkage disequilibrium (LD), showed a gene-wide significant association (p values between 1.46 × 10−6 and 2.66 × 10−6). One gene, WASL, is involved in neuronal development. Both SNP- and gene-based analyses indicated overlap with the PGC meta-analysis results with the genetic correlation estimated at 0.96. Conclusion The SNP-based heritability for ADHD symptom scores indicates a polygenic architecture, and genes involved in neurite outgrowth are possibly involved. Continuous and dichotomous measures of ADHD appear to assess a genetically common phenotype. A next step is to combine data from population-based and case-control cohorts in genetic association studies to increase sample size and to improve statistical power for identifying genetic variants. The aims of this study were to elucidate the influence of common genetic variants on childhood attention-deficit/hyperactivity disorder (ADHD) symptoms, to identify genetic variants that explain its high heritability, and to investigate the genetic overlap of ADHD symptom scores with ADHD diagnosis. Within the EArly Genetics and Lifecourse Epidemiology (EAGLE) consortium, genome-wide single nucleotide polymorphisms (SNPs) and ADHD symptom scores were available for 17,666 children (<13 years of age) from nine population-based cohorts. SNP-based heritability was estimated in data from the three largest cohorts. Meta-analysis based on genome-wide association (GWA) analyses with SNPs was followed by gene-based association tests, and the overlap in results with a meta-analysis in the Psychiatric Genomics Consortium (PGC) case-control ADHD study was investigated. SNP-based heritability ranged from 5% to 34%, indicating that variation in common genetic variants influences ADHD symptom scores. The meta-analysis did not detect genome-wide significant SNPs, but three genes, lying close to each other with SNPs in high linkage disequilibrium (LD), showed a gene-wide significant association (p values between 1.46 × 10−6 and 2.66 × 10−6). One gene, WASL, is involved in neuronal development. Both SNP- and gene-based analyses indicated overlap with the PGC meta-analysis results with the genetic correlation estimated at 0.96. The SNP-based heritability for ADHD symptom scores indicates a polygenic architecture, and genes involved in neurite outgrowth are possibly involved. Continuous and dichotomous measures of ADHD appear to assess a genetically common phenotype. A next step is to combine data from population-based and case-control cohorts in genetic association studies to increase sample size and to improve statistical power for identifying genetic variants.

Abstract Background The prevalence of allergic rhinitis is high, but the role of environmental factors remains unclear. We examined cohort‐specific and combined associations of residential greenness with allergic rhinitis and aeroallergen sensitization based on individual data from Swedish ( BAMSE ), Australian ( MACS ), Dutch ( PIAMA ), Canadian ( CAPPS and SAGE ), and German ( GINI plus and LISA plus) birth cohorts ( n = 13 016). Methods Allergic rhinitis (doctor diagnosis/symptoms) and aeroallergen sensitization were assessed in children aged 6–8 years in six cohorts and 10–12 years in five cohorts. Residential greenness was defined as the mean Normalized Difference Vegetation Index ( NDVI ) in a 500‐m buffer around the home address at the time of health assessment. Cohort‐specific associations per 0.2 unit increase in NDVI were assessed using logistic regression models and combined in a random‐effects meta‐analysis. Results Greenness in a 500‐m buffer was positively associated with allergic rhinitis at 6–8 years in BAMSE (odds ratio = 1.42, 95% confidence interval [1.13, 1.79]) and GINI / LISA South (1.69 [1.19, 2.41]) but inversely associated in GINI / LISA North (0.61 [0.36, 1.01]) and PIAMA (0.67 [0.47, 0.95]). Effect estimates in CAPPS and SAGE were also conflicting but not significant (0.63 [0.32, 1.24] and 1.31 [0.81, 2.12], respectively). All meta‐analyses were nonsignificant. Results were similar for aeroallergen sensitization at 6–8 years and both outcomes at 10–12 years. Stratification by NO 2 concentrations, population density, an urban vs rural marker, and moving did not reveal consistent trends within subgroups. Conclusion Although residential greenness appears to be associated with childhood allergic rhinitis and aeroallergen sensitization, the effect direction varies by location.

The evidence supporting an association between traffic-related air pollution exposure and incident childhood asthma is inconsistent and may depend on genetic factors.To identify gene-environment interaction effects on childhood asthma using genome-wide single-nucleotide polymorphism (SNP) data and air pollution exposure. Identified loci were further analyzed at epigenetic and transcriptomic levels.We used land use regression models to estimate individual air pollution exposure (represented by outdoor NO2 levels) at the birth address and performed a genome-wide interaction study for doctors' diagnoses of asthma up to 8 years in three European birth cohorts (n = 1,534) with look-up for interaction in two separate North American cohorts, CHS (Children's Health Study) and CAPPS/SAGE (Canadian Asthma Primary Prevention Study/Study of Asthma, Genetics and Environment) (n = 1,602 and 186 subjects, respectively). We assessed expression quantitative trait locus effects in human lung specimens and blood, as well as associations among air pollution exposure, methylation, and transcriptomic patterns.In the European cohorts, 186 SNPs had an interaction P < 1 × 10-4 and a look-up evaluation of these disclosed 8 SNPs in 4 loci, with an interaction P < 0.05 in the large CHS study, but not in CAPPS/SAGE. Three SNPs within adenylate cyclase 2 (ADCY2) showed the same direction of the interaction effect and were found to influence ADCY2 gene expression in peripheral blood (P = 4.50 × 10-4). One other SNP with P < 0.05 for interaction in CHS, rs686237, strongly influenced UDP-Gal:betaGlcNAc β-1,4-galactosyltransferase, polypeptide 5 (B4GALT5) expression in lung tissue (P = 1.18 × 10-17). Air pollution exposure was associated with differential discs, large homolog 2 (DLG2) methylation and expression.Our results indicated that gene-environment interactions are important for asthma development and provided supportive evidence for interaction with air pollution for ADCY2, B4GALT5, and DLG2.

The genetic background of childhood body mass index (BMI), and the extent to which the well-known associations of childhood BMI with adult diseases are explained by shared genetic factors, are largely unknown. We performed a genome-wide association study meta-analysis of BMI in 61,111 children aged between 2 and 10 years. Twenty-five independent loci reached genome-wide significance in the combined discovery and replication analyses. Two of these, located near NEDD4L and SLC45A3, have not previously been reported in relation to either childhood or adult BMI. Positive genetic correlations of childhood BMI with birth weight and adult BMI, waist-to-hip ratio, diastolic blood pressure and type 2 diabetes were detected (Rg ranging from 0.11 to 0.76, P-values <0.002). A negative genetic correlation of childhood BMI with age at menarche was observed. Our results suggest that the biological processes underlying childhood BMI largely, but not completely, overlap with those underlying adult BMI. The well-known observational associations of BMI in childhood with cardio-metabolic diseases in adulthood may reflect partial genetic overlap, but in light of previous evidence, it is also likely that they are explained through phenotypic continuity of BMI from childhood into adulthood.

<h2>Summary</h2><h3>Background</h3> Gestational diabetes and gestational hypertensive disorders are associated with offspring obesity, but the role of maternal adiposity in these associations remains unclear. We aimed to investigate whether these pregnancy complications affect the odds of offspring obesity independently of maternal obesity. <h3>Methods</h3> We did an individual participant data (IPD) meta-analysis of mother–offspring pairs from prospective birth cohort studies that had IPD on mothers with singleton liveborn children born from 1989 onwards and had information available about maternal gestational diabetes, gestational hypertension or pre-eclampsia, and childhood body-mass index (BMI). We applied multilevel mixed-effects models to assess associations of gestational diabetes, gestational hypertension, and pre-eclampsia with BMI SD scores and the odds of overweight and obesity throughout childhood, adjusting for lifestyle characteristics (offspring's sex, maternal age, educational level, ethnicity, parity, and smoking during pregnancy). We then explored the extent to which any association was explained by maternal pre-pregnancy or early-pregnancy BMI. <h3>Findings</h3> 160 757 mother–offspring pairs from 34 European or North American cohorts were analysed. Compared with uncomplicated pregnancies, gestational diabetes was associated with increased odds of overweight or obesity throughout childhood (odds ratio [OR] 1·59 [95% CI 1·36 to 1·86] for early childhood [age 2·0–4·9 years], 1·41 [1·26 to 1·57] for mid childhood [5·0–9·9 years], and 1·32 [0·97 to 1·78] for late childhood [10·0–17·9 years]); however, these associations attenuated towards the null following adjustment for maternal BMI (OR 1·35 [95% CI 1·15 to 1·58] for early childhood, 1·12 [1·00 to 1·25] for mid childhood, and 0·96 [0·71 to 1·31] for late childhood). Likewise, gestational hypertension was associated with increased odds of overweight throughout childhood (OR 1·19 [95% CI 1·01 to 1·39] for early childhood, 1·23 [1·15 to 1·32] for mid childhood, and 1·49 [1·30 to 1·70] for late childhood), but additional adjustment for maternal BMI largely explained these associations (1·01 [95% CI 0·86 to 1·19] for early childhood, 1·02 [0·95 to 1·10] for mid childhood, and 1·18 [1·03 to 1·36] for late childhood). Pre-eclampsia was associated with decreased BMI in early childhood only (difference in BMI SD score −0·05 SD score [95% CI −0·09 to −0·01]), and this association strengthened following additional adjustment for maternal BMI. <h3>Interpretation</h3> Although lowering maternal risk of gestational diabetes, gestational hypertension, and pre-eclampsia is important in relation to maternal and fetal pregnancy outcomes, such interventions are unlikely to have a direct impact on childhood obesity. Preventive strategies for reducing childhood obesity should focus on maternal BMI rather than on pregnancy complications. <h3>Funding</h3> EU's Horizon 2020 research and innovation programme (LifeCycle Project).

Allergic rhinitis is the most common clinical presentation of allergy, affecting 400 million people worldwide, with increasing incidence in westernized countries1,2. To elucidate the genetic architecture and understand the underlying disease mechanisms, we carried out a meta-analysis of allergic rhinitis in 59,762 cases and 152,358 controls of European ancestry and identified a total of 41 risk loci for allergic rhinitis, including 20 loci not previously associated with allergic rhinitis, which were confirmed in a replication phase of 60,720 cases and 618,527 controls. Functional annotation implicated genes involved in various immune pathways, and fine mapping of the HLA region suggested amino acid variants important for antigen binding. We further performed genome-wide association study (GWAS) analyses of allergic sensitization against inhalant allergens and nonallergic rhinitis, which suggested shared genetic mechanisms across rhinitis-related traits. Future studies of the identified loci and genes might identify novel targets for treatment and prevention of allergic rhinitis. Genome-wide association analyses identify new risk loci for allergic rhinitis and for sensitization to inhalant allergens. The associated regions implicate immune-related pathways, including innate and adaptive IgE-related mechanisms.

Early childhood growth patterns are associated with adult health, yet the genetic factors and the developmental stages involved are not fully understood. Here, we combine genome-wide association studies with modeling of longitudinal growth traits to study the genetics of infant and child growth, followed by functional, pathway, genetic correlation, risk score, and colocalization analyses to determine how developmental timings, molecular pathways, and genetic determinants of these traits overlap with those of adult health. We found a robust overlap between the genetics of child and adult body mass index (BMI), with variants associated with adult BMI acting as early as 4 to 6 years old. However, we demonstrated a completely distinct genetic makeup for peak BMI during infancy, influenced by variation at the LEPR/LEPROT locus. These findings suggest that different genetic factors control infant and child BMI. In light of the obesity epidemic, these findings are important to inform the timing and targets of prevention strategies.

Background Low circulating vitamin D levels have been associated with risk of asthma, atopic dermatitis, and elevated total immunoglobulin E (IgE). These epidemiological associations, if true, would have public health importance, since vitamin D insufficiency is common and correctable. Methods and findings We aimed to test whether genetically lowered vitamin D levels were associated with risk of asthma, atopic dermatitis, or elevated serum IgE levels, using Mendelian randomization (MR) methodology to control bias owing to confounding and reverse causation. The study employed data from the UK Biobank resource and from the SUNLIGHT, GABRIEL and EAGLE eczema consortia. Using four single-nucleotide polymorphisms (SNPs) strongly associated with 25-hydroxyvitamin D (25OHD) levels in 33,996 individuals, we conducted MR studies to estimate the effect of lowered 25OHD on the risk of asthma (n = 146,761), childhood onset asthma (n = 15,008), atopic dermatitis (n = 40,835), and elevated IgE level (n = 12,853) and tested MR assumptions in sensitivity analyses. None of the four 25OHD-lowering alleles were associated with asthma, atopic dermatitis, or elevated IgE levels (p ≥ 0.2). The MR odds ratio per standard deviation decrease in log-transformed 25OHD was 1.03 (95% confidence interval [CI] 0.90–1.19, p = 0.63) for asthma, 0.95 (95% CI 0.69–1.31, p = 0.76) for childhood-onset asthma, and 1.12 (95% CI 0.92–1.37, p = 0.27) for atopic dermatitis, and the effect size on log-transformed IgE levels was −0.40 (95% CI −1.65 to 0.85, p = 0.54). These results persisted in sensitivity analyses assessing population stratification and pleiotropy and vitamin D synthesis and metabolism pathways. The main limitations of this study are that the findings do not exclude an association between the studied outcomes and 1,25-dihydoxyvitamin D, the active form of vitamin D, the study was underpowered to detect effects smaller than an OR of 1.33 for childhood asthma, and the analyses were restricted to white populations of European ancestry. This research has been conducted using the UK Biobank Resource and data from the SUNLIGHT, GABRIEL and EAGLE Eczema consortia. Conclusions In this study, we found no evidence that genetically determined reduction in 25OHD levels conferred an increased risk of asthma, atopic dermatitis, or elevated total serum IgE, suggesting that efforts to increase vitamin D are unlikely to reduce risks of atopic disease.

Although hundreds of genome-wide association studies-implicated loci have been reported for adult obesity-related traits, less is known about the genetics specific for early-onset obesity and with only a few studies conducted in non-European populations to date. Searching for additional genetic variants associated with childhood obesity, we performed a trans-ancestral meta-analysis of 30 studies consisting of up to 13 005 cases (≥95th percentile of body mass index (BMI) achieved 2-18 years old) and 15 599 controls (consistently <50th percentile of BMI) of European, African, North/South American and East Asian ancestry. Suggestive loci were taken forward for replication in a sample of 1888 cases and 4689 controls from seven cohorts of European and North/South American ancestry. In addition to observing 18 previously implicated BMI or obesity loci, for both early and late onset, we uncovered one completely novel locus in this trans-ancestral analysis (nearest gene, METTL15). The variant was nominally associated with only the European subgroup analysis but had a consistent direction of effect in other ethnicities. We then utilized trans-ancestral Bayesian analysis to narrow down the location of the probable causal variant at each genome-wide significant signal. Of all the fine-mapped loci, we were able to narrow down the causative variant at four known loci to fewer than 10 single nucleotide polymorphisms (SNPs) (FAIM2, GNPDA2, MC4R and SEC16B loci). In conclusion, an ethnically diverse setting has enabled us to both identify an additional pediatric obesity locus and further fine-map existing loci.

Abstract Background Data on the long‐term impact of hydrolyzed formulas on allergies are scarce. Objective To assess the association between early intervention with hydrolyzed formulas in high‐risk children and allergic outcomes in adolescence. Methods GINI trial participants ( n = 2252) received one of four formulas in the first four months of life as breastmilk substitute if necessary: partial or extensive whey hydrolyzate ( pHF ‐W, eHF ‐W), extensive casein hydrolyzate ( eHF ‐C) or standard cow′s milk formula ( CMF ) as reference. Associations between these formulas and the cumulative incidence and prevalence of parent‐reported physician‐diagnosed asthma, allergic rhinitis ( AR ) and eczema, as well as spirometric indices and sensitization, were examined using generalized linear models. Results Between 11 and 15 years, the prevalence of asthma was reduced in the eHF ‐C group compared to CMF (odds ratio ( OR ) 0.49, 95% confidence interval ( CI ) 0.26–0.89), which is consistent with the spirometric results. The cumulative incidence of AR was lower in eHF ‐C (risk ratio ( RR ) 0.77, 95% CI 0.59–0.99]) and the AR prevalence in pHF ‐W ( OR 0.67, 95% CI 0.47–0.95) and eHF ‐C ( OR 0.59, 95% CI 0.41–0.84). The cumulative incidence of eczema was reduced in pHF ‐W ( RR 0.75, 95% CI 0.59–0.96) and eHF ‐C ( RR 0.60, 95% CI 0.46–0.77), as was the eczema prevalence between 11 and 15 years in eHF ‐C ( OR 0.42, 95% CI 0.23–0.79). No significant effects were found in the eHF ‐W group on any manifestation,nor was there an effect on sensitization with any formula. Conclusion In high‐risk children, early intervention using different hydrolyzed formulas has variable preventative effects on asthma, allergic rhinitis and eczema up to adolescence.

The FTO gene harbors variation with the strongest effect on adiposity and obesity risk. Previous data support a role for FTO variation in influencing food intake. We conducted a combined analysis of 16,094 boys and girls aged 1–18 years from 14 studies to examine the following: 1) the association between the FTO rs9939609 variant (or a proxy) and total energy and macronutrient intake; and 2) the interaction between the FTO variant and dietary intake, and the effect on BMI. We found that the BMI-increasing allele (minor allele) of the FTO variant was associated with increased total energy intake (effect per allele = 14.3 kcal/day [95% CI 5.9, 22.7 kcal/day], P = 6.5 × 10−4), but not with protein, carbohydrate, or fat intake. We also found that protein intake modified the association between the FTO variant and BMI (interactive effect per allele = 0.08 SD [0.03, 0.12 SD], P for interaction = 7.2 × 10−4): the association between FTO genotype and BMI was much stronger in individuals with high protein intake (effect per allele = 0.10 SD [0.07, 0.13 SD], P = 8.2 × 10−10) than in those with low intake (effect per allele = 0.04 SD [0.01, 0.07 SD], P = 0.02). Our results suggest that the FTO variant that confers a predisposition to higher BMI is associated with higher total energy intake, and that lower dietary protein intake attenuates the association between FTO genotype and adiposity in children and adolescents.

Gestational weight gain differs according to pre-pregnancy body mass index and is related to the risks of adverse maternal and child health outcomes. Gestational weight gain charts for women in different pre-pregnancy body mass index groups enable identification of women and offspring at risk for adverse health outcomes. We aimed to construct gestational weight gain reference charts for underweight, normal weight, overweight, and grades 1, 2 and 3 obese women and to compare these charts with those obtained in women with uncomplicated term pregnancies.We used individual participant data from 218,216 pregnant women participating in 33 cohorts from Europe, North America, and Oceania. Of these women, 9065 (4.2%), 148,697 (68.1%), 42,678 (19.6%), 13,084 (6.0%), 3597 (1.6%), and 1095 (0.5%) were underweight, normal weight, overweight, and grades 1, 2, and 3 obese women, respectively. A total of 138, 517 women from 26 cohorts had pregnancies with no hypertensive or diabetic disorders and with term deliveries of appropriate for gestational age at birth infants. Gestational weight gain charts for underweight, normal weight, overweight, and grade 1, 2, and 3 obese women were derived by the Box-Cox t method using the generalized additive model for location, scale, and shape.We observed that gestational weight gain strongly differed per maternal pre-pregnancy body mass index group. The median (interquartile range) gestational weight gain at 40 weeks was 14.2 kg (11.4-17.4) for underweight women, 14.5 kg (11.5-17.7) for normal weight women, 13.9 kg (10.1-17.9) for overweight women, and 11.2 kg (7.0-15.7), 8.7 kg (4.3-13.4) and 6.3 kg (1.9-11.1) for grades 1, 2, and 3 obese women, respectively. The rate of weight gain was lower in the first half than in the second half of pregnancy. No differences in the patterns of weight gain were observed between cohorts or countries. Similar weight gain patterns were observed in mothers without pregnancy complications.Gestational weight gain patterns are strongly related to pre-pregnancy body mass index. The derived charts can be used to assess gestational weight gain in etiological research and as a monitoring tool for weight gain during pregnancy in clinical practice.

AllergyVolume 71, Issue 11 p. 1513-1525 Review ArticleOpen Access Paving the way of systems biology and precision medicine in allergic diseases: the MeDALL success story Mechanisms of the Development of ALLergy; EU FP7-CP-IP; Project No: 261357; 2010–2015 J. Bousquet, Corresponding Author J. Bousquet jean.bousquet@orange.fr University Hospital, Montpellier, France MACVIA-LR, Contre les MAladies Chroniques pour un VIeillissement Actif en Languedoc-Roussillon, European Innovation Partnership on Active and Healthy Ageing Reference Site, France INSERM, VIMA: Ageing and Chronic Diseases, Epidemiological and Public Health Approaches, UVSQ, Université Versailles St-Quentin-en-Yvelines, Paris, FranceThe first two authors contributed equally to the paper. Correspondence J Bousquet, CHRU Montpellier, 34295 Montpellier Cedex 5, France. Tel.: 33 4 67 41 67 00 E-mail: jean.bousquet@orange.frSearch for more papers by this authorJ. M. Anto, J. M. Anto Centre for Research in Environmental Epidemiology (CREAL), ISGLoBAL, Barcelona, Spain IMIM (Hospital del Mar Research Institute), Barcelona, Spain CIBER Epidemiología y Salud Pública (CIBERESP), Barcelona, Spain Universitat Pompeu Fabra (UPF), Barcelona, SpainThe first two authors contributed equally to the paper.Search for more papers by this authorM. Akdis, M. Akdis Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, Davos, SwitzerlandSearch for more papers by this authorC. Auffray, C. Auffray European Institute for Systems Biology and Medicine, CNRS-ENS-UCBL, Université de Lyon, Lyon, FranceSearch for more papers by this authorT. Keil, T. Keil Institute of Social Medicine, Epidemiology and Health Economics, Charité–Universitätsmedizin Berlin, Berlin, Germany Institute for Clinical Epidemiology and Biometry, University of Wuerzburg, Wuerzburg, GermanySearch for more papers by this authorI. Momas, I. Momas Department of Public Health and Health Products, Paris Descartes University-Sorbonne Paris Cité, Paris, France Paris Municipal Department of Social Action, Childhood, and Health, Paris, FranceSearch for more papers by this authorD.S. Postma, D.S. Postma Department of Pulmonary Medicine and Tuberculosis, GRIAC Research Institute, University Medical Center Groningen, University of Groningen, Groningen, the NetherlandsSearch for more papers by this authorR. Valenta, R. Valenta Division of Immunopathology, Department of Pathophysiology and Allergy Research, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, AustriaSearch for more papers by this authorM. Wickman, M. Wickman Sachs’ Children and Youth Hospital, Södersjukhuset, Stockholm and Institute of Environmental Medicine, Karolinska Institutet, Stockholm, SwedenSearch for more papers by this authorA. Cambon-Thomsen, A. Cambon-Thomsen UMR Inserm U1027 and Université de Toulouse III Paul Sabatier, Toulouse, FranceSearch for more papers by this authorT. Haahtela, T. Haahtela Skin and Allergy Hospital, Helsinki University Hospital, Helsinki, FinlandSearch for more papers by this authorB. N. Lambrecht, B. N. Lambrecht VIB Inflammation Research Center, Ghent University, Ghent, BelgiumSearch for more papers by this authorK. C. Lodrup Carlsen, K. C. Lodrup Carlsen Department of Paediatrics, Faculty of Medicine, Institute of Clinical Medicine, Oslo University Hospital, University of Oslo, Oslo, NorwaySearch for more papers by this authorG. H. Koppelman, G. H. Koppelman Department of Pediatric Pulmonology and Pediatric Allergology, Beatrix Children's Hospital, GRIAC Research Institute, University Medical Center Groningen, University of Groningen, Groningen, the NetherlandsSearch for more papers by this authorJ. Sunyer, J. Sunyer Centre for Research in Environmental Epidemiology (CREAL), ISGLoBAL, Barcelona, Spain IMIM (Hospital del Mar Research Institute), Barcelona, Spain CIBER Epidemiología y Salud Pública (CIBERESP), Barcelona, Spain Universitat Pompeu Fabra (UPF), Barcelona, SpainSearch for more papers by this authorT. Zuberbier, T. Zuberbier Secretary General of the Global Allergy and Asthma European Network (GA2LEN), Allergy-Centre-Charité at the Department of Dermatology, Charité–Universitätsmedizin Berlin, Berlin, GermanySearch for more papers by this authorI. Annesi-Maesano, I. Annesi-Maesano EPAR U707 INSERM, EPAR UMR-S UPMC, Paris VI, Paris, FranceSearch for more papers by this authorA. Arno, A. Arno Onmedic Networks, Barcelona, SpainSearch for more papers by this authorC. Bindslev-Jensen, C. Bindslev-Jensen Department of Dermatology and Allergy Centre, Odense University Hospital, Odense, DenmarkSearch for more papers by this authorG. De Carlo, G. De Carlo EFA European Federation of Allergy and Airways Diseases Patients’ Associations, Brussels, BelgiumSearch for more papers by this authorF. Forastiere, F. Forastiere Department of Epidemiology, Regional Health Service Lazio Region, Rome, ItalySearch for more papers by this authorJ. Heinrich, J. Heinrich Institute of Epidemiology I, German Research Centre for Environmental Health, Helmholtz Zentrum München, Neuherberg, GermanySearch for more papers by this authorM. L. Kowalski, M. L. Kowalski Department of Immunology, Rheumatology and Allergy, Medical University of Lodz, Lodz, PolandSearch for more papers by this authorD. Maier, D. Maier Biomax Informatics AG, Munich, GermanySearch for more papers by this authorE. Melén, E. Melén Department of Pulmonary Medicine and Tuberculosis, GRIAC Research Institute, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands Stockholm County Council, Centre for Occupational and Environmental Medicine, Stockholm, SwedenSearch for more papers by this authorS. Palkonen, S. Palkonen EFA European Federation of Allergy and Airways Diseases Patients’ Associations, Brussels, BelgiumSearch for more papers by this authorH. A. Smit, H. A. Smit Julius Center of Health Sciences and Primary Care, University Medical Center Utrecht, University of Utrecht, Utrecht, the NetherlandsSearch for more papers by this authorM. Standl, M. Standl Institute of Epidemiology I, German Research Centre for Environmental Health, Helmholtz Zentrum München, Neuherberg, GermanySearch for more papers by this authorJ. Wright, J. Wright Bradford Institute for Health Research, Bradford Royal Infirmary, Bradford, UKSearch for more papers by this authorA. Asarnoj, A. Asarnoj Clinical Immunology and Allergy Unit, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden Astrid Lindgren Children's Hospital, Department of Pediatric Pulmonology and Allergy, Karolinska University Hospital, Stockholm, SwedenSearch for more papers by this authorM. Benet, M. Benet Centre for Research in Environmental Epidemiology (CREAL), ISGLoBAL, Barcelona, SpainSearch for more papers by this authorN. Ballardini, N. Ballardini Sachs’ Children and Youth Hospital, Södersjukhuset, Stockholm and Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden St John's Institute of Dermatology, King's College London, London, UKSearch for more papers by this authorJ. Garcia-Aymerich, J. Garcia-Aymerich Centre for Research in Environmental Epidemiology (CREAL), ISGLoBAL, Barcelona, Spain IMIM (Hospital del Mar Research Institute), Barcelona, Spain CIBER Epidemiología y Salud Pública (CIBERESP), Barcelona, Spain Universitat Pompeu Fabra (UPF), Barcelona, SpainSearch for more papers by this authorU. Gehring, U. Gehring Institute for Risk Assessment Sciences, Utrecht University, Utrecht, the NetherlandsSearch for more papers by this authorS. Guerra, S. Guerra Centre for Research in Environmental Epidemiology (CREAL), ISGLoBAL, Barcelona, SpainSearch for more papers by this authorC. Hohman, C. Hohman Institute of Social Medicine, Epidemiology and Health Economics, Charité–Universitätsmedizin, Berlin, GermanySearch for more papers by this authorI. Kull, I. Kull Sachs’ Children and Youth Hospital, Södersjukhuset, Stockholm and Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden Department of Clinical Science and Education, Södersjukhuset, Karolinska Institutet, Stockholm, SwedenSearch for more papers by this authorC. Lupinek, C. Lupinek Division of Immunopathology, Department of Pathophysiology and Allergy Research, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, AustriaSearch for more papers by this authorM. Pinart, M. Pinart Centre for Research in Environmental Epidemiology (CREAL), ISGLoBAL, Barcelona, SpainSearch for more papers by this authorI. Skrindo, I. Skrindo Department of Paediatrics, Faculty of Medicine, Institute of Clinical Medicine, Oslo University Hospital, University of Oslo, Oslo, NorwaySearch for more papers by this authorM. Westman, M. Westman Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden Department of ENT Diseases, Karolinska University Hospital, Stockholm, SwedenSearch for more papers by this authorD. Smagghe, D. Smagghe Inserm Transfert, Paris, FranceSearch for more papers by this authorC. Akdis, C. Akdis Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, Davos, SwitzerlandSearch for more papers by this authorR. Albang, R. Albang Biomax Informatics AG, Munich, GermanySearch for more papers by this authorV. Anastasova, V. Anastasova UMR Inserm U1027 and Université de Toulouse III Paul Sabatier, Toulouse, FranceSearch for more papers by this authorN. Anderson, N. Anderson Institute of Environmental Medicine, Karolinska Institutet, Stockholm, SwedenSearch for more papers by this authorC. Bachert, C. Bachert ENT Department, Ghent University Hospital, Gent, BelgiumSearch for more papers by this authorS. Ballereau, S. Ballereau European Institute for Systems Biology and Medicine, CNRS-ENS-UCBL, Université de Lyon, Lyon, FranceSearch for more papers by this authorF. Ballester, F. Ballester Environment and Health Area, Centre for Public Health Research (CSISP), CIBERESP, Department of Nursing, University of Valencia, Valencia, SpainSearch for more papers by this authorX. Basagana, X. Basagana Centre for Research in Environmental Epidemiology (CREAL), ISGLoBAL, Barcelona, SpainSearch for more papers by this authorA. Bedbrook, A. Bedbrook MACVIA-LR, Contre les MAladies Chroniques pour un VIeillissement Actif en Languedoc-Roussillon, European Innovation Partnership on Active and Healthy Ageing Reference Site, FranceSearch for more papers by this authorA. Bergstrom, A. Bergstrom Institute of Environmental Medicine, Karolinska Institutet, Stockholm, SwedenSearch for more papers by this authorA. von Berg, A. von Berg Research Institute, Department of Pediatrics, Marien-Hospital, Wesel, GermanySearch for more papers by this authorB. Brunekreef, B. Brunekreef Julius Center of Health Sciences and Primary Care, University Medical Center Utrecht, University of Utrecht, Utrecht, the NetherlandsSearch for more papers by this authorE. Burte, E. Burte INSERM, VIMA: Ageing and Chronic Diseases, Epidemiological and Public Health Approaches, UVSQ, Université Versailles St-Quentin-en-Yvelines, Paris, FranceSearch for more papers by this authorK. H. Carlsen, K. H. Carlsen Department of Paediatrics, Oslo University Hospital, University of Oslo, Oslo, NorwaySearch for more papers by this authorL. Chatzi, L. Chatzi Department of Social Medicine, Faculty of Medicine, University of Crete, Heraklion, Crete, GreeceSearch for more papers by this authorJ. M. Coquet, J. M. Coquet VIB Inflammation Research Center, Ghent University, Ghent, BelgiumSearch for more papers by this authorM. Curin, M. Curin Division of Immunopathology, Department of Pathophysiology and Allergy Research, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, AustriaSearch for more papers by this authorP. Demoly, P. Demoly Department of Respiratory Diseases, Montpellier University Hospital, FranceSearch for more papers by this authorE. Eller, E. Eller Department of Dermatology and Allergy Centre, Odense University Hospital, Odense, DenmarkSearch for more papers by this authorM. P. Fantini, M. P. Fantini Department of Medicine and Public Health, Alma Mater Studiorum–University of Bologna, Bologna, ItalySearch for more papers by this authorB. Gerhard, B. Gerhard Biomax Informatics AG, Munich, GermanySearch for more papers by this authorH. Hammad, H. Hammad VIB Inflammation Research Center, Ghent University, Ghent, BelgiumSearch for more papers by this authorL. von Hertzen, L. von Hertzen Skin and Allergy Hospital, Helsinki University Hospital, Helsinki, FinlandSearch for more papers by this authorV. Hovland, V. Hovland Department of Paediatrics, Oslo University Hospital, University of Oslo, Oslo, NorwaySearch for more papers by this authorB. Jacquemin, B. Jacquemin Centre for Research in Environmental Epidemiology (CREAL), ISGLoBAL, Barcelona, SpainSearch for more papers by this authorJ. Just, J. Just Allergology Department, Centre de l'Asthme et des Allergies, Hôpital d'Enfants Armand-Trousseau (APHP), Sorbonne Universités, Institut Pierre Louis d'Epidémiologie et de Santé Publique, Paris, FranceSearch for more papers by this authorT. Keller, T. Keller Institute of Social Medicine, Epidemiology and Health Economics, Charité–Universitätsmedizin, Berlin, GermanySearch for more papers by this authorM. Kerkhof, M. Kerkhof Department of Pulmonary Medicine and Tuberculosis, GRIAC Research Institute, University Medical Center Groningen, University of Groningen, Groningen, the NetherlandsSearch for more papers by this authorR. Kiss, R. Kiss Division of Immunopathology, Department of Pathophysiology and Allergy Research, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, AustriaSearch for more papers by this authorM. Kogevinas, M. Kogevinas Centre for Research in Environmental Epidemiology (CREAL), ISGLoBAL, Barcelona, Spain IMIM (Hospital del Mar Research Institute), Barcelona, Spain CIBER Epidemiología y Salud Pública (CIBERESP), Barcelona, Spain Universitat Pompeu Fabra (UPF), Barcelona, SpainSearch for more papers by this authorS. Koletzko, S. Koletzko Division of Paediatric Gastroenterology and Hepatology, Ludwig Maximilians University of Munich, Munich, GermanySearch for more papers by this authorS. Lau, S. Lau Department for Pediatric Pneumology and Immunology, Charité Medical University, Berlin, GermanySearch for more papers by this authorI. Lehmann, I. Lehmann Department of Environmental Immunology/Core Facility Studies, Helmholtz Centre for Environmental Research, UFZ, Leipzig, GermanySearch for more papers by this authorN. Lemonnier, N. Lemonnier European Institute for Systems Biology and Medicine, CNRS-ENS-UCBL, Université de Lyon, Lyon, FranceSearch for more papers by this authorR. McEachan, R. McEachan Bradford Institute for Health Research, Bradford Royal Infirmary, Bradford, UKSearch for more papers by this authorM. Mäkelä, M. Mäkelä Skin and Allergy Hospital, Helsinki University Hospital, Helsinki, FinlandSearch for more papers by this authorJ. Mestres, J. Mestres Chemotargets SL and Chemogenomics Laboratory, GRIB Unit, IMIM-Hospital del Mar and University Pompeu Fabra, Barcelona, Catalonia, SpainSearch for more papers by this authorE. Minina, E. Minina Biomax Informatics AG, Munich, GermanySearch for more papers by this authorP. Mowinckel, P. Mowinckel Department of Paediatrics, Oslo University Hospital, University of Oslo, Oslo, NorwaySearch for more papers by this authorR. Nadif, R. Nadif INSERM, VIMA: Ageing and Chronic Diseases, Epidemiological and Public Health Approaches, UVSQ, Université Versailles St-Quentin-en-Yvelines, Paris, FranceSearch for more papers by this authorM. Nawijn, M. Nawijn Department of Pediatric Pulmonology and Pediatric Allergology, Beatrix Children's Hospital, GRIAC Research Institute, University Medical Center Groningen, University of Groningen, Groningen, the NetherlandsSearch for more papers by this authorS. Oddie, S. Oddie Bradford Institute for Health Research, Bradford Royal Infirmary, Bradford, UKSearch for more papers by this authorJ. Pellet, J. Pellet European Institute for Systems Biology and Medicine, CNRS-ENS-UCBL, Université de Lyon, Lyon, FranceSearch for more papers by this authorI. Pin, I. Pin Département de Pédiatrie, CHU de Grenoble, Grenoble Cedex 9, FranceSearch for more papers by this authorD. Porta, D. Porta Department of Epidemiology, Regional Health Service Lazio Region, Rome, ItalySearch for more papers by this authorF. Rancière, F. Rancière Department of Public Health and Health Products, Paris Descartes University-Sorbonne Paris Cité, Paris, FranceSearch for more papers by this authorA. Rial-Sebbag, A. Rial-Sebbag UMR Inserm U1027 and Université de Toulouse III Paul Sabatier, Toulouse, FranceSearch for more papers by this authorY. Saeys, Y. Saeys VIB Inflammation Research Center, Ghent University, Ghent, BelgiumSearch for more papers by this authorM. J. Schuijs, M. J. Schuijs VIB Inflammation Research Center, Ghent University, Ghent, BelgiumSearch for more papers by this authorV. Siroux, V. Siroux Inserm, U823, Grenoble, FranceSearch for more papers by this authorC. G. Tischer, C. G. Tischer Institute of Epidemiology I, German Research Centre for Environmental Health, Helmholtz Zentrum München, Neuherberg, GermanySearch for more papers by this authorM. Torrent, M. Torrent Centre for Research in Environmental Epidemiology (CREAL), ISGLoBAL, Barcelona, Spain ib-salut, Area de Salut de Menorca, SpainSearch for more papers by this authorR. Varraso, R. Varraso INSERM, VIMA: Ageing and Chronic Diseases, Epidemiological and Public Health Approaches, UVSQ, Université Versailles St-Quentin-en-Yvelines, Paris, FranceSearch for more papers by this authorJ. De Vocht, J. De Vocht EFA European Federation of Allergy and Airways Diseases Patients’ Associations, Brussels, BelgiumSearch for more papers by this authorK. Wenger, K. Wenger Biomax Informatics AG, Munich, GermanySearch for more papers by this authorS. Wieser, S. Wieser Division of Immunopathology, Department of Pathophysiology and Allergy Research, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, AustriaSearch for more papers by this authorC. Xu, C. Xu Department of Pulmonary Medicine and Tuberculosis, GRIAC Research Institute, University Medical Center Groningen, University of Groningen, Groningen, the NetherlandsSearch for more papers by this author J. Bousquet, Corresponding Author J. Bousquet jean.bousquet@orange.fr University Hospital, Montpellier, France MACVIA-LR, Contre les MAladies Chroniques pour un VIeillissement Actif en Languedoc-Roussillon, European Innovation Partnership on Active and Healthy Ageing Reference Site, France INSERM, VIMA: Ageing and Chronic Diseases, Epidemiological and Public Health Approaches, UVSQ, Université Versailles St-Quentin-en-Yvelines, Paris, FranceThe first two authors contributed equally to the paper. Correspondence J Bousquet, CHRU Montpellier, 34295 Montpellier Cedex 5, France. Tel.: 33 4 67 41 67 00 E-mail: jean.bousquet@orange.frSearch for more papers by this authorJ. M. Anto, J. M. Anto Centre for Research in Environmental Epidemiology (CREAL), ISGLoBAL, Barcelona, Spain IMIM (Hospital del Mar Research Institute), Barcelona, Spain CIBER Epidemiología y Salud Pública (CIBERESP), Barcelona, Spain Universitat Pompeu Fabra (UPF), Barcelona, SpainThe first two authors contributed equally to the paper.Search for more papers by this authorM. Akdis, M. Akdis Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, Davos, SwitzerlandSearch for more papers by this authorC. Auffray, C. Auffray European Institute for Systems Biology and Medicine, CNRS-ENS-UCBL, Université de Lyon, Lyon, FranceSearch for more papers by this authorT. Keil, T. Keil Institute of Social Medicine, Epidemiology and Health Economics, Charité–Universitätsmedizin Berlin, Berlin, Germany Institute for Clinical Epidemiology and Biometry, University of Wuerzburg, Wuerzburg, GermanySearch for more papers by this authorI. Momas, I. Momas Department of Public Health and Health Products, Paris Descartes University-Sorbonne Paris Cité, Paris, France Paris Municipal Department of Social Action, Childhood, and Health, Paris, FranceSearch for more papers by this authorD.S. Postma, D.S. Postma Department of Pulmonary Medicine and Tuberculosis, GRIAC Research Institute, University Medical Center Groningen, University of Groningen, Groningen, the NetherlandsSearch for more papers by this authorR. Valenta, R. Valenta Division of Immunopathology, Department of Pathophysiology and Allergy Research, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, AustriaSearch for more papers by this authorM. Wickman, M. Wickman Sachs’ Children and Youth Hospital, Södersjukhuset, Stockholm and Institute of Environmental Medicine, Karolinska Institutet, Stockholm, SwedenSearch for more papers by this authorA. Cambon-Thomsen, A. Cambon-Thomsen UMR Inserm U1027 and Université de Toulouse III Paul Sabatier, Toulouse, FranceSearch for more papers by this authorT. Haahtela, T. Haahtela Skin and Allergy Hospital, Helsinki University Hospital, Helsinki, FinlandSearch for more papers by this authorB. N. Lambrecht, B. N. Lambrecht VIB Inflammation Research Center, Ghent University, Ghent, BelgiumSearch for more papers by this authorK. C. Lodrup Carlsen, K. C. Lodrup Carlsen Department of Paediatrics, Faculty of Medicine, Institute of Clinical Medicine, Oslo University Hospital, University of Oslo, Oslo, NorwaySearch for more papers by this authorG. H. Koppelman, G. H. Koppelman Department of Pediatric Pulmonology and Pediatric Allergology, Beatrix Children's Hospital, GRIAC Research Institute, University Medical Center Groningen, University of Groningen, Groningen, the NetherlandsSearch for more papers by this authorJ. Sunyer, J. Sunyer Centre for Research in Environmental Epidemiology (CREAL), ISGLoBAL, Barcelona, Spain IMIM (Hospital del Mar Research Institute), Barcelona, Spain CIBER Epidemiología y Salud Pública (CIBERESP), Barcelona, Spain Universitat Pompeu Fabra (UPF), Barcelona, SpainSearch for more papers by this authorT. Zuberbier, T. Zuberbier Secretary General of the Global Allergy and Asthma European Network (GA2LEN), Allergy-Centre-Charité at the Department of Dermatology, Charité–Universitätsmedizin Berlin, Berlin, GermanySearch for more papers by this authorI. Annesi-Maesano, I. Annesi-Maesano EPAR U707 INSERM, EPAR UMR-S UPMC, Paris VI, Paris, FranceSearch for more papers by this authorA. Arno, A. Arno Onmedic Networks, Barcelona, SpainSearch for more papers by this authorC. Bindslev-Jensen, C. Bindslev-Jensen Department of Dermatology and Allergy Centre, Odense University Hospital, Odense, DenmarkSearch for more papers by this authorG. De Carlo, G. De Carlo EFA European Federation of Allergy and Airways Diseases Patients’ Associations, Brussels, BelgiumSearch for more papers by this authorF. Forastiere, F. Forastiere Department of Epidemiology, Regional Health Service Lazio Region, Rome, ItalySearch for more papers by this authorJ. Heinrich, J. Heinrich Institute of Epidemiology I, German Research Centre for Environmental Health, Helmholtz Zentrum München, Neuherberg, GermanySearch for more papers by this authorM. L. Kowalski, M. L. Kowalski Department of Immunology, Rheumatology and Allergy, Medical University of Lodz, Lodz, PolandSearch for more papers by this authorD. Maier, D. Maier Biomax Informatics AG, Munich, GermanySearch for more papers by this authorE. Melén, E. Melén Department of Pulmonary Medicine and Tuberculosis, GRIAC Research Institute, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands Stockholm County Council, Centre for Occupational and Environmental Medicine, Stockholm, SwedenSearch for more papers by this authorS. Palkonen, S. Palkonen EFA European Federation of Allergy and Airways Diseases Patients’ Associations, Brussels, BelgiumSearch for more papers by this authorH. A. Smit, H. A. Smit Julius Center of Health Sciences and Primary Care, University Medical Center Utrecht, University of Utrecht, Utrecht, the NetherlandsSearch for more papers by this authorM. Standl, M. Standl Institute of Epidemiology I, German Research Centre for Environmental Health, Helmholtz Zentrum München, Neuherberg, GermanySearch for more papers by this authorJ. Wright, J. Wright Bradford Institute for Health Research, Bradford Royal Infirmary, Bradford, UKSearch for more papers by this authorA. Asarnoj, A. Asarnoj Clinical Immunology and Allergy Unit, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden Astrid Lindgren Children's Hospital, Department of Pediatric Pulmonology and Allergy, Karolinska University Hospital, Stockholm, SwedenSearch for more papers by this authorM. Benet, M. Benet Centre for Research in Environmental Epidemiology (CREAL), ISGLoBAL, Barcelona, SpainSearch for more papers by this authorN. Ballardini, N. Ballardini Sachs’ Children and Youth Hospital, Södersjukhuset, Stockholm and Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden St John's Institute of Dermatology, King's College London, London, UKSearch for more papers by this authorJ. Garcia-Aymerich, J. Garcia-Aymerich Centre for Research in Environmental Epidemiology (CREAL), ISGLoBAL, Barcelona, Spain IMIM (Hospital del Mar Research Institute), Barcelona, Spain CIBER Epidemiología y Salud Pública (CIBERESP), Barcelona, Spain Universitat Pompeu Fabra (UPF), Barcelona, SpainSearch for more papers by this authorU. Gehring, U. Gehring Institute for Risk Assessment Sciences, Utrecht University, Utrecht, the NetherlandsSearch for more papers by this authorS. Guerra, S. Guerra Centre for Research in Environmental Epidemiology (CREAL), ISGLoBAL, Barcelona, SpainSearch for more papers by this authorC. Hohman, C. Hohman Institute of Social Medicine, Epidemiology and Health Economics, Charité–Universitätsmedizin, Berlin, GermanySearch for more papers by this authorI. Kull, I. Kull Sachs’ Children and Youth Hospital, Södersjukhuset, Stockholm and Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden Department of Clinical Science and Education, Södersjukhuset, Karolinska Institutet, Stockholm, SwedenSearch for more papers by this authorC. Lupinek, C. Lupinek Division of Immunopathology, Department of Pathophysiology and Allergy Research, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, AustriaSearch for more papers by this authorM. Pinart, M. Pinart Centre for Research in Environmental Epidemiology (CREAL), ISGLoBAL, Barcelona, SpainSearch for more papers by this authorI. Skrindo, I. Skrindo Department of Paediatrics, Faculty of Medicine, Institute of Clinical Medicine, Oslo University Hospital, University of Oslo, Oslo, NorwaySearch for more papers by this authorM. Westman, M. Westman Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden Department of ENT Diseases, Karolinska University Hospital, Stockholm, SwedenSearch for more papers by this authorD. Smagghe, D. Smagghe Inserm Transfert, Paris, FranceSearch for more papers by this authorC. Akdis, C. Akdis Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, Davos, SwitzerlandSearch for more papers by this authorR. Albang, R. Albang Biomax Informatics AG, Munich, GermanySearch for more papers by this authorV. Anastasova, V. Anastasova UMR Inserm U1027 and Université de Toulouse III Paul Sabatier, Toulouse, FranceSearch for more papers by this authorN. Anderson, N. Anderson Institute of Environmental Medicine, Karolinska Institutet, Stockholm, SwedenSearch for more papers by this authorC. Bachert, C. Bachert ENT Department, Ghent University Hospital, Gent, BelgiumSearch for more papers by this authorS. Ballereau, S. Ballereau European Institute for Systems Biology and Medicine, CNRS-ENS-UCBL, Université de Lyon, Lyon, FranceSearch for more papers by this authorF. Ballester, F. Ballester Environment and Health Area, Centre for Public Health Research (CSISP), CIBERESP, Department of Nursing, University of Valencia, Valencia, SpainSearch for more papers by this authorX. Basagana, X. Basagana Centre for Research in Environmental Epidemiology (CREAL), ISGLoBAL, Barcelona, SpainSearch for more papers by this authorA. Bedbrook, A. Bedbrook MACVIA-LR, Contre les MAladies Chroniques pour un VIeillissement Actif en Languedoc-Roussillon, European Innovation Partnership on Active and Healthy Ageing Reference Site, FranceSearch for more papers by this authorA. Bergstrom, A. Bergstrom Institute of Environmental Medicine, Karolinska Institutet, Stockholm, SwedenSearch for more papers by this authorA. von Berg, A. von Berg Research Institute, Department of Pediatrics, Marien-Hospital, Wesel, GermanySearch for more papers by this authorB. Brunekreef, B. Brunekreef Julius Center of Health Sciences and Primary Care, University Medical Center Utrecht, University of Utrecht, Utrecht, the NetherlandsSearch for more papers by this authorE. Burte, E. Burte INSERM, VIMA: Ageing and Chronic Diseases, Epidemiological and Public Health Approaches, UVSQ, Université Versailles St-Quentin-en-Yvelines, Paris, FranceSearch for more papers by this authorK. H. Carlsen, K. H. Carlsen Department of Paediatrics, Oslo University Hospital, University of Oslo, Oslo, NorwaySearch for more papers by this authorL. Chatzi, L. Chatzi Department of Social Medicine, Faculty of Medicine, University of Crete, Heraklion,

Epidemiological studies suggested an association between atopic dermatitis (AD) and cardiovascular disease. Therefore, we investigate associations and potential underlying pathways of AD and cardiovascular disease in large cohort studies: the AOK PLUS cohort (n = 1.2 Mio), the GINIplus/LISAplus birth cohorts (n = 2,286), and the Cooperative Health Research in the Region of Augsburg (KORA) F4 cohort (n = 2,990). In addition, metabolomics in KORA F4 and established cardiovascular risk loci in genome-wide data on 10,788 AD cases and 30,047 controls were analyzed. Longitudinal analysis of patients with AD in AOK PLUS showed slightly increased risk for incident angina pectoris (adjusted risk ratio 1.17 [95% confidence interval 1.12–1.23]), hypertension (1.04 [1.02–1.06]), and peripheral arterial disease (1.15 [1.11–1.19]) but not for myocardial infarction (1.05 [0.99–1.12]) and stroke (1.02 [0.98–1.07]). In KORA F4 and GINIplus/LISAplus, AD was not associated with cardiovascular risk factors and no differences in metabolite levels were detected. There was no robust evidence for shared genetic risk variants of AD and cardiovascular disease. This study indicates only a marginally increased risk for angina pectoris, hypertension, and peripheral arterial disease and no increased risk for myocardial infarction or stroke in patients with AD. Relevant associations of AD with cardiovascular risk factors reported in US populations could not be confirmed. Likewise, patients with AD did not have increased genetic risk factors for cardiovascular disease. Epidemiological studies suggested an association between atopic dermatitis (AD) and cardiovascular disease. Therefore, we investigate associations and potential underlying pathways of AD and cardiovascular disease in large cohort studies: the AOK PLUS cohort (n = 1.2 Mio), the GINIplus/LISAplus birth cohorts (n = 2,286), and the Cooperative Health Research in the Region of Augsburg (KORA) F4 cohort (n = 2,990). In addition, metabolomics in KORA F4 and established cardiovascular risk loci in genome-wide data on 10,788 AD cases and 30,047 controls were analyzed. Longitudinal analysis of patients with AD in AOK PLUS showed slightly increased risk for incident angina pectoris (adjusted risk ratio 1.17 [95% confidence interval 1.12–1.23]), hypertension (1.04 [1.02–1.06]), and peripheral arterial disease (1.15 [1.11–1.19]) but not for myocardial infarction (1.05 [0.99–1.12]) and stroke (1.02 [0.98–1.07]). In KORA F4 and GINIplus/LISAplus, AD was not associated with cardiovascular risk factors and no differences in metabolite levels were detected. There was no robust evidence for shared genetic risk variants of AD and cardiovascular disease. This study indicates only a marginally increased risk for angina pectoris, hypertension, and peripheral arterial disease and no increased risk for myocardial infarction or stroke in patients with AD. Relevant associations of AD with cardiovascular risk factors reported in US populations could not be confirmed. Likewise, patients with AD did not have increased genetic risk factors for cardiovascular disease.

Allergic diseases often occur in combination (multimorbidity). Human blood transcriptome studies have not addressed multimorbidity. Large-scale gene expression data were combined to retrieve biomarkers and signaling pathways to disentangle allergic multimorbidity phenotypes.Integrated transcriptomic analysis was conducted in 1233 participants with a discovery phase using gene expression data (Human Transcriptome Array 2.0) from whole blood of 786 children from three European birth cohorts (MeDALL), and a replication phase using RNA Sequencing data from an independent cohort (EVA-PR, n = 447). Allergic diseases (asthma, atopic dermatitis, rhinitis) were considered as single disease or multimorbidity (at least two diseases), and compared with no disease.Fifty genes were differentially expressed in allergic diseases. Thirty-two were not previously described in allergy. Eight genes were consistently overexpressed in all types of multimorbidity for asthma, dermatitis, and rhinitis (CLC, EMR4P, IL5RA, FRRS1, HRH4, SLC29A1, SIGLEC8, IL1RL1). All genes were replicated the in EVA-PR cohort. RT-qPCR validated the overexpression of selected genes. In MeDALL, 27 genes were differentially expressed in rhinitis alone, but none was significant for asthma or dermatitis alone. The multimorbidity signature was enriched in eosinophil-associated immune response and signal transduction. Protein-protein interaction network analysis identified IL5/JAK/STAT and IL33/ST2/IRAK/TRAF as key signaling pathways in multimorbid diseases. Synergistic effect of multimorbidity on gene expression levels was found.A signature of eight genes identifies multimorbidity for asthma, rhinitis, and dermatitis. Our results have clinical and mechanistic implications, and suggest that multimorbidity should be considered differently than allergic diseases occurring alone.

Background Fetal smoke exposure is a common and key avoidable risk factor for birth complications and seems to influence later risk of overweight. It is unclear whether this increased risk is also present if mothers smoke during the first trimester only or reduce the number of cigarettes during pregnancy, or when only fathers smoke. We aimed to assess the associations of parental smoking during pregnancy, specifically of quitting or reducing smoking and maternal and paternal smoking combined, with preterm birth, small size for gestational age, and childhood overweight. Methods and findings We performed an individual participant data meta-analysis among 229,158 families from 28 pregnancy/birth cohorts from Europe and North America. All 28 cohorts had information on maternal smoking, and 16 also had information on paternal smoking. In total, 22 cohorts were population-based, with birth years ranging from 1991 to 2015. The mothers’ median age was 30.0 years, and most mothers were medium or highly educated. We used multilevel binary logistic regression models adjusted for maternal and paternal sociodemographic and lifestyle-related characteristics. Compared with nonsmoking mothers, maternal first trimester smoking only was not associated with adverse birth outcomes but was associated with a higher risk of childhood overweight (odds ratio [OR] 1.17 [95% CI 1.02–1.35], P value = 0.030). Children from mothers who continued smoking during pregnancy had higher risks of preterm birth (OR 1.08 [95% CI 1.02–1.15], P value = 0.012), small size for gestational age (OR 2.15 [95% CI 2.07–2.23], P value < 0.001), and childhood overweight (OR 1.42 [95% CI 1.35–1.48], P value < 0.001). Mothers who reduced the number of cigarettes between the first and third trimester, without quitting, still had a higher risk of small size for gestational age. However, the corresponding risk estimates were smaller than for women who continued the same amount of cigarettes throughout pregnancy (OR 1.89 [95% CI 1.52–2.34] instead of OR 2.20 [95% CI 2.02–2.42] when reducing from 5–9 to ≤4 cigarettes/day; OR 2.79 [95% CI 2.39–3.25] and OR 1.93 [95% CI 1.46–2.57] instead of OR 2.95 [95% CI 2.75–3.15] when reducing from ≥10 to 5–9 and ≤4 cigarettes/day, respectively [P values < 0.001]). Reducing the number of cigarettes during pregnancy did not affect the risks of preterm birth and childhood overweight. Among nonsmoking mothers, paternal smoking was associated with childhood overweight (OR 1.21 [95% CI 1.16–1.27], P value < 0.001) but not with adverse birth outcomes. Limitations of this study include the self-report of parental smoking information and the possibility of residual confounding. As this study only included participants from Europe and North America, results need to be carefully interpreted regarding other populations. Conclusions We observed that as compared to nonsmoking during pregnancy, quitting smoking in the first trimester is associated with the same risk of preterm birth and small size for gestational age, but with a higher risk of childhood overweight. Reducing the number of cigarettes, without quitting, has limited beneficial effects. Paternal smoking seems to be associated, independently of maternal smoking, with the risk of childhood overweight. Population strategies should focus on parental smoking prevention before or at the start, rather than during, pregnancy.

Background Early-life respiratory tract infections might affect chronic obstructive respiratory diseases, but conclusive studies from general populations are lacking. Our objective was to examine if children with early-life respiratory tract infections had increased risks of lower lung function and asthma at school age. Methods We used individual participant data of 150 090 children primarily from the EU Child Cohort Network to examine the associations of upper and lower respiratory tract infections from age 6 months to 5 years with forced expiratory volume in 1 s (FEV 1 ), forced vital capacity (FVC), FEV 1 /FVC, forced expiratory flow at 75% of FVC (FEF 75% ) and asthma at a median (range) age of 7 (4–15) years. Results Children with early-life lower, not upper, respiratory tract infections had a lower school-age FEV 1 , FEV 1 /FVC and FEF 75% (z-score range: −0.09 (95% CI −0.14– −0.04) to −0.30 (95% CI −0.36– −0.24)). Children with early-life lower respiratory tract infections had a higher increased risk of school-age asthma than those with upper respiratory tract infections (OR range: 2.10 (95% CI 1.98–2.22) to 6.30 (95% CI 5.64–7.04) and 1.25 (95% CI 1.18–1.32) to 1.55 (95% CI 1.47–1.65), respectively). Adjustment for preceding respiratory tract infections slightly decreased the strength of the effects. Observed associations were similar for those with and without early-life wheezing as a proxy for early-life asthma. Conclusions Our findings suggest that early-life respiratory tract infections affect development of chronic obstructive respiratory diseases in later life, with the strongest effects for lower respiratory tract infections.

<h3>Objective</h3> To investigate the genetic architecture of internalizing symptoms in childhood and adolescence. <h3>Method</h3> In 22 cohorts, multiple univariate genome-wide association studies (GWASs) were performed using repeated assessments of internalizing symptoms, in a total of 64,561 children and adolescents between 3 and 18 years of age. Results were aggregated in meta-analyses that accounted for sample overlap, first using all available data, and then using subsets of measurements grouped by rater, age, and instrument. <h3>Results</h3> The meta-analysis of overall internalizing symptoms (INT_overall) detected no genome-wide significant hits and showed low single nucleotide polymorphism (SNP) heritability (1.66%, 95% CI = 0.84-2.48%, n_effective = 132,260). Stratified analyses indicated rater-based heterogeneity in genetic effects, with self-reported internalizing symptoms showing the highest heritability (5.63%, 95% CI = 3.08%-8.18%). The contribution of additive genetic effects on internalizing symptoms appeared to be stable over age, with overlapping estimates of SNP heritability from early childhood to adolescence. Genetic correlations were observed with adult anxiety, depression, and the well-being spectrum (|<i>r</i>_g| > 0.70), as well as with insomnia, loneliness, attention-deficit/hyperactivity disorder, autism, and childhood aggression (range |<i>r</i>_g| = 0.42-0.60), whereas there were no robust associations with schizophrenia, bipolar disorder, obsessive-compulsive disorder, or anorexia nervosa. <h3>Conclusion</h3> Genetic correlations indicate that childhood and adolescent internalizing symptoms share substantial genetic vulnerabilities with adult internalizing disorders and other childhood psychiatric traits, which could partially explain both the persistence of internalizing symptoms over time and the high comorbidity among childhood psychiatric traits. Reducing phenotypic heterogeneity in childhood samples will be key in paving the way to future GWAS success.

Adolescents, especially females, tend to experience poorer mental health if they are higher in introversion and neuroticism. As a result, they also may have more to gain from having quality green space (e.g. parks) nearby to enable restoration, but this remains tested.Cross-sectional data on 2946 adolescents aged 16-17y were extracted from the Longitudinal Study of Australian Children. Multilevel linear regressions assessed association between parent/caregiver green space quality perception with self-reported Strengths and Difficulties Questionnaire Total Difficulties Scores (TDS) and internalising (e.g. anxiety) and externalising (e.g. fidgetiness) subscales. Models were weighted for representativeness, accounted for spatial clustering within postcodes, and adjusted for geographic stratum and socioeconomic confounders. This was followed by adjustment for introversion and neuroticism, and then three-way interaction terms between each trait, green space quality and sex to assess for potential effect modification.Quality green spaces was associated with higher TDS (β = 1.506; SE = 0.371), internalising (β = 0.982; SE = 0.220) and externalising (β = 0.518; SE = 0.234) scores (i.e. poorer mental health). Introversion was associated with higher TDS (β = 1.416; SE = 0.089), higher internalising (β = 1.233; SE = 0.050) and higher externalising scores (β = 0.181; SE = 0.056). Similar associations were observed for neuroticism and TDS (β = 2.283; SE = 0.084), internalising (β = 1.627; SE = 0.046) and externalising scores (β = 0.656; SE = 0.056). Mean levels of introversion were similar for girls and boys (1.73 vs 1.76, p = 0.6573), but mean levels of neuroticism were notably higher in girls than boys (2.42 and 1.67, p < 0.0001). Likelihood ratio tests indicated three-way interactions improved models analysing the internalising subscale outcome only. Green space quality made no difference to associations between introversion or neuroticism and internalising scores in males. Quality green space was associated with 3.2 and 2.1 reductions in mean internalising scores among females with the highest levels of introversion or neuroticism, respectively.Individual differences in psychological traits may predispose some adolescents, and females especially, to restoration from green space.

Asthma, rhinitis, and atopic dermatitis (AD) are interrelated clinical phenotypes that partly overlap in the human interactome. The concept of "one-airway-one-disease," coined over 20 years ago, is a simplistic approach of the links between upper- and lower-airway allergic diseases. With new data, it is time to reassess the concept. This article reviews (i) the clinical observations that led to Allergic Rhinitis and its Impact on Asthma (ARIA), (ii) new insights into polysensitization and multimorbidity, (iii) advances in mHealth for novel phenotype definitions, (iv) confirmation in canonical epidemiologic studies, (v) genomic findings, (vi) treatment approaches, and (vii) novel concepts on the onset of rhinitis and multimorbidity. One recent concept, bringing together upper- and lower-airway allergic diseases with skin, gut, and neuropsychiatric multimorbidities, is the "Epithelial Barrier Hypothesis." This review determined that the "one-airway-one-disease" concept does not always hold true and that several phenotypes of disease can be defined. These phenotypes include an extreme "allergic" (asthma) phenotype combining asthma, rhinitis, and conjunctivitis. Rhinitis alone and rhinitis and asthma multimorbidity represent two distinct diseases with the following differences: (i) genomic and transcriptomic background (Toll-Like Receptors and IL-17 for rhinitis alone as a local disease; IL-33 and IL-5 for allergic and non-allergic multimorbidity as a systemic disease), (ii) allergen sensitization patterns (mono- or pauci-sensitization versus polysensitization), (iii) severity of symptoms, and (iv) treatment response. In conclusion, rhinitis alone (local disease) and rhinitis with asthma multimorbidity (systemic disease) should be considered as two distinct diseases, possibly modulated by the microbiome, and may be a model for understanding the epidemics of chronic and autoimmune diseases.

Lung development starts in utero and continues during childhood through to adolescence, reaching its peak in early adulthood. This growth is followed by gradual decline due to physiological lung ageing. Lung-function development can be altered by several host and environmental factors during the life course. As a result, a range of lung-function trajectories exist in the population. Below average trajectories are associated with respiratory, cardiovascular, metabolic, and mental health comorbidities, as well as with premature death. This Review presents progressive research into lung-function trajectories and assists the implementation of this knowledge in clinical practice as an innovative approach to detect poor lung health early, monitor respiratory disease progression, and promote lung health. Specifically, we propose that, similar to paediatric height and weight charts used globally to monitor children's growth, lung-function charts could be used for both children and adults to monitor lung health status across the life course. To achieve this proposal, we introduce our free online Lung Function Tracker tool. Finally, we discuss challenges and opportunities for effective implementation of the trajectory concept at population level and outline an agenda for crucial research needed to support such implementation.

To assess the association between food intake and diet quality and behavioral problems at the 10-year follow-up of the two population-based birth cohorts of the studies German Infant Nutritional Intervention and 'Influences of lifestyle-related factors on the immune system and the development of allergies in childhood'.Cross-sectional data on food intake over the past year were collected by a parent-reported food frequency questionnaire. Diet quality was based on reference values of food amounts of the optimized mixed diet. Behavioral problems were assessed by a parent-reported Strengths and Difficulties Questionnaire. Relationships between food category intake, diet quality and behavior problems were examined using multivariable regression modeling adjusted for gender, sociodemographic characteristics, body mass index, physical exercise, television viewing/PC use and total energy intake. A total of 3,361 children with complete data were analyzed.Children with increased intake of confectionery had increased odds of having emotional symptoms [adjusted odds ratio (OR(adj)) 1.19, 95% confidence interval (CI) 1.08-1.32] compared to children with low intake. A higher diet quality score was associated with lower likelihood of emotional symptoms (OR(adj) 0.89, 95% CI 0.80-0.98). The unadjusted significant relationship between diet quality and hyperactivity/inattention was attenuated by adjusting for several confounders to an OR(adj) of 0.92 (95% CI 0.82-1.03).Increased consumption of high-sugar products and lower diet quality are associated with a higher likelihood of emotional symptoms in children.

Evidence on the long-term effects of air pollution exposure on childhood allergy is limited.We investigated the association between air pollution exposure and allergic sensitization to common allergens in children followed prospectively during the first 10 years of life.Five European birth cohorts participating in the European Study of Cohorts for Air Pollution Effects project were included: BAMSE (Sweden), LISAplus and GINIplus (Germany), MAAS (Great Britain), and PIAMA (The Netherlands). Land-use regression models were applied to assess the individual residential outdoor levels of particulate matter with an aerodynamic diameter of less than 2.5 μm (PM2.5), the mass concentration of particles between 2.5 and 10 μm in size, and levels of particulate matter with an aerodynamic diameter of less than 10 μm (PM10), as well as measurement of the blackness of PM2.5 filters and nitrogen dioxide and nitrogen oxide levels. Blood samples drawn at 4 to 6 years of age, 8 to 10 years of age, or both from more than 6500 children were analyzed for allergen-specific serum IgE against common allergens. Associations were assessed by using multiple logistic regression and subsequent meta-analysis.The prevalence of sensitization to any common allergen within the 5 cohorts ranged between 24.1% and 40.4% at the age of 4 to 6 years and between 34.8% and 47.9% at the age of 8 to 10 years. Overall, air pollution exposure was not associated with sensitization to any common allergen, with odds ratios ranging from 0.94 (95% CI, 0.63-1.40) for a 1 × 10(-5) ∙ m(-1) increase in measurement of the blackness of PM2.5 filters to 1.26 (95% CI, 0.90-1.77) for a 5 μg/m(3) increase in PM2.5 exposure at birth address. Further analyses did not provide consistent evidence for a modification of the air pollution effects by sex, family history of atopy, or moving status.No clear associations between air pollution exposure and development of allergic sensitization in children up to 10 years of age were revealed.

Summary Background Both asthma and obesity are complex disorders that are influenced by environmental and genetic factors. Shared genetic factors between asthma and obesity have been proposed to partly explain epidemiological findings of co‐morbidity between these conditions. Objective To identify genetic variants that are associated with body mass index ( BMI ) in asthmatic children and adults, and to evaluate if there are differences between the genetics of BMI in asthmatics and healthy individuals. Methods In total, 19 studies contributed with genome‐wide analysis study ( GWAS ) data from more than 23 000 individuals with predominantly European descent, of whom 8165 are asthmatics. In total, 19 studies contributed with genome‐wide analysis study ( GWAS ) data from more than 23 000 individuals with predominantly European descent, of whom 8165 are asthmatics. In total, 19 studies contributed with genome‐wide analysis study ( GWAS ) data from more than 23 000 individuals with predominantly European descent, of whom 8165 are asthmatics. In total, 19 studies contributed with genome‐wide analysis study ( GWAS ) data from more than 23 000 individuals with predominantly European descent, of whom 8165 are asthmatics. In total, 19 studies contributed with genome‐wide analysis study ( GWAS ) data from more than 23 000 individuals with predominantly European descent, of whom 8165 are asthmatics. In total, 19 studies contributed with genome‐wide analysis study ( GWAS ) data from more than 23 000 individuals with predominantly European descent, of whom 8165 are asthmatics. In total, 19 studies contributed with genome‐wide analysis study ( GWAS ) data from more than 23 000 individuals with predominantly European descent, of whom 8165 are asthmatics. In total, 19 studies contributed with genome‐wide analysis study ( GWAS ) data from more than 23 000 individuals with predominantly European descent, of whom 8165 are asthmatics. In total, 19 studies contributed with genome‐wide analysis study ( GWAS ) data from more than 23 000 individuals with predominantly European descent, of whom 8165 are asthmatics. Results We report associations between several DENND 1B variants ( P = 2.2 × 10 −7 for rs4915551) on chromosome 1q31 and BMI from a meta‐analysis of GWAS data using 2691 asthmatic children (screening data). The top DENND 1B single nucleotide polymorphisms ( SNP s) were next evaluated in seven independent replication data sets comprising 2014 asthmatics, and rs4915551 was nominally replicated ( P &lt; 0.05) in two of the seven studies and of borderline significance in one ( P = 0.059). However, strong evidence of effect heterogeneity was observed and overall, the association between rs4915551 and BMI was not significant in the total replication data set, P = 0.71. Using a random effects model, BMI was overall estimated to increase by 0.30 kg/m 2 ( P = 0.01 for combined screening and replication data sets, N = 4705) per additional G allele of this DENND 1B SNP . FTO was confirmed as an important gene for adult and childhood BMI regardless of asthma status. Conclusions and Clinical Relevance DENND 1B was recently identified as an asthma susceptibility gene in a GWAS on children, and here, we find evidence that DENND 1B variants may also be associated with BMI in asthmatic children. However, the association was overall not replicated in the independent data sets and the heterogeneous effect of DENND 1B points to complex associations with the studied diseases that deserve further study.

Background. There is a need to study whether the adverse effects of traffic-related air pollution (TRAP) on childhood asthma and allergic diseases documented during early-life persist into later childhood. This longitudinal study examined whether TRAP is associated with the prevalence of asthma, allergic rhinitis and aeroallergen sensitization in two German cohorts followed from birth to 10 years. Materials. Questionnaire-derived annual reports of doctor diagnosed asthma and allergic rhinitis, as well as eye and nose symptoms, were collected from 6,604 children. Aeroallergen sensitization was assessed for 3,655 children who provided blood samples. Associations between these health outcomes and nitrogen dioxide (NO2), particles with aerodynamic diameters less than 2.5 µg/m(3) (PM2.5) mass, PM2.5 absorbance and ozone, individually estimated for each child at the birth, six and 10 year home addresses, were assessed using generalized estimation equations including adjustments for relevant covariates. Odds ratios [95% confidence intervals] per increase in interquartile range of pollutant are presented for the total population and per geographical area (GINI/LISA South, GINI/LISA North and LISA East, Germany). Results. The risk estimates for the total population were generally null across outcomes and pollutants. The area-specific results were heterogeneous. In GINI/LISA North, all associations were null. In LISA East, associations with ozone were elevated for all outcomes, and those for allergic rhinitis and eyes and nose symptom prevalence reached statistical significance (1.30 [1.02, 1.64] and 1.35 [1.16, 1.59], respectively). For GINI/LISA South, two associations with aeroallergen sensitization were significant (0.84 [0.73, 0.97] for NO2 and 0.87 [0.78, 0.97] for PM2.5 absorbance), as well as the association between allergic rhinitis and PM2.5 absorbance (0.83 [0.72, 0.96]). Conclusions. This study did not find consistent evidence that TRAP increases the prevalence of childhood asthma, allergic rhinitis or aeroallergen sensitization in later childhood using data from birth cohort participants followed for 10 years in three locations in Germany. Results were heterogeneous across the three areas investigated.

Abstract Background The march from early aeroallergen sensitization to subsequent respiratory allergy is well established, but it is unclear whether early life food sensitization precedes and further increases risk of allergic airway disease. Objective To assess the association between food sensitization in the first 2 years of life and subsequent asthma and allergic rhinitis by age 10–12 years. Methods We used data from two independent cohorts: the high‐risk Melbourne Atopic Cohort Study (MACS) (n = 620) and the population‐based LISAplus (n = 3094). Food sensitization was assessed at 6, 12, and 24 months in MACS and 24 months in LISAplus. Multiple logistic regressions were used to estimate associations between sensitization to food only, aeroallergen only, or both and allergic airway disease. Results When compared to non‐sensitized children, sensitization to food only at 12 months in MACS and 24 months in LISAplus was associated with increased risk of current asthma (aOR = 2.2; 95% CI 1.1, 4.6 in MACS and aOR = 4.9; 2.4, 10.1 in LISAplus). Similar results were seen for allergic rhinitis. Additionally, cosensitization to food and aeroallergen in both cohorts at any tested point was a stronger predictor of asthma (at 24 months, aOR = 8.3; 3.7, 18.8 in MACS and aOR = 14.4; 5.0, 41.6 in LISAplus) and allergic rhinitis (at 24 months, aOR = 3.9; 1.9, 8.1 in MACS and aOR = 7.6; 3.0, 19.6 in LISAplus). Conclusions In both cohorts, food sensitization (with or without aeroallergen sensitization) in the first two years of life increased the risk of subsequent asthma and allergic rhinitis. These findings support the role of early life food sensitization in the atopic march and suggest trials to prevent early onset have the potential to reduce the development of allergic airways disease.

The parallel epidemics of childhood asthma and obesity over the past few decades have spurred research into obesity as a risk factor for asthma. However, little is known regarding the role of asthma in obesity incidence. We examined whether early-onset asthma and related phenotypes are associated with the risk of developing obesity in childhood. This study includes 21 130 children born from 1990 to 2008 in Denmark, France, Germany, Greece, Italy, The Netherlands, Spain, Sweden and the UK. We followed non-obese children at 3–4 years of age for incident obesity up to 8 years of age. Physician-diagnosed asthma, wheezing and allergic rhinitis were assessed up to 3–4 years of age. Children with physician-diagnosed asthma had a higher risk for incident obesity than those without asthma (adjusted hazard ratio (aHR) 1.66, 95% CI 1.18–2.33). Children with active asthma (wheeze in the last 12 months and physician-diagnosed asthma) exhibited a higher risk for obesity (aHR 1.98, 95% CI 1.31–3.00) than those without wheeze and asthma. Persistent wheezing was associated with increased risk for incident obesity compared to never wheezers (aHR 1.51, 95% CI 1.08–2.09). Early-onset asthma and wheezing may contribute to an increased risk of developing obesity in later childhood.

Few studies have examined the link between air pollution exposure and behavioural problems and learning disorders during late childhood and adolescence.To determine whether traffic-related air pollution exposure is associated with hyperactivity/inattention, dyslexia and dyscalculia up to age 15years using the German GINIplus and LISAplus birth cohorts (recruitment 1995-1999).Hyperactivity/inattention was assessed using the German parent-completed (10years) and self-completed (15years) Strengths and Difficulties Questionnaire. Responses were categorized into normal versus borderline/abnormal. Parent-reported dyslexia and dyscalculia (yes/no) at age 10 and 15years were defined using parent-completed questionnaires. Individual-level annual average estimates of nitrogen dioxide (NO2), particulate matter (PM)10 mass, PM2.5 mass and PM2.5 absorbance concentrations were assigned to each participant's birth, 10year and 15year home address. Longitudinal associations between the air pollutants and the neurodevelopmental outcomes were assessed using generalized estimation equations, separately for both study areas, and combined in a random-effects meta-analysis. Odds ratios and 95% confidence intervals are given per interquartile range increase in pollutant concentration.The prevalence of abnormal/borderline hyperactivity/inattention scores and parental-reported dyslexia and dyscalculia at 15years of age was 12.9%, 10.5% and 3.4%, respectively, in the combined population (N=4745). In the meta- analysis, hyperactivity/inattention was associated with PM2.5 mass estimated to the 10 and 15year addresses (1.12 [1.01, 1.23] and 1.11 [1.01, 1.22]) and PM2.5 absorbance estimated to the 10 and 15year addresses (1.14 [1.05, 1.25] and 1.13 [1.04, 1.23], respectively).We report associations suggesting a potential link between air pollution exposure and hyperactivity/inattention scores, although these findings require replication.

Fetal metabolism may be changed by the exposure to maternal factors, and the route to obesity may already set in utero. Cord blood metabolites might predict growth patterns and later obesity. We aimed to characterize associations of cord blood with birth weight, postnatal weight gain, and BMI in adolescence.Over 700 cord blood samples were collected from infants participating in the German birth cohort study LISAplus. Glycerophospholipid fatty acids (GPL-FA), polar lipids, non-esterified fatty acids (NEFA), and amino acids were analyzed with a targeted, liquid chromatography-tandem mass spectrometry based metabolomics platform. Cord blood metabolites were related to growth factors by linear regression models adjusted for confounding variables.Cord blood metabolites were highly associated with birth weight. Lysophosphatidylcholines C16:1, C18:1, C20:3, C18:2, C20:4, C14:0, C16:0, C18:3, GPL-FA C20:3n-9, and GPL-FA C22:5n-6 were positively related to birth weight, while higher cord blood concentrations of NEFA C22:6, NEFA C20:5, GPL-FA C18:3n-3, and PCe C38:0 were associated with lower birth weight. Postnatal weight gain and BMI z-scores in adolescents were not significantly associated with cord blood metabolites after adjustment for multiple testing.Potential long-term programming effects of the intrauterine environment and metabolism on later health cannot be predicted with profiling of the cord blood metabolome.

The association between air pollution exposure and emotional and behavioural problems in children is unclear. We aimed to assess prenatal and postnatal exposure to several air pollutants and child's depressive and anxiety symptoms, and aggressive symptoms in children of 7–11 years. We analysed data of 13182 children from 8 European population-based birth cohorts. Concentrations of nitrogen dioxide (NO2), nitrogen oxides (NOx), particulate matter (PM) with diameters of ≤10 μm (PM10), ≤ 2.5 μm (PM2.5), and between 10 and 2.5 μm (PMcoarse), the absorbance of PM2.5 filters (PM2.5abs), and polycyclic aromatic hydrocarbons (PAHs) were estimated at residential addresses of each participant. Depressive and anxiety symptoms and aggressive symptoms were assessed at 7–11 years of age using parent reported tests. Children were classified in borderline/clinical range or clinical range using validated cut offs. Region specific models were adjusted for various socio-economic and lifestyle characteristics and then combined using random effect meta-analysis. Multiple imputation and inverse probability weighting methods were applied to correct for potential attrition bias. A total of 1896 (14.4%) children were classified as having depressive and anxiety symptoms in the borderline/clinical range, and 1778 (13.4%) as having aggressive symptoms in the borderline/clinical range. Overall, 1108 (8.4%) and 870 (6.6%) children were classified as having depressive and anxiety symptoms, and aggressive symptoms in the clinical range, respectively. Prenatal exposure to air pollution was not associated with depressive and anxiety symptoms in the borderline/clinical range (e.g. OR 1.02 [95%CI 0.95 to 1.10] per 10 μg/m3 higher NO2) nor with aggressive symptoms in the borderline/clinical range (e.g. OR 1.04 [95%CI 0.96 to 1.12] per 10 μg/m3 higher NO2). Similar results were observed for the symptoms in the clinical range, and for postnatal exposures to air pollution. Overall, our results suggest that prenatal and postnatal exposure to air pollution is not associated with depressive and anxiety symptoms or aggressive symptoms in children of 7 to 11 years old.

The relationship between allergy and autoimmune disorders is complex and poorly understood.We sought to investigate commonalities in genetic loci and pathways between allergy and autoimmune diseases to elucidate shared disease mechanisms.We meta-analyzed 2 genome-wide association studies on self-reported allergy and sensitization comprising a total of 62,330 subjects. These results were used to calculate enrichment for single nucleotide polymorphisms (SNPs) previously associated with autoimmune diseases. Furthermore, we probed for enrichment within genetic pathways and of transcription factor binding sites and characterized commonalities in variant burden on tissue-specific regulatory sites by calculating the enrichment of allergy SNPs falling in gene regulatory regions in various cells using Encode Roadmap DNase-hypersensitive site data. Finally, we compared the allergy data with those of all known diseases.Among 290 loci previously associated with 16 autoimmune diseases, we found a significant enrichment of loci also associated with allergy (P = 1.4e-17) encompassing 29 loci at a false discovery rate of less than 0.05. Such enrichment seemed to be a general characteristic for autoimmune diseases. Among the common loci, 48% had the same direction of effect for allergy and autoimmune diseases. Additionally, we observed an enrichment of allergy SNPs falling within immune pathways and regions of chromatin accessible in immune cells that was also represented in patients with autoimmune diseases but not those with other diseases.We identified shared susceptibility loci and commonalities in pathways between allergy and autoimmune diseases, suggesting shared disease mechanisms. Further studies of these shared genetic mechanisms might help in understanding the complex relationship between these diseases, including the parallel increase in disease prevalence.

Background: Exposure to air pollution during pregnancy may increase attention-deficit/hyperactivity disorder (ADHD) symptoms in children, but findings have been inconsistent. We aimed to study this association in a collaborative study of eight European population-based birth/child cohorts, including 29,127 mother–child pairs. Methods: Air pollution concentrations (nitrogen dioxide [NO2] and particulate matter [PM]) were estimated at the birth address by land-use regression models based on monitoring campaigns performed between 2008 and 2011. We extrapolated concentrations back in time to exact pregnancy periods. Teachers or parents assessed ADHD symptoms at 3–10 years of age. We classified children as having ADHD symptoms within the borderline/clinical range and within the clinical range using validated cutoffs. We combined all adjusted area-specific effect estimates using random-effects meta-analysis and multiple imputations and applied inverse probability-weighting methods to correct for loss to follow-up. Results: We classified a total of 2,801 children as having ADHD symptoms within the borderline/clinical range, and 1,590 within the clinical range. Exposure to air pollution during pregnancy was not associated with a higher odds of ADHD symptoms within the borderline/clinical range (e.g., adjusted odds ratio [OR] for ADHD symptoms of 0.95, 95% confidence interval [CI] = 0.89, 1.01 per 10 µg/m3 increase in NO2 and 0.98, 95% CI = 0.80, 1.19 per 5 µg/m3 increase in PM2.5). We observed similar associations for ADHD within the clinical range. Conclusions: There was no evidence for an increase in risk of ADHD symptoms with increasing prenatal air pollution levels in children aged 3–10 years. See video abstract at, https://links.lww.com/EDE/B379.

Background: The role of tobacco smoke exposure in the development and persistence of asthma and rhinoconjunctivitis through childhood into adolescence is unclear. Objectives: We assessed the associations of parental smoking from fetal life through adolescence with asthma and rhinoconjunctivitis during childhood and adolescence. Methods: We analyzed data for 10,860 participants of five European birth cohort studies from the Mechanisms of the Development of Allergy (MeDALL) consortium. Parental smoking habits and health outcomes (early transient, persistent, and adolescent-onset asthma and rhinoconjunctivitis) were based on questionnaires covering the period from pregnancy to 14–16 y of age. Data were combined and analyzed using a one-stage and two-stage individual participant data meta-analysis. Results: Overall, any maternal smoking during pregnancy tended to be associated with an increased odds of prevalent asthma [adjusted odds ratio (aOR)=1.19 (95% CI: 0.98, 1.43)], but not prevalent rhinoconjunctivitis [aOR=1.05 (95% CI: 0.90, 1.22)], during childhood and adolescence. In analyses with phenotypes related to age of onset and persistence of disease, any maternal smoking during pregnancy was associated with early transient asthma [aOR=1.79 (95% CI: 1.14, 2.83)]. Maternal smoking of ≥10 cigarettes/day during pregnancy was associated with persistent asthma [aOR=1.66 (95% CI: 1.29, 2.15)] and persistent rhinoconjunctivitis [aOR=1.55 (95% CI, 1.09, 2.20)]. Tobacco smoke exposure during fetal life, infancy, childhood, and adolescence was not associated with adolescent-onset asthma or rhinoconjunctivitis. Conclusions: Findings from this combined analysis of five European birth cohorts strengthen evidence linking early exposure to tobacco smoke with asthma during childhood and adolescence. Children with high early-life exposure were more likely than unexposed children to have early transient and persistent asthma and persistent rhinoconjunctivitis. https://doi.org/10.1289/EHP2738

Interleukin 6 (IL-6) is a multifunctional cytokine with both pro- and anti-inflammatory properties with a heritability estimate of up to 61%. The circulating levels of IL-6 in blood have been associated with an increased risk of complex disease pathogenesis. We conducted a two-staged, discovery and replication meta genome-wide association study (GWAS) of circulating serum IL-6 levels comprising up to 67 428 (ndiscovery = 52 654 and nreplication = 14 774) individuals of European ancestry. The inverse variance fixed effects based discovery meta-analysis, followed by replication led to the identification of two independent loci, IL1F10/IL1RN rs6734238 on chromosome (Chr) 2q14, (Pcombined = 1.8 × 10-11), HLA-DRB1/DRB5 rs660895 on Chr6p21 (Pcombined = 1.5 × 10-10) in the combined meta-analyses of all samples. We also replicated the IL6R rs4537545 locus on Chr1q21 (Pcombined = 1.2 × 10-122). Our study identifies novel loci for circulating IL-6 levels uncovering new immunological and inflammatory pathways that may influence IL-6 pathobiology.

<h3>Background</h3> Whether long-term exposure air to pollution has effects on allergic sensitization is controversial. <h3>Objective</h3> Our aim was to investigate associations of air pollution exposure at birth and at the time of later biosampling with IgE sensitization against common food and inhalant allergens, or specific allergen molecules, in children aged up to 16 years. <h3>Methods</h3> A total of 6163 children from 4 European birth cohorts participating in the Mechanisms of the Development of ALLergy [MeDALL] consortium were included in this meta-analysis of the following studies: Children, Allergy, Milieu, Stockholm, Epidemiology (BAMSE) (Sweden), Influences of Lifestyle-Related Factors on the Human Immune System and Development of Allergies in Childhood (LISA)/German Infant Study on the Influence of Nutrition Intervention PLUS Environmental and Genetic Influences on Allergy Development (GINIplus) (Germany), and Prevention and Incidence of Asthma and Mite Allergy (PIAMA) (The Netherlands). The following indicators were modeled by land use regression: individual residential outdoor levels of particulate matter with aerodynamic diameters less than 2.5 μm, less than 10 μm, and between 2.5 and 10 μm; PM_2.5 absorbance (a measurement of the blackness of PM_2.5 filters); and nitrogen oxides levels. Blood samples drawn at ages 4 to 6 (n = 5989), 8 to 10 (n = 6603), and 15 to 16 (n = 5825) years were analyzed for IgE sensitization to allergen extracts by ImmunoCAP. Additionally, IgE against 132 allergen molecules was measured by using the MedALL microarray chip (n = 1021). <h3>Results</h3> Air pollution was not consistently associated with IgE sensitization to any common allergen extract up to age 16 years. However, allergen-specific analyses suggested increased risks of sensitization to birch (odds ratio [OR] = 1.12 [95% CI = 1.01-1.25] per 10-μg/m³ increase in NO₂ exposure). In a subpopulation with microarray data, IgE to the major timothy grass allergen <i>Phleum pratense</i> 1 (Phl p 1) and the cat allergen <i>Felis domesticus</i> 1 (Fel d 1) greater than 3.5 Immuno Solid-phase Allergen Chip standardized units for detection of IgE antibodies were related to PM_2.5 exposure at birth (OR = 3.33 [95% CI = 1.40-7.94] and OR = 4.98 [95% CI = 1.59-15.60], respectively, per 5-μg/m³ increase in exposure). <h3>Conclusion</h3> Air pollution exposure does not seem to increase the overall risk of allergic sensitization; however, sensitization to birch as well as grass pollen Phl p 1 and cat Fel d 1 allergen molecules may be related to specific pollutants.

Association of genetic-variants in the FADS1-FADS2-gene-cluster with fatty-acid-composition in blood of adult-populations is well established. We analyze this genetic-association in two children-cohort-studies. In addition, the association between variants in the FADS-gene-cluster and blood-fatty-acid-composition with eczema was studied.Data of two population-based-birth-cohorts in The Netherlands and Germany (KOALA, LISA) were pooled (n = 879) and analyzed by (logistic) regression regarding the mutual influence of single-nucleotide-polymorphisms (SNPs) in the FADS-gene-cluster (rs174545, rs174546, rs174556, rs174561, rs3834458), on polyunsaturated fatty acids (PUFA) in blood and parent-reported eczema until the age of 2 years. All SNPs were highly significantly associated with all PUFAs except for alpha-linolenic-acid and eicosapentaenoic-acid, also after correction for multiple-testing. All tested SNPs showed associations with eczema in the LISA-study, but not in the KOALA-study. None of the PUFAs was significantly associated with eczema neither in the pooled nor in the analyses stratified by study-cohort.PUFA-composition in young children's blood is under strong control of the FADS-gene-cluster. Inconsistent results were found for a link between these genetic-variants with eczema. PUFA in blood was not associated with eczema. Thus the hypothesis of an inflammatory-link between PUFA and eczema by the metabolic-pathway of LC-PUFAs as precursors for inflammatory prostaglandins and leukotrienes could not be confirmed by these data.

The protective effect of breastfeeding (BF) on the development of asthma has been widely recognized, even if not all results have been consistent. Gene variants of the FADS gene cluster have a major impact on fatty acid composition in blood and in breast milk. Therefore, we evaluated the influence of the FADS1 FADS2 gene cluster polymorphisms on the association between BF and asthma. The analysis was based on data (N=2245) from two German prospective birth cohort studies. Information on asthma and BF during the first 6 months was collected using questionnaires completed by the parents. Logistic regression modelling was used to analyse the association between exclusive BF and ever having asthma stratified by genotype. In the stratified analyses, BF for 3 or 4 months after birth had a protective effect for heterozygous and homozygous carriers of the minor allele (adjusted odds ratio between 0.37 (95% CI: 0.18-0.80) and 0.42 (95% CI: 0.20-0.88). Interaction terms of BF with genotype were significant and ranged from -1.17 (P-value: 0.015) to -1.33 (0.0066). Moreover, heterozygous and homozygous carriers of the minor allele who were exclusively breastfed for 5 or 6 months after birth had a reduced risk of asthma [0.32 (0.18-0.57) to 0.47 (0.27-0.81)] in the stratified analyses. For individuals carrying the homozygous major allele, BF showed no significant effect on the development of asthma. The association between exclusive BF and asthma is modified by the genetic variants of FADS genotypes in children.

Background: Little is known about the effect of fatty acid (FA) concentrations in cord blood on long-term behavioral outcomes. Objective: We assessed the effect of FAs in cord blood serum on children's behavioral difficulties at the age of 10 y. Design: A longitudinal study of 416 children from the population-based Influences of Lifestyle-Related Factors on the Immune System and the Development of Allergies in Childhood (LISAplus) birth cohort from Munich was conducted. Individual glycerophospholipid FAs in blood were analyzed in venous cord blood. Data on children's behavior were collected with a parent-reported Strength and Difficulties Questionnaire at 10 y of age. Zero-inflated Poisson regression models were applied and adjusted for sex, parental income, smoking during pregnancy, and dietary intake of arachidonic acid (AA) and DHA at 10 y. Results: A 1% increase in DHA in cord blood serum was found to decrease total difficulties by (exp)β5adj = 0.93 (SE = 0.02, P < 0.0001) and hyperactivity or inattention by (exp)βadj = 0.94 (SE = 0.03, P < 0.04). Higher long-chain (LC) PUFA concentrations in cord blood serum were associated with fewer emotional symptoms [(exp)βadj = 0.95, SE = 0.03, P = 0.01], and similarly higher AA concentrations were associated with fewer emotional symptoms [(exp)βadj = 0.94, SE = 0.03, P = 0.03]. Conclusion: Increased concentrations of DHA, LC-PUFAs, and AA in cord blood serum were associated with lower scores on a parent-completed behavioral screen. An appropriate FA supply to the developing fetus may be essential for optimal long-term behavioral outcomes in children.

Elevated cholesterol levels in children can be a risk factor for cardiovascular diseases in later life. In adults, it has been shown that blood lipid levels are strongly influenced by polymorphisms in the fatty acid desaturase (FADS) gene cluster in addition to nutritional and other exogenous and endogenous determinants. Our aim was to investigate whether lipid levels are determined by the FADS genotype already in children and whether this association interacts with dietary intake of n-3 fatty acids.The analysis was based on data of 2006 children from two German prospective birth cohort studies. Total cholesterol, HDL, LDL and triglycerides were measured at 10 years of age. Six single nucleotide polymorphisms (SNPs) of the FADS gene cluster were genotyped. Dietary n-3 fatty acid intake was assessed by food frequency questionnaire. Linear regression modeling was used to assess the association between lipid levels, n-3 fatty acid intake and FADS genotype.Individuals carrying the homozygous minor allele had lower levels of total cholesterol [means ratio (MR) ranging from 0.96 (p = 0.0093) to 0.98 (p = 0.2949), depending on SNPs] and LDL [MR between 0.94 (p = 0.0179) and 0.97 (p = 0.2963)] compared to homozygous major allele carriers. Carriers of the heterozygous allele showed lower HDL levels [β between -0.04 (p = 0.0074) to -0.01 (p = 0.3318)] and higher triglyceride levels [MR ranging from 1.06 (p = 0.0065) to 1.07 (p = 0.0028)] compared to homozygous major allele carriers. A higher n-3 PUFA intake was associated with higher concentrations of total cholesterol, LDL, HDL and lower triglyceride levels, but these associations did not interact with the FADS1 FADS2 genotype.Total cholesterol, HDL, LDL and triglyceride concentrations may be influenced by the FADS1 FADS2 genotype already in 10 year old children. Genetically determined blood lipid levels during childhood might differentially predispose individuals to the development of cardiovascular diseases later in life.

Abstract Background Cross‐sectional studies suggested that allergy prevalence in childhood is higher in boys compared to girls, but it remains unclear whether this inequality changes after puberty. We examined the sex‐specific prevalence of asthma and rhinitis as single and as multimorbid diseases before and after puberty onset in longitudinal cohort data. Methods In six European population‐based birth cohorts of MeDALL, we assessed the outcomes: current rhinitis, current asthma, current allergic multimorbidity (ie, concurrent asthma and rhinitis), puberty status and allergic sensitization by specific serum antibodies (immunoglobulin E) against aero‐allergens. With generalized estimating equations, we analysed the effects of sex, age, puberty (yes/no) and possible confounders on the prevalence of asthma and rhinitis, and allergic multimorbidity in each cohort separately and performed individual participant data meta‐analysis. Findings We included data from 19 013 participants from birth to age 14‐20 years. Current rhinitis only affected girls less often than boys before and after puberty onset: adjusted odds ratio for females vs males 0.79 (95%‐confidence interval 0.73‐0.86) and 0.86 (0.79‐0.94), respectively (sex‐puberty interaction P = .089). Similarly, for current asthma only, females were less often affected than boys both before and after puberty onset: 0.71, 0.63‐0.81 and 0.81, 0.64‐1.02, respectively (sex‐puberty interaction P = .327). The prevalence of allergic multimorbidity showed the strongest sex effect before puberty onset (female‐male‐OR 0.55, 0.46‐0.64) and a considerable shift towards a sex‐balanced prevalence after puberty onset (0.89, 0.74‐1.04); sex‐puberty interaction: P &lt; .001. Interpretation The male predominance in prevalence before puberty and the “sex‐shift” towards females after puberty onset were strongest in multimorbid patients who had asthma and rhinitis concurrently.

Investigations in urban areas have just begun to explore how the indoor dust microbiome may affect the pathogenesis of asthma and allery.We aimed to investigate the early fungal and bacterial microbiome in house dust with allergic sensitization and wheezing later in childhood.Individual dust samples from 189 homes of the LISAplus birth cohort study were collected shortly after birth from living room floors and profiled for fungal and bacterial microbiome. Fungal and bacterial diversity was assessed with terminal restriction fragment length polymorphism (tRFLP) and defined by Simpson's Diversity Index. Information on wheezing outcomes and covariates until the age of 10 years was obtained by parent questionnaires. Information on specific allergic sensitization was available at child's age 6 and 10 years. Logistic regression and general estimation equation (GEE) models were used to examine the relationship between microbial diversity and health outcomes.Adjusted logistic regression analyses revealed a significantly reduced risk of developing sensitization to aero-allergens at 6 years and ever wheezing until the age of 10 years for exposure to higher fungal diversity [adjusted odds ratio (aOR) = 0.26 (95% CI: 0.10, 0.70), and 0.42 (95% CI: 0.18, 0.96), respectively]. The associations were attenuated for the longitudinal analyses (GEE) until the age of 10 years. There was no association between higher exposure to bacterial diversity and the tested health outcomes.Higher early exposure to fungal diversity might help to prevent a child from developing sensitization to aero-allergens in early childhood, but the reasons for attenuated effects in later childhood require further prospective studies. Citation: Tischer C, Weikl F, Probst AJ, Standl M, Heinrich J, Pritsch K. 2016. Urban dust microbiome: impact on later atopy and wheezing. Environ Health Perspect 124:1919-1923; http://dx.doi.org/10.1289/EHP158.

<h3>Importance</h3> Observational studies have shown associations of birth weight with type 2 diabetes (T2D) and glycemic traits, but it remains unclear whether these associations represent causal associations. <h3>Objective</h3> To test the association of birth weight with T2D and glycemic traits using a mendelian randomization analysis. <h3>Design, Setting, and Participants</h3> This mendelian randomization study used a genetic risk score for birth weight that was constructed with 7 genome-wide significant single-nucleotide polymorphisms. The associations of this score with birth weight and T2D were tested in a mendelian randomization analysis using study-level data. The association of birth weight with T2D was tested using both study-level data (7 single-nucleotide polymorphisms were used as an instrumental variable) and summary-level data from the consortia (43 single-nucleotide polymorphisms were used as an instrumental variable). Data from 180 056 participants from 49 studies were included. <h3>Main Outcomes and Measures</h3> Type 2 diabetes and glycemic traits. <h3>Results</h3> This mendelian randomization analysis included 49 studies with 41 155 patients with T2D and 80 008 control participants from study-level data and 34 840 patients with T2D and 114 981 control participants from summary-level data. Study-level data showed that a 1-SD decrease in birth weight due to the genetic risk score was associated with higher risk of T2D among all participants (odds ratio [OR], 2.10; 95% CI, 1.69-2.61;<i>P</i> = 4.03 × 10⁻⁵), among European participants (OR, 1.96; 95% CI, 1.42-2.71;<i>P</i> = .04), and among East Asian participants (OR, 1.39; 95% CI, 1.18-1.62;<i>P</i> = .04). Similar results were observed from summary-level analyses. In addition, each 1-SD lower birth weight was associated with 0.189 SD higher fasting glucose concentration (β = 0.189; SE = 0.060;<i>P</i> = .002), but not with fasting insulin, 2-hour glucose, or hemoglobin A_1cconcentration. <h3>Conclusions and Relevance</h3> In this study, a genetic predisposition to lower birth weight was associated with increased risk of T2D and higher fasting glucose concentration, suggesting genetic effects on retarded fetal growth and increased diabetes risk that either are independent of each other or operate through alterations of integrated biological mechanisms.

Few studies have reported the association between greenspace and academic performance at school level. We examined associations between both residential and school greenspace and individual school grades in German adolescents. German and maths grades from the latest school certificate, residential and school greenspace, and covariates were available for 1351 10 and 15 years old Munich children and 1078 Wesel children from two German birth cohorts – GINIplus and LISA. Residential and school greenspace was assessed by the Normalized Difference Vegetation Index (NDVI), tree cover, and (in Munich only) proportion of agricultural land, forest, and urban green space in 500-m and 1000-m circular buffers. Longitudinal associations between each exposure-outcome pair were assessed by logistic mixed effects models with person and school as random intercepts and adjusted for potential confounders. No associations were observed between any of the greenspace variables and grades in Wesel children. Several statistically significant associations were observed with German and maths grades in Munich children, however associations were inconsistent across sensitivity analyses. There is no evidence of an association of higher greenspace at residence, school or combined with improved academic performance in German adolescents from the GINIplus and LISA longitudinal studies.

Introduction To understand the puberty-related sex shift in the prevalence of asthma and rhinitis as single entities and as respiratory multimorbidities, we investigated if there is also a sex-specific and puberty-related pattern of their incidences. Methods We used harmonised questionnaire data from 18 451 participants in five prospective observational European birth cohorts within the collaborative MeDALL (Mechanisms of the Development of Allergy) project. Outcome definitions for IgE-associated and non-IgE-associated asthma, rhinitis and respiratory multimorbidity (first occurrence of coexisting asthma and rhinitis) were based on questionnaires and the presence of specific antibodies (IgE) against common allergens in serum. For each outcome, we used proportional hazard models with sex–puberty interaction terms and conducted a one-stage individual participant data meta-analysis. Results Girls had a lower risk of incident asthma (adjusted HR 0.67, 95% CI 0.61 to 0.74), rhinitis (0.73, 0.69 to 0.78) and respiratory multimorbidity (0.58, 0.51 to 0.66) before puberty compared with boys. After puberty onset, these incidences became more balanced across the sexes (asthma 0.84, 0.64 to 1.10; rhinitis 0.90, 0.80 to 1.02; respiratory multimorbidity 0.84, 0.63 to 1.13). The incidence sex shift was slightly more distinct for non-IgE-associated respiratory diseases (asthma 0.74, 0.63 to 0.87 before vs 1.23, 0.75 to 2.00 after puberty onset; rhinitis 0.88, 0.79 to 0.98 vs 1.20, 0.98 to 1.47; respiratory multimorbidity 0.66, 0.49 to 0.88 vs 0.96, 0.54 to 1.71) than for IgE-associated respiratory diseases. Discussion We found an incidence ‘sex shift’ in chronic respiratory diseases from a male predominance before puberty to a more sex-balanced incidence after puberty onset, which may partly explain the previously reported sex shift in prevalence. These differences need to be considered in public health to enable effective diagnoses and timely treatment in adolescent girls.

We investigated whether residing in places with higher greenness, more trees and more allergenic trees early in life increases the risk of allergic outcomes, and whether these associations differ depending on the concentration of air pollutants. The analytic sample included 631 children from the German birth cohort LISA Leipzig. Asthma and allergic rhinitis, sensitization to aeroallergens and food allergens, as well as confounders, were collected prospectively up to 15 years. Greenness was assessed by Normalized Difference Vegetation Index (NDVI). A tree registry was used to derive information on trees, which were classified into allergenic and non-allergenic. Annual average concentrations of nitrogen dioxide (NO2) and ozone were also used. Geographic exposures were assigned to home addresses at birth. Longitudinal associations were analysed using generalized estimating equations. Medium and high numbers (tertiles) of trees and allergenic trees in a 500 m buffer around birth addresses were associated with increased odds of allergic rhinitis up to 15 years regardless of NDVI. These exposures were also related to higher odds of sensitization to aeroallergens. Associations with asthma and sensitization to food allergens were less consistent. Effect estimates for allergic rhinitis were stronger in the high tertile of NO2 compared to the low tertile, while an opposite tendency was observed for ozone. We observed that early life residence in places with many trees, and allergenic trees specifically, may increase the prevalence of allergic rhinitis later in life. This association and its modification by air pollution should be pursued in further studies.

<h3>Background</h3> Fifteen percent of atopic dermatitis (AD) liability-scale heritability could be attributed to 31 susceptibility loci identified by using genome-wide association studies, with only 3 of them (<i>IL13</i>, IL-6 receptor <i>[IL6R]</i>, and filaggrin <i>[FLG]</i>) resolved to protein-coding variants. <h3>Objective</h3> We examined whether a significant portion of unexplained AD heritability is further explained by low-frequency and rare variants in the gene-coding sequence. <h3>Methods</h3> We evaluated common, low-frequency, and rare protein-coding variants using exome chip and replication genotype data of 15,574 patients and 377,839 control subjects combined with whole-transcriptome data on lesional, nonlesional, and healthy skin samples of 27 patients and 38 control subjects. <h3>Results</h3> An additional 12.56% (SE, 0.74%) of AD heritability is explained by rare protein-coding variation. We identified docking protein 2 <i>(DOK2)</i> and CD200 receptor 1 <i>(CD200R1)</i> as novel genome-wide significant susceptibility genes. Rare coding variants associated with AD are further enriched in 5 genes (IL-4 receptor <i>[IL4R]</i>, <i>IL13</i>, Janus kinase 1 <i>[JAK1]</i>, <i>JAK2</i>, and tyrosine kinase 2 <i>[TYK2]</i>) of the <i>IL13</i> pathway, all of which are targets for novel systemic AD therapeutics. Multiomics-based network and RNA sequencing analysis revealed <i>DOK2</i> as a central hub interacting with, among others, <i>CD200R1</i>, <i>IL6R</i>, and signal transducer and activator of transcription 3 <i>(STAT3)</i>. Multitissue gene expression profile analysis for 53 tissue types from the Genotype-Tissue Expression project showed that disease-associated protein-coding variants exert their greatest effect in skin tissues. <h3>Conclusion</h3> Our discoveries highlight a major role of rare coding variants in AD acting independently of common variants. Further extensive functional studies are required to detect all potential causal variants and to specify the contribution of the novel susceptibility genes <i>DOK2</i> and <i>CD200R1</i> to overall disease susceptibility.

Substantial genetic correlations have been reported across psychiatric disorders and numerous cross-disorder genetic variants have been detected. To identify the genetic variants underlying general psychopathology in childhood, we performed a genome-wide association study using a total psychiatric problem score. We analyzed 6,844,199 common SNPs in 38,418 school-aged children from 20 population-based cohorts participating in the EAGLE consortium. The SNP heritability of total psychiatric problems was 5.4% (SE = 0.01) and two loci reached genome-wide significance: rs10767094 and rs202005905. We also observed an association of SBF2, a gene associated with neuroticism in previous GWAS, with total psychiatric problems. The genetic effects underlying the total score were shared with common psychiatric disorders only (attention-deficit/hyperactivity disorder, anxiety, depression, insomnia) (rG > 0.49), but not with autism or the less common adult disorders (schizophrenia, bipolar disorder, or eating disorders) (rG < 0.01). Importantly, the total psychiatric problem score also showed at least a moderate genetic correlation with intelligence, educational attainment, wellbeing, smoking, and body fat (rG > 0.29). The results suggest that many common genetic variants are associated with childhood psychiatric symptoms and related phenotypes in general instead of with specific symptoms. Further research is needed to establish causality and pleiotropic mechanisms between related traits.

Childhood asthma is a result of a complex interaction of genetic and environmental components causing epigenetic and immune dysregulation, airway inflammation and impaired lung function. Although different microarray based EWAS studies have been conducted, the impact of epigenetic regulation in asthma development is still widely unknown. We have therefore applied unbiased whole genome bisulfite sequencing (WGBS) to characterize global DNA-methylation profiles of asthmatic children compared to healthy controls.Peripheral blood samples of 40 asthmatic and 42 control children aged 5-15 years from three birth cohorts were sequenced together with paired cord blood samples. Identified differentially methylated regions (DMRs) were categorized in genotype-associated, cell-type-dependent, or prenatally primed. Network analysis and subsequent natural language processing of DMR-associated genes was complemented by targeted analysis of functional translation of epigenetic regulation on the transcriptional and protein level.In total, 158 DMRs were identified in asthmatic children compared to controls of which 37% were related to the eosinophil content. A global hypomethylation was identified affecting predominantly enhancer regions and regulating key immune genes such as IL4, IL5RA, and EPX. These DMRs were confirmed in n = 267 samples and could be linked to aberrant gene expression. Out of the 158 DMRs identified in the established phenotype, 56 were perturbed already at birth and linked, at least in part, to prenatal influences such as tobacco smoke exposure or phthalate exposure.This is the first epigenetic study based on whole genome sequencing to identify marked dysregulation of enhancer regions as a hallmark of childhood asthma.

Abstract Background Pubertal growth patterns correlate with future health outcomes. However, the genetic mechanisms mediating growth trajectories remain largely unknown. Here, we modeled longitudinal height growth with Super-Imposition by Translation And Rotation (SITAR) growth curve analysis on ~ 56,000 trans-ancestry samples with repeated height measurements from age 5 years to adulthood. We performed genetic analysis on six phenotypes representing the magnitude, timing, and intensity of the pubertal growth spurt. To investigate the lifelong impact of genetic variants associated with pubertal growth trajectories, we performed genetic correlation analyses and phenome-wide association studies in the Penn Medicine BioBank and the UK Biobank. Results Large-scale growth modeling enables an unprecedented view of adolescent growth across contemporary and 20th-century pediatric cohorts. We identify 26 genome-wide significant loci and leverage trans-ancestry data to perform fine-mapping. Our data reveals genetic relationships between pediatric height growth and health across the life course, with different growth trajectories correlated with different outcomes. For instance, a faster tempo of pubertal growth correlates with higher bone mineral density, HOMA-IR, fasting insulin, type 2 diabetes, and lung cancer, whereas being taller at early puberty, taller across puberty, and having quicker pubertal growth were associated with higher risk for atrial fibrillation. Conclusion We report novel genetic associations with the tempo of pubertal growth and find that genetic determinants of growth are correlated with reproductive, glycemic, respiratory, and cardiac traits in adulthood. These results aid in identifying specific growth trajectories impacting lifelong health and show that there may not be a single “optimal” pubertal growth pattern.

Although urticaria is considered one of the most frequent skin diseases, reliable epidemiologic data are scarce.To evaluate the incidence and cumulative prevalence of urticaria in infants and children up to age of 10, to characterize the relationship of specific IgE levels (food and inhalative allergens) with urticaria, and to monitor the joint occurrence of urticaria with other diseases, such as eczema, asthma, and hay fever.The study population consisted of two prospective birth cohort studies: the LISAplus and GINIplus studies. Information on physician-diagnosed urticaria, asthma, eczema, or hay fever was collected using self-administered questionnaires completed by the parents. Blood samples were drawn, and specific immunoglobulin E measured at 2 (only LISAplus), 6 and 10 yr of age.The incidence of urticaria was approximately 1% per year of age. The cumulative prevalence of urticaria in children up to the age of 10 yr was 14.5% for boys and 16.2% for girls. Cumulative prevalence of urticaria at the age of ten was significantly (p < 0.05) associated with allergic sensitization to peanut, soy, and wheat flour, but not with inhalant allergens. Both a parental history of atopy/urticaria and the children's diagnosis of asthma, eczema, and hay fever were strongly related (p < 0.0001) to the occurrence of urticaria.Urticaria is a frequent event during childhood, with highest incidence in infants and preschool children. Comorbidity with atopic disease is high.

While there is evidence for variations in prevalence rates of childhood wheeze and asthma between countries, longitudinal, individual-level data are needed to understand these differences. The aim of this study was to examine variations in prevalence rates of childhood asthma, wheeze and wheeze with asthma in Europe. We analysed datasets from 10 MeDALL (Mechanisms of the Development of ALLergy) cohorts in eight countries, representing 26 663 children, to calculate prevalence rates of wheeze and asthma by child age and wheeze with asthma at age 4 years. Harmonised variables included outcomes parent-reported wheeze and parent-reported doctor-diagnosed asthma, and covariates maternal education, parental smoking, pets, parental asthma, doctor-diagnosed allergic rhinitis, doctor-diagnosed eczema and wheeze severity. At age 4 years, asthma prevalence varied from 1.72% in Germany to 13.48% in England and the prevalence of wheeze varied from 9.82% in Greece to 55.37% in Spain. Adjusted estimates of the proportion of 4-year-old children with wheeze diagnosed with asthma remained highest in England (38.14%, 95% CI 31.38-44.90%) and lowest in Spain (15.94%, 95% CI 6.16-25.71%). The large differences in prevalence rates of asthma, wheeze and wheeze with asthma at age 4 years between European cohorts may indicate that childhood asthma is more readily diagnosed in some countries while going unrecognised elsewhere.

Understanding changes in dietary intake during puberty could aid the mapping of dietary interventions for primary prevention. The present study describes dietary changes from childhood to adolescence, and their associations with parental education, family income, child education, body mass index (BMI), pubertal onset and screen-time sedentary behaviour.Dietary data (n = 1232) were obtained from food frequency questionnaires at the 10- and 15-year follow-ups of the GINIplus birth cohort study. Intakes of 17 food groups, macronutrients and antioxidant vitamins, were described by a) paired Wilcoxon rank sum tests, comparing average intakes at each time-point, and b) Cohen's kappa "tracking" coefficients, measuring stability of intakes (maintenance of relative tertile positions across time). Further, associations of changes (tertile position increase or decrease vs. tracking) with parental education, family income, child education, pubertal onset, BMI, and screen-time, were assessed by logistic regression and multinomial logistic regression models stratified by baseline intake tertile.Both sexes increased average intakes of water and decreased starchy vegetables, margarine and dairy. Females decreased meat and retinol intakes and increased vegetables, grains, oils and tea. Males decreased fruit and carbohydrates and increased average intakes of meat, caloric drinks, water, protein, fat, polyunsaturated fatty acids (PUFAs), vitamin C and alpha-tocopherol. Both sexes presented mainly "fair" tracking levels [κw = 0.21-0.40]. Females with high (vs. low) parental education were more likely to increase their nut intake [OR = 3.8; 95 % CI = (1.7;8.8)], and less likely to decrease vitamin C intakes [0.2 (0.1;0.5)], while males were less likely to increase egg consumption [0.2 (0.1;0.5)] and n3 PUFAs [0.2 (0.1;0.5)]. Females with a higher (vs. low) family income were more likely to maintain medium wholegrain intakes [0.2 (0.1;0.7) for decrease vs. tracking, and 0.1 (0.0;0.5) for increase vs. tracking], and were less likely to decrease vitamin C intakes [0.2 (0.1;0.6)]. Males with high education were less likely to increase sugar-sweetened foods [0.1 (0.1;0.4)]. Finally, BMI in females was negatively associated with decreasing protein intakes [0.7 (0.6;0.9)]. In males BMI was positively associated with increasing margarine [1.4 (1.1;1.6)] and vitamin C intakes [1.4 (1.1;1.6)], and negatively associated with increasing n3 PUFA.Average dietary intakes changed significantly, despite fair tracking levels, suggesting the presence of trends in dietary behaviour during puberty. Family income and parental education predominantly influenced intake changes. Our results support the rationale for dietary interventions targeting children, and suggest that sex-specific subpopulations, e.g. low socio-economic status, should be considered for added impact.

Impact of neighbourhood on physical activity (PA) is under-investigated in European adolescents, and few studies have used objective data on both exposures and outcomes. Therefore we investigated the association between objectively measured neighbourhood characteristics and PA in 15-year-old German adolescents. Study populations comprised of 688 adolescents residing in the urban Munich area and 504 from the rural Wesel area from the GINIplus and LISAplus birth cohorts. Neighbourhood was defined as a circular 500-m buffer around the residence. Greenness was calculated 1) as the mean Normalized Difference Vegetation Index (NDVI), and 2) as percent tree cover. Neighbourhood green spaces and sport and leisure facilities were defined as present or absent in a neighbourhood (data only available for Munich). Data on PA were collected from one-week triaxial accelerometry (hip-worn ActiGraph GT3X). Minutes of PA were classified into moderate-to-vigorous (MVPA), light and sedentary using Romanzini's et al. triaxial cutoffs, and averaged over the recording period. Activity diaries were used for differentiation between school and leisure (total minus school) PA. Area-specific associations were assessed by adjusted negative binomial regressions. In the Wesel area, residing in a neighbourhood with higher NDVI was associated with 9% more leisure MVPA among females and with 8% more leisure MVPA in rural dwellers. In the Munich area, residing in a neighbourhood with sport facilities was associated with 9% more leisure MVPA. The latter association was only significant in urban dwellers while neighbourhood leisure facilities increased MVPA in rural dwellers. Estimates were very similar when total MVPA was considered rather than solely leisure. There is indication that neighbourhood features could be associated with MVPA in German adolescents. However, different features seem to be important across sexes and in rural/urban settings, which need to be specifically addressed in future studies.

There is some evidence of decreased cardiovascular disease (CVD) mortality and morbidity among adults residing in greener places. Among others, blood lipids are well established risk factors for CVD. In our previous study, we observed the inverse association between greenness and blood pressure in 10-year-old children. In the current study, we investigated whether there is also a link between residential greenness and blood lipids in 10- and 15-year-old children.Complete data on blood lipids (total cholesterol, HDL, LDL and triglyceride), residential greenness (NDVI in 100-m, 300- and 500-m buffers around residences) and confounders were available for 1,552 participants at 10 and 15 years of age, residing in two study areas of two German birth cohorts - GINIplus and LISAplus. Longitudinal associations between NDVI and blood lipids were assessed by generalized estimation equations.No associations were observed between residential greenness in any of the chosen buffers and blood lipids in children (e.g., change in blood lipids per interquartile increase in NDVI in 100-m buffer for total cholesterol and LDL: means ratio=1.00 (95% confidence interval: 0.99-1.01), for triglyceride: 0.98 (0.96-1.00)). No area- or sex-varying effects were evident. Change of the residence between 10 and 15 years also did not yield any consistent associations.There is no evidence of an association between greenness and blood lipids in 10- and 15-years old children.

Assessment of health benefits associated with physical activity depend on the activity duration, intensity and frequency, therefore their correct identification is very valuable and important in epidemiological and clinical studies. The aims of this study are: to develop an algorithm for automatic identification of intended jogging periods; and to assess whether the identification performance is improved when using two accelerometers at the hip and ankle, compared to when using only one at either position.The study used diarized jogging periods and the corresponding accelerometer data from thirty-nine, 15-year-old adolescents, collected under field conditions, as part of the GINIplus study. The data was obtained from two accelerometers placed at the hip and ankle. Automated feature engineering technique was performed to extract features from the raw accelerometer readings and to select a subset of the most significant features. Four machine learning algorithms were used for classification: Logistic regression, Support Vector Machines, Random Forest and Extremely Randomized Trees. Classification was performed using only data from the hip accelerometer, using only data from ankle accelerometer and using data from both accelerometers.The reported jogging periods were verified by visual inspection and used as golden standard. After the feature selection and tuning of the classification algorithms, all options provided a classification accuracy of at least 0.99, independent of the applied segmentation strategy with sliding windows of either 60s or 180s. The best matching ratio, i.e. the length of correctly identified jogging periods related to the total time including the missed ones, was up to 0.875. It could be additionally improved up to 0.967 by application of post-classification rules, which considered the duration of breaks and jogging periods. There was no obvious benefit of using two accelerometers, rather almost the same performance could be achieved from either accelerometer position.Machine learning techniques can be used for automatic activity recognition, as they provide very accurate activity recognition, significantly more accurate than when keeping a diary. Identification of jogging periods in adolescents can be performed using only one accelerometer. Performance-wise there is no significant benefit from using accelerometers on both locations.

Abstract Background Associations between traffic‐related air pollution ( TRAP ) and childhood atopic dermatitis ( AD ) remain inconsistent, possibly due to unexplored gene‐environment interactions. The aim of this study was to examine whether a potential effect of TRAP on AD prevalence in children is modified by selected single nucleotide polymorphisms ( SNP s) related to oxidative stress and inflammation. Methods Doctor‐diagnosed AD up to age 2 years and at 7‐8 years, as well as AD symptoms up to age 2 years, was assessed using parental‐reported questionnaires in six birth cohorts (N = 5685). Associations of nitrogen dioxide ( NO 2 ) estimated at the home address of each child at birth and nine SNP s within the GSTP 1 , TNF , TLR 2 , or TLR 4 genes with AD were examined. Weighted genetic risk scores ( GRS ) were calculated from the above SNP s and used to estimate combined marginal genetic effects of oxidative stress and inflammation on AD and its interaction with TRAP . Results GRS was associated with childhood AD and modified the association between NO 2 and doctor‐diagnosed AD up to the age of 2 years ( P (interaction) = .029). This interaction was mainly driven by a higher susceptibility to air pollution in TNF rs1800629 minor allele (A) carriers. TRAP was not associated with the prevalence of AD in the general population. Conclusions The marginal genetic association of a weighted GRS from GSTP 1 , TNF , TLR 2 , and TLR 4 SNP s and its interaction with air pollution supports the role of oxidative stress and inflammation in AD .

Clinical recommendations to limit gestational weight gain (GWG) imply high GWG is causally related to adverse outcomes in mother or offspring, but GWG is the sum of several inter-related complex phenotypes (maternal fat deposition and vascular expansion, placenta, amniotic fluid and fetal growth). Understanding the genetic contribution to GWG could help clarify the potential effect of its different components on maternal and offspring health. Here we explore the genetic contribution to total, early and late GWG.A genome-wide association study was used to identify maternal and fetal variants contributing to GWG in up to 10 543 mothers and 16 317 offspring of European origin, with replication in 10 660 mothers and 7561 offspring. Additional analyses determined the proportion of variability in GWG from maternal and fetal common genetic variants and the overlap of established genome-wide significant variants for phenotypes relevant to GWG (for example, maternal body mass index (BMI) and glucose, birth weight).Approximately 20% of the variability in GWG was tagged by common maternal genetic variants, and the fetal genome made a surprisingly minor contribution to explain variation in GWG. Variants near the pregnancy-specific beta-1 glycoprotein 5 (PSG5) gene reached genome-wide significance (P=1.71 × 10-8) for total GWG in the offspring genome, but did not replicate. Some established variants associated with increased BMI, fasting glucose and type 2 diabetes were associated with lower early, and higher later GWG. Maternal variants related to higher systolic blood pressure were related to lower late GWG. Established maternal and fetal birth weight variants were largely unrelated to GWG.We found a modest contribution of maternal common variants to GWG and some overlap of maternal BMI, glucose and type 2 diabetes variants with GWG. These findings suggest that associations between GWG and later offspring/maternal outcomes may be due to the relationship of maternal BMI and diabetes with GWG.

More than a million childhood diarrhoeal episodes occur worldwide each year, and in developed countries a considerable part of them are caused by viral infections. In this study, we aimed to search for genetic variants associated with diarrhoeal disease in young children by meta-analyzing genome-wide association studies, and to elucidate plausible biological mechanisms. The study was conducted in the context of the Early Genetics and Lifecourse Epidemiology (EAGLE) consortium. Data about diarrhoeal disease in two time windows (around 1 year of age and around 2 years of age) was obtained via parental questionnaires, doctor interviews or medical records. Standard quality control and statistical tests were applied to the 1000 Genomes imputed genotypic data. The meta-analysis (N = 5758) followed by replication (N = 3784) identified a genome-wide significant association between rs8111874 and diarrhoea at age 1 year. Conditional analysis suggested that the causal variant could be rs601338 (W154X) in the FUT2 gene. Children with the A allele, which results in a truncated FUT2 protein, had lower risk of diarrhoea. FUT2 participates in the production of histo-blood group antigens and has previously been implicated in the susceptibility to infections, including Rotavirus and Norovirus Gene-set enrichment analysis suggested pathways related to the histo-blood group antigen production, and the regulation of ion transport and blood pressure. Among others, the gastrointestinal tract, and the immune and neuro-secretory systems were detected as relevant organs. In summary, this genome-wide association meta-analysis suggests the implication of the FUT2 gene in diarrhoeal disease in young children from the general population.

Low or excessive sleep duration has been associated with multiple outcomes, but the biology behind these associations remains elusive. Specifically, genetic studies in children are scarce. In this study, we aimed to: (1) estimate the proportion of genetic variance of sleep duration in children attributed to common single nucleotide polymorphisms (SNPs), (2) identify novel SNPs associated with sleep duration in children, and (3) investigate the genetic overlap of sleep duration in children and related metabolic and psychiatric traits.We performed a population-based molecular genetic study, using data form the EArly Genetics and Life course Epidemiology (EAGLE) Consortium. 10,554 children of European ancestry were included in the discovery, and 1,250 children in the replication phase.We found evidence of significant but modest SNP heritability of sleep duration in children (SNP h2 0.14, 95% CI [0.05, 0.23]) using the LD score regression method. A novel region at chromosome 11q13.4 (top SNP: rs74506765, P = 2.27e-08) was associated with sleep duration in children, but this was not replicated in independent studies. Nominally significant genetic overlap was only found (rG = 0.23, P = 0.05) between sleep duration in children and type 2 diabetes in adults, supporting the hypothesis of a common pathogenic mechanism.The significant SNP heritability of sleep duration in children and the suggestive genetic overlap with type 2 diabetes support the search for genetic mechanisms linking sleep duration in children to multiple outcomes in health and disease.

Prior studies suggest dental caries traits in children and adolescents are partially heritable, but there has been no large-scale consortium genome-wide association study (GWAS) to date. We therefore performed GWAS for caries in participants aged 2.5–18.0 years from nine contributing centres. Phenotype definitions were created for the presence or absence of treated or untreated caries, stratified by primary and permanent dentition. All studies tested for association between caries and genotype dosage and the results were combined using fixed-effects meta-analysis. Analysis included up to 19 003 individuals (7530 affected) for primary teeth and 13 353 individuals (5875 affected) for permanent teeth. Evidence for association with caries status was observed at rs1594318-C for primary teeth [intronic within ALLC, odds ratio (OR) 0.85, effect allele frequency (EAF) 0.60, P 4.13e-8] and rs7738851-A (intronic within NEDD9, OR 1.28, EAF 0.85, P 1.63e-8) for permanent teeth. Consortium-wide estimated heritability of caries was low [h2 of 1% (95% CI: 0%: 7%) and 6% (95% CI 0%: 13%) for primary and permanent dentitions, respectively] compared with corresponding within-study estimates [h2 of 28% (95% CI: 9%: 48%) and 17% (95% CI: 2%: 31%)] or previously published estimates. This study was designed to identify common genetic variants with modest effects which are consistent across different populations. We found few single variants associated with caries status under these assumptions. Phenotypic heterogeneity between cohorts and limited statistical power will have contributed; these findings could also reflect complexity not captured by our study design, such as genetic effects which are conditional on environmental exposure.

Abstract While the association between early life determinants and the development of the gut microbiome composition in infancy has been widely investigated, a potential persistent influence of early life determinants on the gut microbial community after its stabilization at later childhood remains largely unknown. Therefore, we aimed to identify the association between several early life determinants and the gut microbiome composition in six-year-old children from the LISA birth cohort. A total number of 166 fecal samples were analyzed using 16S rRNA gene-based barcoding to assess bacterial diversity pattern. The bacterial profiles were investigated for their association with maternal smoking during pregnancy, mode of delivery, breastfeeding, antibiotic treatment between one and two years of age, gender and socioeconomic status (SES). While alpha and beta diversity of the infants’ gut microbiome remained unaffected, amplicon sequence variants (ASVs) annotated to Firmicutes and Actinobacteria responded to early life determinants, mostly to feeding practice and antibiotics use. ASVs associated to Bacteriodetes remained unaffected. Our findings indicate that early life determinants could have a long-term sustainable effect on the gut microflora of six-year-old children, however, associations with early life determinates are weaker than reported for infants.

Air pollution has been associated with adverse health effects across the life-course. Although underlying mechanisms are unclear, several studies suggested pollutant-induced changes in transcriptomic profiles. In this meta-analysis of transcriptome-wide association studies of 656 children and adolescents from three European cohorts participating in the MeDALL Consortium, we found two differentially expressed transcript clusters (FDR p < 0.05) associated with exposure to particulate matter < 2.5 µm in diameter (PM2.5) at birth, one of them mapping to the MIR1296 gene. Further, by integrating gene expression with DNA methylation using Functional Epigenetic Modules algorithms, we identified 9 and 6 modules in relation to PM2.5 exposure at birth and at current address, respectively (including NR1I2, MAPK6, TAF8 and SCARA3). In conclusion, PM2.5 exposure at birth was linked to differential gene expression in children and adolescents. Importantly, we identified several significant interactome hotspots of gene modules of relevance for complex diseases in relation to PM2.5 exposure.

Microbial exposures in early childhood direct the development of the immune system and their diversity may influence the risk of allergy development. We aimed to determine whether the indoor microbial diversity at early-life is associated with the development of allergic rhinitis and inhalant atopy. The study population included children within two birth cohorts: Finnish rural-suburban LUKAS (N = 312), and German urban LISA from Munich and Leipzig study centers (N = 248). The indoor microbiota diversity (Chao1 richness and Shannon entropy) was characterized from floor dust samples collected at the child age of 2–3 months by Illumina MiSeq sequencing of bacterial and fungal DNA amplicons. Allergic rhinitis and inhalant atopy were determined at the age of 10 years and analyzed using logistic regression models. High bacterial richness (aOR 0.19, 95%CI 0.09–0.42 for middle and aOR 0.12, 95%CI 0.05–0.29 for highest vs. lowest tertile) and Shannon entropy were associated with lower risk of allergic rhinitis in LISA, and similar trend was seen in LUKAS. We observed some significant associations between bacterial and fungal diversity measured and the risk of inhalant atopy, but the associations were inconsistent between the two cohorts. High bacterial diversity tended to be associated with increased risk of inhalant atopy in rural areas, but lower risk in more urban areas. Fungal diversity tended to be associated with increased risk of inhalant atopy only in LISA. Our study suggests that a higher bacterial diversity may reduce the risk of allergic rhinitis later in childhood. The environment-dependent heterogeneity in the associations with inhalant atopy – visible here as inconsistent results between two differing cohorts - suggests that specific constituents of the diversity may be relevant.

Allergic diseases, especially inhalation allergies, have reached epidemic levels and environmental factors play an important role in their development. Climate change influences the occurrence, frequency, and severity of allergic diseases.The contents of this article were selected by the authors and developed section by section according to their expertise and the current state of knowledge. The sections were then discussed and agreed upon amongst all authors.The article highlights direct and indirect effects of climate change on allergies. It goes into detail about the connections between climate change and (new) pollen allergens as well as (new) occupational inhalation allergens, explains the effects of climate change on the clinical picture of atopic dermatitis, discusses the connections between air pollutants and allergies, and provides information about the phenomenon of thunderstorm asthma.There is a need for action in the field of pollen and fungal spore monitoring, allergy and sensitisation monitoring, urban planning from an allergological perspective, and changes in the working environment, among others.

<h3>Background</h3> The fraction of exhaled nitric oxide (Feno) value is a biomarker of eosinophilic airway inflammation and is associated with childhood asthma. Identification of common genetic variants associated with childhood Feno values might help to define biological mechanisms related to specific asthma phenotypes. <h3>Objective</h3> We sought to identify the genetic variants associated with childhood Feno values and their relation with asthma. <h3>Methods</h3> Feno values were measured in children age 5 to 15 years. In 14 genome-wide association studies (N = 8,858), we examined the associations of approximately 2.5 million single nucleotide polymorphisms (SNPs) with Feno values. Subsequently, we assessed whether significant SNPs were expression quantitative trait loci in genome-wide expression data sets of lymphoblastoid cell lines (n = 1,830) and were related to asthma in a previously published genome-wide association data set (cases, n = 10,365; control subjects: n = 16,110). <h3>Results</h3> We identified 3 SNPs associated with Feno values: rs3751972 in LYR motif containing 9 (<i>LYRM9</i>; <i>P</i> = 1.97 × 10⁻¹⁰) and rs944722 in inducible nitric oxide synthase 2 (<i>NOS2</i>; <i>P</i> = 1.28 × 10⁻⁹), both of which are located at 17q11.2-q12, and rs8069176 near gasdermin B (<i>GSDMB</i>; <i>P</i> = 1.88 × 10⁻⁸) at 17q12-q21. We found a <i>cis</i> expression quantitative trait locus for the transcript soluble galactoside-binding lectin 9 <i>(LGALS9)</i> that is in linkage disequilibrium with rs944722. rs8069176 was associated with <i>GSDMB</i> and ORM1-like 3 <i>(ORMDL3)</i> expression. rs8069176 at 17q12-q21, but not rs3751972 and rs944722 at 17q11.2-q12, were associated with physician-diagnosed asthma. <h3>Conclusion</h3> This study identified 3 variants associated with Feno values, explaining 0.95% of the variance. Identification of functional SNPs and haplotypes in these regions might provide novel insight into the regulation of Feno values. This study highlights that both shared and distinct genetic factors affect Feno values and childhood asthma.

It has been suggested that n-6 and n-3 long-chain polyunsaturated fatty acids (LC-PUFAs) in blood are associated with risk of allergic diseases, although results are inconclusive. Low levels of n-6 LC-PUFA and high levels of n-3 LC-PUFA are anticipated to have beneficial effects. Pregnancy is considered a critical time period for imprinting the developing immune system. We examined whether n-6 LC-PUFA, n-3 LC-PUFA concentrations or the n-6/n-3 ratio in cord blood (CB) serum are associated with allergic diseases up to the age of 10 yr.This analysis included 436 children from the Munich LISAplus birth cohort study. Information on doctor-diagnosed asthma, hay fever/allergic rhinitis, and eczema was collected using questionnaires completed at the ages 6 and 10 yr, and for eczema additionally at 2 yr. Specific immunoglobulin E (IgE) against inhalant allergens was measured at 6 and 10 yr. Fatty acid composition was measured by gas chromatography in serum from CB and from blood collected at 2, 6, and 10 yr. Associations between n-3, n-6 LC-PUFA concentrations, and the n-6/n-3 ratio in CB serum and allergic diseases or atopy were assessed using generalized estimating equations (GEE) considering the longitudinal structure. Models were adjusted for LC-PUFA concentrations at follow-up and potential confounding factors.There was no significant association between n-3 LC-PUFA, n-6 LC-PUFA, or the n-6/n-3 ratio in CB serum with eczema, asthma, hay fever/allergic rhinitis, or aeroallergen sensitization.There is no indication of a beneficial effect of increased n-3 LC-PUFA in CB serum on the development of any of the disease entities.

Depression has been associated with air pollution, as reported by animal and epidemiological studies. However, the relationship between ozone exposure and depression, especially among adolescents, is scarcely investigated.The study aimed to analyze associations between ozone exposure and depressive symptoms among German adolescents.The analyses were based on 2827 adolescents aged 15 from Munich and Wesel areas of the GINIplus and LISA birth cohorts. The depressive symptoms were assessed by the Depression Screener for Teenagers (DesTeen). Long-term ozone exposure was estimated by optimal interpolation techniques and assigned to home addresses. Nitrogen dioxide (NO2) and particulate matter with an aerodynamic diameter < 10 µm (PM10) were assessed by land use regression models. For short-term exposure, maximum 8-h averages of ozone and daily average concentrations of NO2 and PM10 from the background monitoring sites 0 (same day), 1, 2, 3, and 7 days prior to depressive symptoms assessment were adopted. The cross-sectional analyses were conducted by adjusted logistic regression models controlling for residuals of NO2 and PM10, and covariates identified by a directed acyclic graph.The prevalence of depressive symptoms ranged from 10.9% to 13.8% depending on regions. Overall, long- and short-term exposure to ozone were not statistically significantly associated with depressive symptoms. However, subgroup analysis showed inconsistent significant protective associations for short-term exposure to ozone lag 0 day (same day) and depressive symptoms in Wesel (OR = 0.76, 95% CI: (0.59, 0.98)), but not in Munich (OR = 1.00, 95% CI: (0.83, 1.21)).Our study does not support the hypothesis that ambient ozone exposure might increase the prevalence of depressive symptoms in German adolescents. Nevertheless, due to a lack of similar studies, these results need to be replicated in other samples.

Increasing evidence suggests adults living in greener areas tend to have more favourable sleep-related outcomes, but children and adolescents are under-researched. We hypothesised that children and adolescents living in greener areas would have better quality and more sufficient levels of sleep on average, especially within the context of high traffic noise exposure. These hypotheses were tested using multilevel logistic regressions fitted on samples from the nationally representative Longitudinal Study of Australian Children (10–11 years old, n = 3469, and 14–15 years old, n = 2814) and the GINIplus and LISA cohorts (10 years old, n = 1461, and 15 years old, n = 4172) from the Munich, Wesel, and Leipzig areas of Germany. Questionnaire-based binary indicators of sleep sufficiency and sleep quality in each cohort were assessed with respect to objectively measured green space exposures adjusting for age, sex, and maternal education. Models were augmented with proxy measures of traffic noise and two-way interaction terms to test for effect modification. Cross-tabulations illustrated little convincing evidence of association between green space and insufficient sleep or poor sleep quality in either sample, except for insufficient sleep among 10 year old participants in Germany. These null findings were replicated in adjusted models. The proxy for traffic noise was associated with poor quality sleep in 15 year old participants in Germany, but no convincing evidence of modified association with green space was observed.

Allergic diseases often develop jointly during early childhood but differ in timing of onset, remission, and progression. Their disease course over time is often difficult to predict and determinants are not well understood.We aimed to identify trajectories of allergic diseases up to adolescence and to investigate their association with early-life and genetic determinants and clinical characteristics.Longitudinal k-means clustering was used to derive trajectories of allergic diseases (asthma, atopic dermatitis, and rhinitis) in two German birth cohorts (GINIplus/LISA). Associations with early-life determinants, polygenic risk scores, food and aeroallergen sensitization, and lung function were estimated by multinomial models. The results were replicated in the independent Swedish BAMSE cohort.Seven allergic disease trajectories were identified: "Intermittently allergic," "rhinitis," "early-resolving dermatitis," "mid-persisting dermatitis," "multimorbid," "persisting dermatitis plus rhinitis," and "early-transient asthma." Family history of allergies was more prevalent in all allergic disease trajectories compared the non-allergic controls with stronger effect sizes for clusters comprising more than one allergic disease (e.g., RRR = 5.0, 95% CI = [3.1-8.0] in the multimorbid versus 1.8 [1.4-2.4] in the mild intermittently allergic cluster). Specific polygenic risk scores for single allergic diseases were significantly associated with their relevant trajectories. The derived trajectories and their association with genetic effects and clinical characteristics showed similar results in BAMSE.Seven robust allergic clusters were identified and showed associations with early life and genetic factors as well as clinical characteristics.

Summary Background The association between dietary fatty acid intake and the development of atopic diseases has been inconsistent. This could be due to inter‐individual genetic differences in fatty acid metabolism. Objective The aim of the current study was to assess the influence of FADS1 FADS2 gene cluster polymorphisms on the association between dietary fatty acid intake and atopic diseases and allergic sensitization in 10‐year‐old children. Methods The analysis was based on data from two German prospective birth cohort studies. Data on margarine and fatty acid intake were collected using a food frequency questionnaire. Information on atopic diseases was collected using a questionnaire completed by the parents. Specific IgE against common food and inhalant allergens were measured. Six variants of the FADS1 FADS2 gene cluster (rs174545, rs174546, rs174556, rs174561, rs174575 and rs3834458) were tested. Logistic regression modelling, adjusted for gender, age, maternal education level and study centre, was used to analyse the association between fatty acid intake and atopic diseases stratified by genotype. Results No significant association was found between the six FADS single nucleotide polymorphisms (SNPs) and allergic diseases or atopic sensitization. The total n‐3/total n‐6 ratio was positive associated with an increased risk of hayfever in homozygous major allele carriers ranging from an adjusted odds ratios of 1.25 (95%‐CI: 1.00–1.57) to 1.31 (95%‐CI: 1.01–1.69) across the six tested SNPs although this association was not significant anymore after correcting for multiple testing. Daily margarine intake was significantly associated with asthma [1.17 (1.03–1.34) to 1.22 (1.06–1.40)] in individuals carrying the homozygous major allele. This association was also significant after correcting for multiple testing. Conclusions &amp; Clinical Relevance The association between dietary intake of fatty acids and allergic diseases might be modulated by FADS gene variants in children. Cite this as : M. Standl, S. Sausenthaler, E. Lattka, S. Koletzko, C.‐P. Bauer, H.‐E. Wichmann, A. von Berg, D. Berdel, U. Krämer, B. Schaaf, S. Röder, O. Herbarth, N. Klopp, B. Koletzko and J. Heinrich for the GINIplus and LISAplus Study Group, Clinical &amp; Experimental Allergy , 2011 (41) 1757–1766.

The public health burden of hypertension is high, but its relationship with long-term residential air pollution, road traffic, and greenness remains unclear.To investigate associations between residential air pollution, traffic, greenness, and hypertension among mothers.Information on doctor-diagnosed maternal hypertension was collected at the 15-year follow-up of two large population-based multicenter German birth cohorts-GINIplus and LISAplus (n=3063). Residential air pollution was modelled by land use regression models within the ESCAPE and universal kriging within the APMoSPHERE projects. Road traffic was defined as traffic load on major roads within a 100-m buffer around residences. Vegetation level (ie, greenness) was defined as the mean Normalized Difference Vegetation Index in a 500-m buffer around residences and was assessed from Landsat 5 TM satellite images. All the exposure variables were averaged over three residential addresses during the last 10 years and categorized into tertiles or dichotomized. The individual associations between each of the exposure variables and hypertension were assessed using logistic regression analysis.No significant and consistent associations across different levels of adjustment were observed between the exposures of interest and hypertension. The only significant estimate was found with coarse particulate matter concentrations (OR 1.66, 95% CI 1.01 to 2.74; 3rdvs 1st tertile) among mothers residing in the Wesel area. No significant associations were observed with traffic load or greenness.This study does not provide evidence on detrimental effects of air pollution and road traffic or beneficial effects of greenness on hypertension among German adults.

While exposure to ambient particulate matter (PM) and nitrogen dioxide (NO2) is thought to be associated with diseases via inflammatory response, the association between exposure to ozone, an oxidative pollutant, and inflammation has been less investigated.We analyzed associations between short-term exposure to ozone and three inflammatory biomarkers among children and adolescents.These cross-sectional analyses were based on two follow-ups of the GINIplus and LISA German birth cohorts. We included 1330 10-year-old and 1591 15-year-old participants. Fractional exhaled nitric oxide (FeNO) and high-sensitivity C-reactive protein (hs-CRP) were available for both age groups while interleukin (IL)-6 was measured at 10 years only. Maximum 8-h averages of ozone and daily average concentrations of NO2 and PM with an aerodynamic diameter <10 μm (PM10) were adopted from two background monitoring stations 0 (same day), 1, 2, 3, 5, 7, 10 and 14 days prior to the FeNO measurement or blood sampling. To assess associations, we utilized linear regression models for FeNO, and logistic regressions for IL-6 and hs-CRP, adjusting for potential covariates and co-pollutants NO2 and PM10.We found that short-term ozone exposure was robustly associated with higher FeNO in adolescents at age 15, but not at age 10. No consistent associations were observed between ozone and IL-6 in children aged 10 years. The relationship between hs-CRP levels and ozone was J-shaped. Relatively low ozone concentrations (e.g., <120 μg/m³) were associated with reduced hs-CRP levels, while high concentrations (e.g., ≥120 μg/m³) tended to be associated with elevated levels for both 10- and 15-year-old participants.Our study demonstrates significant associations between short-term ozone exposure and FeNO at 15 years of age and a J-shaped relationship between ozone and hs-CRP. The finding indicates that high ozone exposure may favor inflammatory responses in adolescents, especially regarding airway inflammation.

Previous genome-wide association studies revealed multiple common variants involved in eczema but the role of rare variants remains to be elucidated. Here, we investigate the role of rare variants in eczema susceptibility. We meta-analyze 21 study populations including 20,016 eczema cases and 380,433 controls. Rare variants are imputed with high accuracy using large population-based reference panels. We identify rare exonic variants in DUSP1, NOTCH4, and SLC9A4 to be associated with eczema. In DUSP1 and NOTCH4 missense variants are predicted to impact conserved functional domains. In addition, five novel common variants at SATB1-AS1/KCNH8, TRIB1/LINC00861, ZBTB1, TBX21/OSBPL7, and CSF2RB are discovered. While genes prioritized based on rare variants are significantly up-regulated in the skin, common variants point to immune cell function. Over 20% of the single nucleotide variant-based heritability is attributable to rare and low-frequency variants. The identified rare/low-frequency variants located in functional protein domains point to promising targets for novel therapeutic approaches to eczema.

Abstract Background Epigenomic (e.g., DNA methylation [DNAm]) changes have been hypothesized as intermediate step linking environmental exposures with allergic disease. Associations between individual DNAm at CpGs and allergic diseases have been reported, but their joint predictive capability is unknown. Methods Data were obtained from 240 children of the German LISA cohort. DNAm was measured in blood clots at 6 ( N = 234) and 10 years ( N = 227) using the Illumina EPIC chip. Presence of aeroallergen sensitization was measured in blood at 6, 10, and 15 years. We calculated six methylation risk scores (MRS) for allergy‐related phenotypes, like total and specific IgE, asthma, or any allergies, based on available publications and assessed their performances both cross‐sectionally (biomarker) and prospectively (predictor of the disease). Dose–response associations between aeroallergen sensitization and MRS were evaluated. Results All six allergy‐related MRS were highly correlated ( r &gt; .86), and seven CpGs were included in more than one MRS. Cross‐sectionally, we observed an 81% increased risk for aeroallergen sensitization at 6 years with an increased MRS by one standard deviation (best‐performing MRS, 95% confidence interval = [43%; 227%]). Significant associations were also seen cross‐sectionally at 10 years and prospectively, though the effect of the latter was attenuated when restricted to participants not sensitized at baseline. A clear dose–response relationship with levels of aeroallergen sensitization could be established cross‐sectionally, but not prospectively. Conclusion We found good classification and prediction capabilities of calculated allergy‐related MRS cross‐sectionally, underlining the relevance of altered gene‐regulation in allergic diseases and providing insights into potential DNAm biomarkers of aeroallergen sensitization.

This study aimed to assess the association of changes in sleep behaviors from adolescence to young adulthood with the risk of overweight/obesity, and the reverse relationship.Data of 1978 participants was obtained from the 15- and 20-year follow-ups of the GINIplus and LISA birth cohorts. Insufficient sleep was defined as reported sleep duration <8 h for adolescents, <7 h for adults, and sleep difficulties as reported having sleeping difficulties. Logistic regression models were used to assess bidirectional associations of changes in insufficient sleep and sleep difficulties with overweight/obesity. The polygenic risk scores (PRS) for body mass index (BMI) was tested in a sub-sample (n = 918).Compared with sufficient sleep in both adolescence and young adulthood, insufficient sleep only in young adulthood was associated with an increased risk of overweight/obesity (odds ratio = 1.85, 95%confidence interval = [1.27-2.69]). Compared with no sleep difficulties at both time-points, only persistent sleep difficulties was associated with a higher risk of overweight/obesity (2.15 [1.22-3.77]). The PRS for BMI was associated with overweight/obesity (1.41 [1.17-1.70]), but no significant gene-sleep interaction effect was observed. Reversely, only persistent overweight/obesity was associated with increased risks of insufficient sleep (1.81 [1.21-2.70]), and sleep difficulties (1.77 [1.18-2.66]), respectively.Insufficient sleep only presented a cross-sectional association with overweight/obesity in young adulthood, while long-term sleep difficulties from adolescence to young adulthood was associated with young adult overweight/obesity. Reversely, long-term overweight/obesity from adolescence to young adulthood was associated with insufficient sleep and sleep difficulties in young adulthood.

To describe regional differences between eastern and western Germany with regard to food, nutrient and supplement intake in 9-12-year-old children, and analyse its association with parental education and equivalent income.Data were obtained from the 10-year follow-up of the two prospective birth cohort studies - GINIplus and LISAplus. Data on food consumption and supplement intake were collected using an FFQ, which had been designed for the specific study population. Information on parental educational level and equivalent income was derived from questionnaires. Logistic regression modelling was used to analyse the effect of parental education, equivalent income and region on food intake, after adjusting for potential confounders.Germany.A total of 3435 children aged 9-12 years.Substantial regional differences in food intake were observed between eastern and western Germany. Intakes of bread, butter, eggs, pasta, vegetables/salad and fruit showed a significant direct relationship with the level of parental education after adjusting for potential confounders, whereas intakes of margarine, meat products, pizza, desserts and soft drinks were inversely associated with parental education. Equivalent income had a weaker influence on the child's food intake.Nutritional education programmes for school-age children should therefore account for regional differences and parental education.

Primary school years seem to represent a critical period for the development of overweight and obesity. However, only a few studies have analysed the prospective relationship between dietary patterns and weight status in children. The aims of the present study were to identify dietary patterns at the beginning of and during the primary school period and to examine their relevance to the development of body composition. Nutritional and anthropometric data from 371 participants of the Dortmund Nutritional and Longitudinally Designed (DONALD) Study at the beginning (ages 6 and 7 years) and end (ages 10 and 11 years) of the primary school period were used. Principal component analyses (PCA) were conducted to identify dietary patterns, which were regressed on changes in BMI and fat mass index (FMI) between ages 6 and 7 years and ages 10 and 11 years. Reduced rank regression (RRR) was used to directly extract patterns explaining variation in changes in BMI and FMI between ages 6 and 7 years and ages 10 and 11 years. PCA yielded interpretable patterns of dietary changes at the beginning of and during the primary school period, which were not related to changes in body composition. Conversely, RRR allowed identifying predictive patterns: higher baseline intakes of white bread and lower baseline intakes of whole-grain products as well as increases in the consumption of savoury snacks, sausages and cheese during primary school years independently predicted increases in BMI and FMI during the primary school period. In conclusion, selection of unfavourable carbohydrate sources at the beginning of the primary school period and increases in the consumption of processed savoury foods during primary school years may adversely affect the development of body composition during the course of primary school.

We investigated whether families with lower individual-level socioeconomic status (SES) reside in less green neighbourhoods in four areas in Germany. Data were collected within two German birth cohorts – GINIplus and LISAplus. Net equivalent household income was categorized into study area-specific tertiles and used as a proxy for individual-level SES. Neighbourhood greenness was calculated in 500-m buffers around home addresses as: 1) the mean normalized difference vegetation index (NDVI); 2) percent tree cover. Associations between income and neighbourhood greenness were assessed per study area using adjusted linear regression models. In the Munich and Leipzig areas, families in the low and medium income tertiles resided in neighbourhoods with lower NDVI compared to those in the high income tertile (mean percent change in NDVI: −4.0 (95% confidence interval = −6.7 to −1.3) and −5.5 (−10.9 to −0.2), respectively). In contrast, in the Wesel area, families in the low income tertile resided in neighbourhoods with higher NDVI (2.9 (0.5–5.3)). Only the association in the Munich area was replicated when using tree cover instead of the NDVI. This study provides suggestive evidence that the presence and direction of associations between greenness and SES is region-specific in Germany. The degree of urbanization did not clarify this heterogeneity completely.

We integratively assessed the effect of different indoor and outdoor environmental exposures early in life on respiratory and allergic health conditions among children from (sub-) urban areas. This study included children participating in four ongoing European birth cohorts located in three different geographical regions: INMA (Spain), LISAplus (Germany), GINIplus (Germany) and BAMSE (Sweden). Wheezing, bronchitis, asthma and allergic rhinitis throughout childhood were assessed using parental-completed questionnaires. We designed “environmental scores” corresponding to different indoor, green- and grey-related exposures (main analysis, a-priori-approach). Cohort-specific associations between these environmental scores and the respiratory health outcomes were assessed using random-effects meta-analyses. In addition, a factor analysis was performed based on the same exposure information used to develop the environmental scores (confirmatory analysis, data-driven-approach). A higher early exposure to the indoor environmental score increased the risk for wheezing and bronchitis within the first year of life (combined adjusted odds ratio: 1.20 [95% confidence interval: 1.13–1.27] and 1.28 [1.18–1.39], respectively). In contrast, there was an inverse association with allergic rhinitis between 6 and 8 years (0.85 [0.79–0.92]). There were no statistically significant associations for the outdoor related environmental scores in relation to any of the health outcomes tested. The factor analysis conducted confirmed these trends. Although a higher exposure to indoor related exposure through occupants was associated with an increased risk for wheezing and bronchitis within the 1st year, it might serve as a preventive mechanism against later childhood allergic respiratory outcomes in urbanized environments through enhanced shared contact with microbial agents.

High dietary acid load may have detrimental effects on mental health during childhood and adolescence. We examined cross-sectional and prospective associations of dietary acid load and mental health problems in a population-based sample, using data from the German birth cohort studies GINIplus (German Infant Nutritional Intervention plus environmental and genetic influences on allergy development) and LISA (Influences of lifestyle-related factors on the immune system and the development of allergies in childhood). These studies included detailed assessments of dietary intake through a food frequency questionnaire (FFQ), mental health outcomes measured through the Strengths and Difficulties Questionnaire (SDQ), and covariates. Using logistic regression, cross-sectional associations between dietary acid load measured as potential renal acid load (PRAL) and SDQ subscales were assessed at age 10 years (N = 2350) and 15 years (N = 2061). Prospective associations were assessed, considering PRAL at 10 years as exposure and SDQ subscales at 15 years as outcome (N = 1685). Results indicate that children with a diet higher in PRAL have more emotional problems (OR = 1.33 (95% CI = 1.15; 1.54); p < 0.001), and show hyperactivity more often (1.22 (1.04; 1.43); p = 0.014) at 10 years. No significant associations were present either cross-sectionally at age 15 years, nor prospectively. Results were confirmed in sensitivity analyses. These findings reveal first evidence for potential relationships between PRAL and mental health in childhood, although we cannot exclude reverse causality, i.e., that dietary behavior and PRAL are influenced by mental status. Future studies should address confirmation and identify biological mechanisms.