Michael Schallert

Anna Köttgen and colleagues report genome-wide association studies for serum urate in over 140,000 individuals from the Global Urate Genetics Consortium (GUGC). They identify 18 loci newly associated with serum urate concentrations and confirm 10 known loci, characterize their associations with gout and include a network analysis suggesting a role for inhibins-activins pathways in regulating urate homeostasis. Elevated serum urate concentrations can cause gout, a prevalent and painful inflammatory arthritis. By combining data from >140,000 individuals of European ancestry within the Global Urate Genetics Consortium (GUGC), we identified and replicated 28 genome-wide significant loci in association with serum urate concentrations (18 new regions in or near TRIM46, INHBB, SFMBT1, TMEM171, VEGFA, BAZ1B, PRKAG2, STC1, HNF4G, A1CF, ATXN2, UBE2Q2, IGF1R, NFAT5, MAF, HLF, ACVR1B-ACVRL1 and B3GNT4). Associations for many of the loci were of similar magnitude in individuals of non-European ancestry. We further characterized these loci for associations with gout, transcript expression and the fractional excretion of urate. Network analyses implicate the inhibins-activins signaling pathways and glucose metabolism in systemic urate control. New candidate genes for serum urate concentration highlight the importance of metabolic control of urate production and excretion, which may have implications for the treatment and prevention of gout.

To examine the association between plasma concentrations of antioxidative micronutrients and leukocyte telomere length (LTL) in elderly adults.Cross-sectional cohort study.Austrian Stroke Prevention Study, a population-based cohort study on brain aging.Individuals with a mean age of 66 ± 7 (n = 786; 58% female).Concentrations of vitamin C, lutein, zeaxanthin, β-cryptoxanthin, canthaxanthin, lycopene, α- and γ-tocopherol, α- and β-carotene, and retinol in plasma, advanced oxidation protein products as a measure of oxidative stress in serum, and LTL were measured. Vitamins and carotenoids were measured using high-performance liquid chromatography, advanced oxidation protein products using spectrophotometry, and telomere length using quantitative real-time polymerase chain reaction.Multiple linear regression analyses with adjustment for age and sex demonstrated that higher lutein, zeaxanthin, and vitamin C concentrations were strongly associated with longer telomere length. The associations were independent of body mass index, maximum oxygen uptake, and vascular risk factors and were not mediated by advanced oxidation protein products content.This study provides first evidence that higher lutein, zeaxanthin, and vitamin C concentrations in plasma are associated with longer LTL in normal elderly persons and suggest a protective role of these vitamins in telomere maintenance.

Physical activity and cardiorespiratory fitness relate to better cognitive performance. Little is known about the effects of fitness on structural brain abnormalities in the elderly.Assess the association between maximal oxygen consumption (VO(2)max), white matter lesion (WML) volume and brain parenchymal fraction (BPF) in a large cohort of community-dwelling elderly individuals.The study population consisted of 715 participants of the Austrian Stroke Prevention Study who underwent brain MRI with semi-automated measurement of WML volume (cm(3)) and automated assessment of BPF (%) by the use of SIENAX. A maximal exercise stress test was done on a bicycle ergometer. VO(2)max was calculated based on maximum and resting heart rate.After adjustment for possible confounders, VO(2)max was independently associated with WML volume (β = -0.10; p = 0.02); no significant relationship existed with silent cerebral infarcts and BPF. Associations between VO(2)max and WML load were only significant in men, but not in women.Our findings may have important preventive implications because WMLs are known to be a major determinant of cognitive decline and disability in old age.

Ischemic stroke (IS) shares many common risk factors with coronary artery disease (CAD). We hypothesized that genetic variants associated with myocardial infarction (MI) or CAD may be similarly involved in the etiology of IS. To test this hypothesis, we evaluated whether single-nucleotide polymorphisms (SNPs) at 11 different loci recently associated with MI or CAD through genome-wide association studies were associated with IS.Meta-analyses of the associations between the 11 MI-associated SNPs and IS were performed using 6865 cases and 11 395 control subjects recruited from 9 studies. SNPs were either genotyped directly or imputed; in a few cases a surrogate SNP in high linkage disequilibrium was chosen. Logistic regression was performed within each study to obtain study-specific βs and standard errors. Meta-analysis was conducted using an inverse variance weighted approach assuming a random effect model.Despite having power to detect odds ratio of 1.09-1.14 for overall IS and 1.20-1.32 for major stroke subtypes, none of the SNPs were significantly associated with overall IS and/or stroke subtypes after adjusting for multiple comparisons.Our results suggest that the major common loci associated with MI risk do not have effects of similar magnitude on overall IS but do not preclude moderate associations restricted to specific IS subtypes. Disparate mechanisms may be critical in the development of acute ischemic coronary and cerebrovascular events.

Abstract Aim This study examined the impact of fluctuations in metabolic control on the intelligence quotient ( IQ ) of children and adolescents with early, continuously treated phenylketonuria ( PKU ). Methods This was a clinic‐based study carried out at University Hospital Munster, Germany, from 2015 to 2017. We investigated 49 patients (28 boys) with early treated PKU , who were aged 6–18 years with a mean age of 11.2 ± 4.1 years. All the patients were on a continuous phenylalanine‐restricted diet. Of the 49 patients, 29 (18 boys) had classic PKU and 21 patients (11 girls) had mild PKU . The patients’ blood phenylalanine levels were assessed every week for 26 weeks and analysed for fluctuations, indicated by the standard deviation of the individual blood phenylalanine levels. We also assessed the concurrent Full Scale IQ ( FSIQ ) of the patients. Results In patients with classic PKU , FSIQ was negatively correlated with blood phenylalanine levels, but not with level fluctuations. In patients with mild PKU , FSIQ was not correlated with blood phenylalanine levels, but was negatively correlated with level fluctuations. Conclusion The blood phenylalanine levels of patients with mild PKU showed minor interindividual differences, which may have allowed fluctuations to exert a negative effect on the FSIQ .