Greta Lee Splansky

For nearly 60 years, the Framingham Heart Study has examined the natural history, risk factors, and prognosis of cardiovascular, lung, and other diseases. Recruitment of the Original Cohort began in 1948. Twenty-three years later, 3,548 children of the Original Cohort, along with 1,576 of their spouses, enrolled in the Offspring Cohort. Beginning in 2002, 4,095 adults having at least one parent in the Offspring Cohort enrolled in the Third Generation Cohort, along with 103 parents of Third Generation Cohort participants who were not previously enrolled in the Offspring Cohort. The objective of new recruitment was to complement phenotypic and genotypic information obtained from prior generations, with priority assigned to larger families. From a pool of 6,553 eligible individuals, 1,912 men and 2,183 women consented and attended the first examination (mean age: 40 (standard deviation: 9) years; range: 19-72 years). The examination included clinical and laboratory assessments of vascular risk factors and imaging for subclinical atherosclerosis, as well as assessment of cardiac structure and function. The comparison of Third Generation Cohort data with measures previously collected from the first two generations will facilitate investigations of genetic and environmental risk factors for subclinical and overt diseases, with a focus on cardiovascular and lung disorders.

To relate cancer since entry into the Framingham Heart Study with the risk of incident Alzheimer's disease and to estimate the risk of incident cancer among participants with and without Alzheimer's disease.Community based prospective cohort study; nested age and sex matched case-control study.Framingham Heart Study, USA.1278 participants with and without a history of cancer who were aged 65 or more and free of dementia at baseline (1986-90).Hazard ratios and 95% confidence intervals for the risks of Alzheimer's disease and cancer.Over a mean follow-up of 10 years, 221 cases of probable Alzheimer's disease were diagnosed. Cancer survivors had a lower risk of probable Alzheimer's disease (hazard ratio 0.67, 95% confidence interval 0.47 to 0.97), adjusted for age, sex, and smoking. The risk was lower among survivors of smoking related cancers (0.26, 0.08 to 0.82) than among survivors of non-smoking related cancers (0.82, 0.57 to 1.19). In contrast with their decreased risk of Alzheimer's disease, survivors of smoking related cancer had a substantially increased risk of stroke (2.18, 1.29 to 3.68). In the nested case-control analysis, participants with probable Alzheimer's disease had a lower risk of subsequent cancer (0.39, 0.26 to 0.58) than reference participants, as did participants with any Alzheimer's disease (0.38) and any dementia (0.44).Cancer survivors had a lower risk of Alzheimer's disease than those without cancer, and patients with Alzheimer's disease had a lower risk of incident cancer. The risk of Alzheimer's disease was lowest in survivors of smoking related cancers, and was not primarily explained by survival bias. This pattern for cancer is similar to that seen in Parkinson's disease and suggests an inverse association between cancer and neurodegeneration.

The extent to which co-occurrence of cardiovascular disease (CVD) and cancer is due to shared risk factors or other mechanisms is unknown.We investigated the association of standard CVD risk factors, CVD biomarkers, preexisting CVD, and ideal CV health metrics with the development of future cancer.We prospectively followed Framingham Heart Study and PREVEND participants free of cancer at baseline, and ascertained histology-proven cancer. We studied the association of baseline CV risk factors, 10-year atherosclerotic CVD risk score, established CVD biomarkers, prevalent CVD, and AHA Life's Simple 7 CV health score with incident cancer using multivariable Cox models. Analyses of interim CVD events with incident cancer used time-dependent covariates.Among 20,305 participants (mean age 50 ± 14 years, 54% women), 2,548 incident cancer cases occurred over a median follow-up of 15.0 (13.3-15.0) surveillance years. Traditional CVD risk factors including age, sex, and smoking status were independently associated with cancer (P <0.001 for all). Estimated 10-year atherosclerotic CVD risk was also associated with future cancer (HR 1.16 per 5% increase in risk, 95% CI 1.14-1.17, P<0.001). We found that natriuretic peptides (NP) (tertile 3 vs 1: HR 1.40, 95% CI 1.03-1.91, p=0.035) was associated with incident cancer, but not high sensitivity troponin (hs-cTn) (p=0.47). Prevalent CVD and the development of interim CV events were not associated with higher risk of subsequent cancer. However, ideal CV health was associated with lower future cancer risk (HR 0.95 per 1-point increase in AHA health score, 95% CI 0.92-0.99, p=0.009).CVD risk as captured by traditional CVD risk factors, 10-year atherosclerotic CVD risk score, and NP concentrations are associated with increased risk of future cancer. Conversely, a heart healthy lifestyle is associated with a reduced risk of future cancer. Our data suggest that the association between CVD and future cancer is attributable to shared risk factors.

We examined the relation between central body fat distribution and breast cancer in a prospective cohort of women who participated in the Framingham Study. At the baseline examination in 1948, a total of 2,201 women aged 30-62 years were analyzed. An index of central to peripheral body fat (the central adiposity ratio) was calculated from the sum of the trunkal skinfolds (chest, subscapular, and abdominal) divided by the sum of the extremity skinfolds (triceps and thigh). These skinfolds were measured at the fourth examination in 1954. The cohort was followed for up to 28 years and yielded 106 cases of breast cancer. When divided into quartiles based on the central adiposity ratio, only women in the fourth quartile (those with the highest central to peripheral body fat distribution) demonstrated an increased risk for breast cancer. The age- and adiposity-adjusted relative risk estimate for having an increased central adiposity ratio (fourth quartile) compared to lower central adiposity ratios was 1.8 (95% confidence interval, 1.2-2.6). Adjustment for potential confounders of height, parity, and education did not appreciably alter this estimate (1.7, 1.1-2.5). There was no association between degree of adiposity, as measured by the sum of the five skinfolds or by body mass index (weight in kg divided by height in m2), and subsequent breast cancer. The results of this study suggest that increased central to peripheral body fat distribution predicts breast cancer risk independently of the degree of adiposity and may be a more specific marker of a premalignant hormonal pattern than degree of adiposity.

The authors analyzed data from the Framingham Heart Study to evaluate the association between physical activity and breast cancer risk. Physical activity was as certained by a physician-administered questionnaire from 2,321 women at the fourth biennial examination conducted in 1954–1956. Breast cancers were identified by self- report, surveillance of admissions to Framingham Union Hospital, and review of death records; all but one were histologically confirmed. During 28 years of follow-up, 117 breast cancer cases were diagnosed among the 2,307 women with data on physical activity and reproductive history (a potential confounder). Analysis was performed using Cox proportional hazards models with age as the underlying time variable. Models were adjusted for age at physical actMty assessment, menopausal status, age at first preg nancy, parity, education, occupation, and alcohol ingestion. We observed a gradient of increasing risk of breast cancer with increasing physical activity (trend p = 0.06). The relative risk for women in the highest versus lowest activity quartile was 1.6 (95% confidence interval 0.9–3.0; p = 0.13). Although both moderate-to-heavy leisure and occupational activities were associated with an increased risk, the association was marginally significant only for leisure activity (p = 0.06). Our findings do not support a protective effect of physical activity during adulthood for breast cancer, but suggest an increased risk among more active women.

Breast and prostate cancer are two commonly diagnosed cancers in the United States. Prior work suggests that cancer causing genes and cancer susceptibility genes can be identified.We conducted a genome-wide association study (Affymetrix 100K SNP GeneChip) of cancer in the community-based Framingham Heart Study. We report on 2 cancer traits--prostate cancer and breast cancer--in up to 1335 participants from 330 families (54% women, mean entry age 33 years). Multivariable-adjusted residuals, computed using Cox proportional hazards models, were tested for association with qualifying SNPs (70, 987 autosomal SNPs with genotypic call rate > or =80%, minor allele frequency > or =10%, Hardy-Weinberg test p > or = 0.001) using generalized estimating equations (GEE) models and family based association tests (FBAT).There were 58 women with breast cancer and 59 men with prostate cancer. No SNP associations attained genome-wide significance. The top SNP associations in GEE models for each trait were as follows: breast cancer, rs2075555, p = 8.0 x 10(-8) in COL1A1; and prostate cancer, rs9311171, p = 1.75 x 10(-6) in CTDSPL. In analysis of selected candidate cancer susceptibility genes, two MSR1 SNPs (rs9325782, GEE p = 0.008 and rs2410373, FBAT p = 0.021) were associated with prostate cancer and three ERBB4 SNPs (rs905883 GEE p = 0.0002, rs7564590 GEE p = 0.003, rs7558615 GEE p = 0.0078) were associated with breast cancer. The previously reported risk SNP for prostate cancer, rs1447295, was not included on the 100K chip. Results of cancer phenotype-genotype associations for all autosomal SNPs are web posted at http://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?id=phs000007 webcite.Although no association attained genome-wide significance, several interesting associations emerged for breast and prostate cancer. These findings can serve as a resource for replication in other populations to identify novel biologic pathways contributing to cancer susceptibility.

This chapter provides an introduction to the Framingham Heart Study and the genetic research related to cardiovascular diseases conducted in this unique population. It briefly describes the origins of the study, the risk factors that contribute to heart disease, and the approaches taken to discover the genetic basis of some of these risk factors. The genetic architecture of several biological risk factors has been explained using family studies, segregation analysis, heritability, and phenotypic and genetic correlations. Many quantitative trait loci underlying cardiovascular diseases have been discovered using different molecular markers. Additionally, initial results from genome-wide association studies using 116,000 markers and the prospects of using 550,000 markers for association studies are presented. Finally, the use of this unique sample to study genotype and environment interactions is described.

To evaluate the value of serial C-reactive protein (CRP) measurements in predicting the risk of cardiovascular disease (CVD), cancer, and mortality.The analysis was performed using data from two prospective, population-based observational cohorts: the Prevention of Renal and Vascular End-Stage Disease (PREVEND) study and the Framingham Heart Study (FHS). A total of 9253 participants had CRP measurements available at two examinations (PREVEND: 1997-1998 and 2001-2002; FHS Offspring cohort: 1995-1998 and 1998-2001). All CRP measurements were natural log-transformed before analyses. Cardiovascular disease included fatal and nonfatal cardiovascular, cerebrovascular and peripheral vascular events, and heart failure. Cancer included all malignancies except nonmelanoma skin cancers.The mean age of the study population at baseline was 52.4±12.1 years and 51.2% (n=4733) were women. Advanced age, female sex, smoking, body mass index, and total cholesterol were associated with greater increases in CRP levels over time (Pall<.001 in the multivariable model). Baseline CRP, as well as increase in CRP over time (ΔCRP), were associated with incident CVD (hazard ratio [HR]: 1.29 per 1-SD increase; 95% confidence interval [CI]: 1.29 to 1.47, and HR per 1-SD increase: 1.19; 95% CI: 1.09 to 1.29 respectively). Similar findings were observed for incident cancer (baseline CRP, HR: 1.17; 95% CI: 1.09 to 1.26; ΔCRP, HR: 1.08; 95% CI: 1.01 to 1.15) and mortality (baseline CRP, HR: 1.29; 95% CI: 1.21 to 1.37; ΔCRP, HR: 1.10; 95% CI: 1.05 to 1.16).Initial as well as subsequent increases in CRP levels predict future CVD, cancer, and mortality in the general population.

Although many studies report that moderate-to-heavy alcohol intake increases breast cancer risk, the effect of light alcohol consumption remains controversial, and a consistent pattern of association with different types of alcoholic beverages is not evident. The authors examined the relation of average alcohol consumption and of different beverages to the risk of breast cancer in the Framingham Study (Framingham, Massachusetts). Of 2,764 women followed more than 40 years in the Original Cohort from 1948 to 1993 and 2,284 followed up to 24 years in the Offspring Cohort from 1971 to 1993, 221 and 66 incident breast cancer cases occurred, respectively. Breast cancer incidence decreased from 3.60 per 1,000 person-years to 2.47, 2.30, and 2.33 in increasing categories of average alcohol consumption (none, <5.0, 5.0–<15.0, and ⩾15.0 g/day) among the Original Cohort and from 3.07 to 1.26, 1.24, and 2.22, respectively, among the Offspring Cohort. With the two cohorts combined, multivariate-adjusted rate ratios of breast cancer in each increased category of alcohol consumption were 1.0 (nondrinkers), 0.8 (95% confidence interval (CI) 0.6–1.1), 0.7 (95% CI 0.5–1.1), and 0.7 (95% CI 0.5–1.1), respectively. Breast cancer was not associated with wine, beer, or spirits consumption when assessed separately. The findings suggest that the light consumption of alcohol or any type of alcoholic beverage is not associated with increased breast cancer risk. Am J Epidemiol 1999;149:93–101.

Background. Some studies have linked low serum cholesterol levels to increased risk of colon cancer, particularly in men. Results have been inconsistent, with pre-clinical disease frequently offered to explain any apparent association. Methods. The Framingham Study cohort of 5209 persons, initially 30-62 years of age and observed more than 30 years, was evaluated. Baseline data included lipoprotein fractions, total cholesterol levels, body mass index, alcohol intake, and cardiovascular risk variables such as cigarette smoking, hypertension, and glucose intolerance. Results. In this population, colon cancer in men is related inversely to serum cholesterol levels, even when the first 10 years of follow-up are eliminated to reduce the effect of preclinical disease. This effect is concentrated in the Svedberg 0-20 fraction, corresponding to low-density lipoprotein levels. Another finding only in men is the direct relation of body mass index to colon cancer incidence. Conclusions. Combined initial low serum cholesterol levels and obesity appear to indicate a four times greater risk for colon cancer in men as compared with people with average values of both variables. The reasons for these observations are unknown.

Obesity and cardiometabolic dysfunction have been associated with cancer risk and severity. Underlying mechanisms remain unclear.The aim of this study was to examine associations of obesity and related cardiometabolic traits with incident cancer.FHS (Framingham Heart Study) and PREVEND (Prevention of Renal and Vascular End-Stage Disease) study participants without prevalent cancer were studied, examining associations of obesity, body mass index (BMI), waist circumference, visceral adipose tissue (VAT) and subcutaneous adipose tissue depots, and C-reactive protein (CRP) with future cancer in Cox models.Among 20,667 participants (mean age 50 years, 53% women), 2,619 cancer events were observed over a median follow-up duration of 15 years. Obesity was associated with increased risk for future gastrointestinal (HR: 1.30; 95% CI: 1.05-1.60), gynecologic (HR: 1.62; 95% CI: 1.08-2.45), and breast (HR: 1.32; 95% CI: 1.05-1.66) cancer and lower risk for lung cancer (HR: 0.62; 95% CI: 0.44-0.87). Similarly, waist circumference was associated with increased risk for overall, gastrointestinal, and gynecologic but not lung cancer. VAT but not subcutaneous adipose tissue was associated with risk for overall cancer (HR: 1.22; 95% CI: 1.05-1.43), lung cancer (HR: 1.92; 95% CI: 1.01-3.66), and melanoma (HR: 1.56; 95% CI: 1.02-2.38) independent of BMI. Last, higher CRP levels were associated with higher risk for overall, colorectal, and lung cancer (P < 0.05 for all).Obesity and abdominal adiposity are associated with future risk for specific cancers (eg, gastrointestinal, gynecologic). Although obesity was associated with lower risk for lung cancer, greater VAT and CRP were associated with higher lung cancer risk after adjusting for BMI.

The authors examined the relation of parental age at birth to the risk of prostate cancer among sons with the use of data from the Framingham Study. During 42 years of follow-up (1949-1993), 141 prostate cancer cases occurred in 2,164 men. All but six cases were confirmed by histologic report. The incidence rate of prostate cancer increased from 1.70 per 1,000 person-years among sons in the lowest quartile of paternal age (<27 years), to 2.00, 2.32, and 2.74 among those of each increased paternal age category (27-<32, 32-<38, and > or =38 years), respectively. After adjustment for age and other covariates, men in the second, third, and oldest quartiles of paternal age had 1.2, 1.3, and 1.7 times increased risk of prostate cancer compared with men in the youngest quartile (p for trend = 0.049). Further adjustment for maternal age did not change the relation materially. The association of older paternal age with risk of early-onset prostate cancer (<65 years) appeared stronger than that with late-onset disease (265 years). No increased risk of prostate cancer was observed among subjects in the older maternal age category. The effect of increased paternal age on prostate cancer risk may operate through increased germ cell mutation rate or by mechanisms not yet defined.

Journal Article Is Alcohol Consumption Related to Breast Cancer? Results From the Framingham Heart Study Get access Arthur Schatzkin, Arthur Schatzkin Cancer Prevention Studies Branch, Division of Cancer Prevention and Control, National Cancer InstituteBethesda, MD Correspondence to: Dr. Arthur Schatzkin, Executive Plaza North, Rm. 211J, National Institutes of Health, Bethesda, MD 20892. Search for other works by this author on: Oxford Academic PubMed Google Scholar Christine L. Carter, Christine L. Carter Cancer Prevention Studies Branch, Division of Cancer Prevention and Control, National Cancer InstituteBethesda, MD Search for other works by this author on: Oxford Academic PubMed Google Scholar Sylvan B. Green, Sylvan B. Green Biometry Branch, Division of Cancer Prevention and Control, National Cancer InstituteBethesda, MD Search for other works by this author on: Oxford Academic PubMed Google Scholar Bernard E. Kreger, Bernard E. Kreger Boston University School of MedicineBoston, MA. Search for other works by this author on: Oxford Academic PubMed Google Scholar Greta L. Splansky, Greta L. Splansky Boston University School of MedicineBoston, MA. Search for other works by this author on: Oxford Academic PubMed Google Scholar Keaven M. Anderson, Keaven M. Anderson Field Studies Branch, Division of Epidemiology and Clinical Applications, National Heart, Lung, and Blood InstituteBethesda, MD. Search for other works by this author on: Oxford Academic PubMed Google Scholar surname Helsel, surname Helsel Information Management ServicesSilver Spring, MD. Search for other works by this author on: Oxford Academic PubMed Google Scholar William B. Kannel William B. Kannel Boston University School of MedicineBoston, MA. Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 81, Issue 1, January 1989, Pages 31–35, https://doi.org/10.1093/jnci/81.1.31 Published: 01 January 1989 Article history Received: 03 August 1988 Revision received: 04 October 1988 Accepted: 11 October 1988 Published: 01 January 1989

Adult weight gain has been associated with a twofold risk of postmenopausal breast cancer. Data are limited regarding whether weight gain at specific periods of marked changes in estrogen- and insulin-related hormones have different risk associations. This study assesses the relation of adult weight change overall and at specific, hormonally relevant times with diagnosis of a first breast cancer after age 55 (late onset).Framingham study data were used to assess premenopausal (25-44 yr), perimenopausal (45-55 yr), postmenopausal (after 55 yr), and adult lifetime (from 25 yr) weight change in relation to late-onset breast cancer in 2,873 women followed for up to 48 yr, with 206 late-onset breast cancers.Adult lifetime weight gain was associated with an increased risk of late-onset breast cancer (P trend = 0.046). Weight gain during specific time periods was not associated with breast cancer. Data suggested a possible decreased risk of breast cancer with weight loss from ages 25 to 44 and 45 to 55 yr (relative risk = 0.4 [0.2-1.2] and 0.5 [0.3-0.9], respectively).These data confirm prior reports of an association between adult lifetime weight gain and increased risk of late-onset breast cancer and support current recommendations to avoid adult weight gain.

Recent studies suggest an association between cardiovascular disease (CVD) and cancer incidence/mortality, but the pathophysiological mechanisms underlying these associations are unclear. We aimed to examine biomarkers previously associated with CVD and study their association with incident cancer and cancer-related death in a prospective cohort study.We used a proteomic platform to measure 71 cardiovascular biomarkers among 5032 participants in the Framingham Heart Study who were free of cancer at baseline. We used multivariable-adjusted Cox models to examine the association of circulating protein biomarkers with risk of cancer incidence and mortality. To account for multiple testing, we set a 2-sided false discovery rate <0.05. Growth differentiation factor-15 (also known as macrophage inhibitory cytokine-1) was associated with increased risk of incident cancer [hazards ratio (HR) per 1 standard deviation increment 1.31, 95% CI 1.17-1.47], incident gastrointestinal cancer (HR 1.85, 95% CI 1.37-2.50), incident colorectal cancer (HR 1.94, 95% CI 1.29-2.91), and cancer-related death (HR 2.15, 95% CI 1.72-2.70). Stromal cell-derived factor-1 showed an inverse association with cancer-related death (HR 0.75, 95% CI 0.65-0.86). Fibroblast growth factor-23 showed an association with colorectal cancer (HR 1.55, 95% CI 1.20-2.00), and granulin was associated with haematologic cancer (HR 1.61, 95% CI 1.30-1.99). Other circulating biomarkers of inflammation, immune activation, metabolism, and fibrosis showed suggestive associations with future cancer diagnosis.We observed several significant associations between circulating CVD biomarkers and cancer, supporting the idea that shared biological pathways underlie both diseases. Further investigations of specific mechanisms that lead to both CVD and cancer are warranted.

The almost 40-year records of The Framingham Heart Study (FHS) cohort were reviewed to establish the cancer experience of this noninstitutionalized group of white subjects. Diagnoses were confirmed from pathology and laboratory reports and clinical notes. Age-specific incidence rates were compared with Connecticut Surveillance, Epidemiology, and End Results (SEER) data. Among the 5209 subjects, 1201 malignancies were confirmed. Median age at diagnosis was 69 for men and 65 for women. Lung, prostate, skin, and colon accounted for more than half of men's cancers; breast, colon, and skin made up half of the women's. FHS and Connecticut SEER rates matched closely, with the same primary tumor sites appearing commonly in both groups. Thus, the FHS cohort should provide a fair database for analysis of risk factors in cancer incidence, as it has done in cardiovascular diseases.

Abstract Extensive efforts have been aimed at understanding the genetic underpinnings of complex diseases that affect humans. Numerous genome‐wide association studies have assessed the association of genes with human disease, including the Framingham Heart Study (FHS), which genotyped 550,000 SNPs in 9,000 participants. The success of such efforts requires high rates of consent by participants, which is dependent on ethical oversight, communications, and trust between research participants and investigators. To study this we calculated percentages of participants who consented to collection of DNA and to various uses of their genetic information in two FHS cohorts between 2002 and 2009. The data included rates of consent for providing a DNA sample, creating an immortalized cell line, conducting research on various genetic conditions including those that might be considered sensitive, and for notifying participants of clinically significant genetic findings were above 95%. Only with regard to granting permission to share DNA or genetic findings with for‐profit companies was the consent rate below 95%. We concluded that the FHS has maintained high rates of retention and consent for genetic research that has provided the scientific freedom to establish collaborations and address a broad range of research questions. We speculate that our high rates of consent have been achieved by establishing frequent and open communications with participants that highlight extensive oversight procedures. Our approach to maintaining high consent rates via ethical oversight of genetic research and communication with study participants is summarized in this report and should be of help to other studies engaged in similar types of research. Published 2010 Wiley‐Liss, Inc.

Two strains of guinea pigs were parenterally immunized with well-characterized diisocyanate-protein conjugates. Hapten-specific IgE antibodies were detected in the sera of English short-hair strain guinea pigs immunized with either toluene diisocyanate-human serum albumin (TDI-HSA) or hexamethylene diisocyanate-HSA (HDI-HSA) when these sera were analyzed by the 168 hr passive cutaneous anaphylaxis (PCA) technique followed by intravenous challenges with conjugates of respective ligands coupled to an unrelated carrier protein, transferrin. IgG1 antibodies and precipitating antibodies were demonstrated in Hartley strain guinea pigs immunized with TDI/HDI-HSA conjugates. The hapten specificity of these antibodies was proved by PCA inhibition experiments and antibody absorption experiments. In the precipitating antibody system, this was further confirmed by immunoelectrophoretic analysis. Cross-reactivity between HDI and TDI was not observed in the PCA experiments. However, apparent cross-reactivity in the double gel diffusion experiments was due to new antigenic determinants formed by isocyanates after conjugation with proteins. It was therefore apparent that immune responses of guinea pigs immunized with protein conjugates of bifunctional isocyanates were heterogeneous and involved multiple specificities for hapten, carrier protein, and new antigenic determinants. It was postulated that the complex nature of the immune response generated by diisocyanate compounds in the guinea pig may also serve as a more appropriate model of isocyanate-induced human sensitivity reactions, which are known to involve diverse immunologic and nonimmunologic mechanisms.

A younger age at menarche and an older age at menopause are well established risk factors for breast cancer. Recent genome-wide association studies have identified several novel genetic loci associated with these two traits. However, the association between these loci and breast cancer risk is unknown.In this study, we investigated 19 and 17 newly identified single nucleotide polymorphisms (SNPs) from the ReproGen Consortium that have been associated with age at menarche and age at natural menopause, respectively, and assessed their associations with breast cancer risk in 6 population-based studies among up to 3,683 breast cancer cases and 34,174 controls in white women of European ancestry. In addition, we used these SNPs to calculate genetic risk scores (GRSs) based on their associations with each trait.After adjusting for age and potential population stratification, two age at menarche associated SNPs (rs1079866 and rs7821178) and one age at natural menopause associated SNP (rs2517388) were associated with breast cancer risk (p values, 0.003, 0.009 and 0.023, respectively). The odds ratios for breast cancer corresponding to per-risk-allele were 1.14 (95% CI, 1.05 to 1.24), 1.08 (95% CI, 1.02 to 1.15) and 1.10 (95% CI, 1.01 to 1.20), respectively, and were in the direction predicted by their associations with age at menarche or age at natural menopause. These associations did not appear to be attenuated by further controlling for self-reported age at menarche, age at natural menopause, or known breast cancer susceptibility loci. Although we did not observe a statistically significant association between any GRS for reproductive aging and breast cancer risk, the 4th and 5th highest quintiles of the younger age at menarche GRS had odds ratios of 1.14 (95% CI, 1.01 to 1.28) and 1.13 (95% CI, 1.00 to 1.27), respectively, compared to the lowest quintile.Our study suggests that three genetic variants, independent of their associations with age at menarche or age at natural menopause, were associated with breast cancer risk and may contribute modestly to breast cancer risk prediction; however, the combination of the 19 age at menarche or the 17 age at natural menopause associated SNPs did not appear to be useful for identifying a high risk subgroup for breast cancer.

Surveys suggest that most research participants desire access to secondary (incidental) genomic findings. However, few studies clarify whether preferences vary by the nature of the finding.We surveyed members of the JHS (Jackson Heart Study, n=960), the FHS (Framingham Heart Study; n=955), and African American members of the FHS Omni cohort (n=160) who had consented to genomic studies. Each factorial survey included 3 vignettes, randomly selected from a set of 64, that described a secondary genomic result. Vignettes varied systematically by 5 factors identified by expert panels as salient: phenotype severity, actionability (preventability), reproductive significance, and relative and absolute risk of the phenotype. Respondents indicated whether they would want to receive the result. Data were analyzed separately by cohort using generalized linear mixed models.Response rates ranged from 67% to 73%. Across vignettes, 88% to 92% of respondents would definitely or probably want to learn the result. In multivariate analyses among JHS respondents, desire for results was associated with positive attitudes towards genetic testing, lower education, higher subjective numeracy, and younger age, but not with any of the 5 factors. Among FHS respondents, desire for results was associated with higher absolute risk, preventability, reproductive risk, and positive attitudes towards genetic testing. Among FHS Omni respondents, desire for results was associated with positive attitudes towards genetic testing and younger age.Most genetic research participants desire return of secondary genetic results. Several factors identified by expert panels as salient are associated with preferences among FHS, but not JHS or FHS Omni, participants.

Diminished platelet aggregation responses to one or more aggregating agents were found in 25 of 32 patients with nasal allergy studied at the peak of the allergy season. Abnormal in-season platelet aggregation induced by epinephrine and collagen was significantly improved when repeated out-of-season, while incomplete platelet aggregation induced by adenosine diphosphate (ADP) and thrombin was unchanged. Recombination of an in-season serum factor with autologous, out-of-season normally aggregating platelets caused market inhibition of platelet aggregation. Mean bleeding times of 20 symptomatic patients were also prolonged during the height of the pollination season. These data suggest that the allergic diathesis is a model for the study of cyclic, nondrug induction of platelet dysfunction.

Genetic analysis has become integral to many large cohort studies. However, little is known about longitudinal cohort study participants’ attitudes toward genetics and genetic testing. We analyzed data from a survey of participants in the Jackson Heart Study (n = 960), Framingham Heart Study (n = 955), and Framingham Heart Study–Omni Cohort (n = 160). Based on a three-question attitude scale, most participants had positive attitudes toward genetic testing (median score = 4.3-5/5). Participants were also asked to select words to describe their attitudes toward genetics. More respondents endorsed the positive words “hopeful” (60%-70%), “optimistic” (44%-64%), “enthusiastic” (35%-43%), or “excited” (28%-30%) than the negative words “cautious” (35%-38%), “concerned” (25%-55%), “worried” (6%-13%), “pessimistic” (2%-5%), or “horrified” (1%-5%). Characteristics associated with favorable attitudes were greater genetics knowledge, higher subjective numeracy, experience with genetic testing, less frequent religious attendance, and not being employed. These findings demonstrate variation in attitudes even among participants in long-standing cohort studies, indicating a need for ongoing participant engagement and education.

Summary The effect of tartrazine (T) (yellow dye No. 5) and one of its metabolites an aminopyrazolone analogue (1‐sulphophenyl‐3‐carboxy‐5‐hydroxypyruzole, SCHP) upon collagen‐induced platelet aggregation (C‐PA) was investigated in fourteen atopic patients and fourteen normal subjects. Both T and SCHP inhibited C‐PA in atopic patients at significantly lower doses than in normal volunteers. The mean inhibitory concentrations of SCHP were similar to aspirin in both atopic and normal individuals. Although the precise mechanism by which these chemicals block C‐PA has not been elucidated, this in vitro system may be a useful method of assessing non‐immune mechanisms involved in reactions to tartrazine.

Background: Previous studies have demonstrated a strong inverse association between cancer and risk of Alzheimer's disease (AD).This study aimed to further investigate this association by examining measures of cognitive performance and neuroimaging.Methods: Neuropsychological (NP) test batteries consisting of quantitative measures of memory and executive function and volumetric brain magnetic resonance imaging (MRI) scans measuring brain and whitematter hyperintensity volumes were administered to 2043 dementia-free participants (54% women) in the Framingham Heart Study (FHS) Offspring cohort from 1999 to 2005.History of cancer was assessed at examination visits and through hospital records.Linear regression was used to examine the association between cancer history and NP/MRI variables.

We appreciate the informative commentary by Dr. Longnecker (1) and agree particularly with his concluding statements that put the alcohol-breast cancer relation into perspective from a public health point of view. While the majority of studies indeed show an increase in breast cancer risk for women consuming larger amounts of alcohol, the effect of light drinking—up to one drink per day, for example, the level considered “moderate” for women according to dietary guidelines from the US Department of Agriculture (2)—is still controversial. Further insight into this controversy is important because the vast majority of women drinkers in the United States average less than one drink per day. This is a level of drinking that, in some women, is associated with a reduced incidence of cardiovascular disease and lower total mortality. We acknowledge that our point estimate for light drinking is lower than that for many other studies, as reflected in a previous meta-analysis by Dr. Longnecker (3). We note, though, that other well-conducted cohort studies have shown little or no increased risk of breast cancer among women consuming less than 15 g of alcohol per day. Indeed, in table 2 of the “recent pooled analysis” (4) referred to by Dr. Longnecker in his commentary (1, p. 102), the estimates of effect on breast cancer risk for 0.5–14.9 g of alcohol per day were essentially 1.0 for four of the seven studies: the Canadian National Breast Screening Study (relative risk (RR) = 0.94), the Iowa Women's Health Study (RR = 0.97), the New York State Cohort (RR = 0.93), and the second report from the Nurses' Health Study included in the analysis (RR = 1.01). Further, the Nurses' Health Study reported a relative risk of 0.96 for mortality from breast cancer among drinkers of this amount (5). We believe that estimated effects of this magnitude do not justify public health interventions to warn all women not to drink alcohol because of the dangers of breast cancer. For now, the best approach seems to be to provide women with scientifically sound, balanced information on the effects of light drinking so that they can make informed decisions regarding their own lifestyle habits.

Introduction: Obesity and cardiometabolic dysfunction may be shared risk factors for development of cancer. We sought to examine the association of obesity and abdominal adiposity with incident cancer. Methods: We studied participants of the Framingham Heart Study and Prevention of Renal and Vascular End-Stage Disease study. We examined the association of obesity, body-mass index (BMI), waist circumference (WC), and visceral adiposity (VAT) with future cancer in Cox models. We adjusted for age, sex, diabetes, systolic blood pressure, hypertension treatment, smoking status (current, former, never), and cholesterol ratio. Results: Among 20,667 individuals (mean age 50, 53% women) free of cancer at baseline, we observed 2,619 incident cancer events over a mean follow-up of 13.3±3.3 years. Obesity (BMI≥30 kg/m 2 ) was associated with 30% increased hazard of future gastrointestinal cancer (HR 1.30, 95% CI 1.05-1.60, P=0.01), 62% increased hazard of gynecologic cancers (HR 1.62, 95% CI 1.08-2.45, P=0.02), and by contrast, 38% lower risk of lung cancer (HR 0.62, 95% CI 0.44-0.87, P=0.006). We found similar associations of future cancer with continuous BMI and WC ( Figure ). Among 3,077 individuals with CT scans, VAT was associated with incident cancer (HR 1.16, 95% CI 1.03-1.31, P=0.01 per 1-SD change in VAT). After adjusting for BMI, higher VAT was associated with greater risk of lung cancer (HR 1.92, 95% CI 1.01-3.65, P=0.045). Conclusions: We observed that obesity and abdominal adiposity were associated with future cancer events, including gastrointestinal and gynecologic cancers. Interestingly, obesity was associated with lower risk of lung cancer. However, greater VAT was associated with greater lung cancer risk after adjusting for BMI. These findings highlight the importance of specific obesity-related phenotypes and adipose depots in better understanding the association between obesity and cancer.