Person:

Buring, Julie

OBJECTIVE—Subclinical inflammation is linked with the development of type 2 diabetes, and epidemiologic data suggest that this association may be stronger in women. Although small clinical studies have shown a prominent hypoglycemic effect of short-term high-dose aspirin, no randomized trials have directly evaluated the efficacy of aspirin in diabetes prevention at doses acceptable for use in routine clinical practice. We evaluated whether chronic low-dose aspirin prevents the development of clinical diabetes among initially healthy American women. RESEARCH DESIGN AND METHODS—Subjects were enrolled in the Women's Health Study, a 10-year randomized double-blind, placebo-controlled trial of aspirin and vitamin E for primary prevention of cardiovascular disease and cancer. Between 1992 and 1995, 38,716 women aged ≥45 years and free of clinical diabetes were randomly assigned to either low-dose aspirin or placebo (median follow-up 10.2 years). Documented clinical type 2 diabetes was prospectively evaluated throughout the trial. RESULTS—Among women randomly assigned to receive aspirin (n = 19,326) or placebo (n = 19,390), there was no statistically significant difference in the incidence of type 2 diabetes. There were 849 cases of diabetes in the aspirin group and 847 in the placebo group (rate ratio 1.01 [95% CI 0.91–1.11]). Stratification by diabetes risk factors including age, BMI, family history of diabetes, physical activity, A1C, and high-sensitivity C-reactive protein did not support a modulating effect of these variables. Analyses accounting for treatment duration and adherence similarly found no beneficial effects. CONCLUSIONS—These data suggest that long-term low-dose aspirin does not prevent the development of clinical type 2 diabetes in initially healthy women.

Objective: To evaluate the association of kidney function with cardiovascular disease and mortality among apparently healthy women. Design: Prospective cohort study. Setting: Women’s Health Study, United States. Participants: 27 939 female health professionals aged ≥45 who were free of cardiovascular disease and other major disease and who provided a blood sample at study entry. Main outcome measures: Time to cardiovascular disease (non-fatal stroke, non-fatal myocardial infarction, coronary revascularisation procedures, or death from cardiovascular cause), specific cardiovascular disease events, and all-cause mortality. End points were confirmed after review of medical records and death certificates. Results: Glomerular filtration rate (GFR) was estimated with the abbreviated Modification of Diet in Renal Disease Study equation. At baseline, 1315 (4.7%) women had GFR <60 ml/min/1.73 m2. During 12 years of follow-up, 1199 incident cardiovascular disease events and 856 deaths (179 from cardiovascular disease) occurred. Compared with women with GFR ≥90 ml/min/1.73 m2, the multivariable adjusted hazard ratios for any first cardiovascular disease were 0.95 (95% CI 0.83 to 1.08), 0.84 (0.70 to 1.00), and 1.00 (0.79 to 1.27) among women with GFR of 75-89.9, 60-74.9, and <60 ml/min/1.73 m2, respectively; the equivalent hazard ratios for all cause mortality were 0.93 (0.79 to 1.09), 1.03 (0.85 to 1.26), and 1.09 (0.83 to 1.45). Similar null findings were observed for myocardial infarction, stroke, coronary revascularisation, and non-cardiovascular death. However, an increased risk of death from cardiovascular disease was found among women with GFR <60 ml/min/1.73 m2 (hazard ratio 1.68 (1.02 to 2.79)). Conclusions: In this large cohort of women, a glomerular filtration rate <60 ml/min/1.73 m2 was associated with increased risk of cardiovascular disease death but not other cardiovascular disease events or non-cardiovascular disease mortality. We observed no increase in risk of any of the outcomes among women with less severe impairment of kidney function.

Early menopause (EM) affects up to 10% of the female population, reducing reproductive lifespan considerably. Currently, it constitutes the leading cause of infertility in the western world, affecting mainly those women who postpone their first pregnancy beyond the age of 30 years. The genetic aetiology of EM is largely unknown in the majority of cases. We have undertaken a meta-analysis of genome-wide association studies (GWASs) in 3493 EM cases and 13 598 controls from 10 independent studies. No novel genetic variants were discovered, but the 17 variants previously associated with normal age at natural menopause as a quantitative trait (QT) were also associated with EM and primary ovarian insufficiency (POI). Thus, EM has a genetic aetiology which overlaps variation in normal age at menopause and is at least partly explained by the additive effects of the same polygenic variants. The combined effect of the common variants captured by the single nucleotide polymorphism arrays was estimated to account for ∼30% of the variance in EM. The association between the combined 17 variants and the risk of EM was greater than the best validated non-genetic risk factor, smoking.

Introduction: 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. Methods: 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. Results: 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. Conclusions: 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.

Migraine is a common and debilitating neurovascular disorder with a complex envirogenomic aetiology. Numerous studies have demonstrated a preponderance of women affected with migraine and previous pedigree linkage studies in our laboratory have identified susceptibility loci on chromosome Xq24-Xq28. In this study we have used the genetic isolate of Norfolk Island to further analyse the X chromosome for migraine susceptibility loci. An association approach was employed to analyse 14,124 SNPs spanning the entire X chromosome. Genotype data from 288 individuals comprising a large core-pedigree, of which 76 were affected with migraine, were analysed. Although no SNP reached chromosome-wide significance (empirical (\alpha) = 1×10(^{−5})) ranking by P-value revealed two primary clusters of SNPs in the top 25. A 10 SNP cluster represents a novel migraine susceptibility locus at Xq12 whilst a 11 SNP cluster represents a previously identified migraine susceptibility locus at Xq27. The strongest association at Xq12 was seen for rs599958 (OR = 1.75, P = 8.92×10(^{−4})), whilst at Xq27 the strongest association was for rs6525667 (OR = 1.53, P = 1.65×10(^{−4})). Further analysis of SNPs at these loci was performed in 5,122 migraineurs from the Women’s Genome Health Study and provided additional evidence for association at the novel Xq12 locus (P<0.05). Overall, this study provides evidence for a novel migraine susceptibility locus on Xq12. The strongest effect SNP (rs102834, joint P = 1.63×10(^{−5})) is located within the 5′UTR of the HEPH gene, which is involved in iron homeostasis in the brain and may represent a novel pathway for involvement in migraine pathogenesis.

Background: Cardiovascular inflammation is a key contributor to the development of atherosclerosis and the prediction of cardiovascular events among healthy women. An emerging literature suggests biomarkers of inflammation vary by geography of residence at the state-level, and are associated with individual-level socioeconomic status. Associations between cardiovascular inflammation and state-level socioeconomic conditions have not been evaluated. The study objective is to estimate whether there are independent associations between state-level socioeconomic conditions and individual-level biomarkers of inflammation, in excess of individual-level income and clinical covariates among healthy women. Methods: The authors examined cross-sectional multilevel associations among state-level socioeconomic conditions, individual-level income, and biomarkers of inflammation among women (n = 26,029) in the Women's Health Study, a nation-wide cohort of healthy women free of cardiovascular diseases at enrollment. High sensitivity C-reactive protein (hsCRP), soluble intercellular adhesion molecule-1 (sICAM-1) and fibrinogen were measured between 1993 and 1996. Biomarker levels were examined among women within quartiles of state-level socioeconomic conditions and within categories of individual-level income. Results: The authors found that favorable state-level socioeconomic conditions were correlated with lower hsCRP, in excess of individual-level income (e.g. state-level real per capital gross domestic product fixed effect standardized Βeta coefficient [Std B] -0.03, 95% CI -0.05, -0.004). Individual-level income was more closely associated with sICAM-1 (Std B -0.04, 95% CI -0.06, -0.03) and fibrinogen (Std B -0.05, 95% CI -0.06, -0.03) than state-level conditions. Conclusions: We found associations between state-level socioeconomic conditions and hsCRP among healthy women. Personal household income was more closely associated with sICAM-1 and fibrinogen than state-level socioeconomic conditions. Additional research should examine these associations in other cohorts, and investigate what more-advantaged states do differently than less-advantaged states that may influence levels of cardiovascular inflammation among healthy women.

Migraine can be sub-classified not only according to presence of migraine aura (MA) or absence of migraine aura (MO), but also by additional features accompanying migraine attacks, e.g. photophobia, phonophobia, nausea, etc. all of which are formally recognized by the International Classification of Headache Disorders. It remains unclear how aura status and the other migraine features may be related to underlying migraine pathophysiology. Recent genome-wide association studies (GWAS) have identified 12 independent loci at which single nucleotide polymorphisms (SNPs) are associated with migraine. Using a likelihood framework, we explored the selective association of these SNPs with migraine, sub-classified according to aura status and the other features in a large population-based cohort of women including 3,003 active migraineurs and 18,108 free of migraine. Five loci met stringent significance for association with migraine, among which four were selective for sub-classified migraine, including rs11172113 (LRP1) for MO. The number of loci associated with migraine increased to 11 at suggestive significance thresholds, including five additional selective associations for MO but none for MA. No two SNPs showed similar patterns of selective association with migraine characteristics. At one extreme, SNPs rs6790925 (near TGFBR2) and rs2274316 (MEF2D) were not associated with migraine overall, MA, or MO but were selective for migraine sub-classified by the presence of one or more of the additional migraine features. In contrast, SNP rs7577262 (TRPM8) was associated with migraine overall and showed little or no selectivity for any of the migraine characteristics. The results emphasize the multivalent nature of migraine pathophysiology and suggest that a complete understanding of the genetic influence on migraine may benefit from analyses that stratify migraine according to both aura status and the additional diagnostic features used for clinical characterization of migraine.

Age at menarche is a marker of timing of puberty in females. It varies widely between individuals, is a heritable trait and is associated with risks for obesity, type 2 diabetes, cardiovascular disease, breast cancer and all-cause mortality1. Studies of rare human disorders of puberty and animal models point to a complex hypothalamic-pituitary-hormonal regulation2,3, but the mechanisms that determine pubertal timing and underlie its links to disease risk remain unclear. Here, using genome-wide and custom-genotyping arrays in up to 182,416 women of European descent from 57 studies, we found robust evidence (P<5×10−8) for 123 signals at 106 genomic loci associated with age at menarche. Many loci were associated with other pubertal traits in both sexes, and there was substantial overlap with genes implicated in body mass index and various diseases, including rare disorders of puberty. Menarche signals were enriched in imprinted regions, with three loci (DLK1/WDR25, MKRN3/MAGEL2 and KCNK9) demonstrating parent-of-origin specific associations concordant with known parental expression patterns. Pathway analyses implicated nuclear hormone receptors, particularly retinoic acid and gamma-aminobutyric acid-B2 receptor signaling, among novel mechanisms that regulate pubertal timing in humans. Our findings suggest a genetic architecture involving at least hundreds of common variants in the coordinated timing of the pubertal transition.

The length of female reproductive lifespan is associated with multiple adverse outcomes, including breast cancer, cardiovascular disease and infertility. The biological processes that govern the timing of the beginning and end of reproductive life are not well understood. Genetic variants are known to contribute to ∼50% of the variation in both age at menarche and menopause, but to date the known genes explain <15% of the genetic component. We have used genome-wide association in a bivariate meta-analysis of both traits to identify genes involved in determining reproductive lifespan. We observed significant genetic correlation between the two traits using genome-wide complex trait analysis. However, we found no robust statistical evidence for individual variants with an effect on both traits. A novel association with age at menopause was detected for a variant rs1800932 in the mismatch repair gene MSH6 (P = 1.9 × 10−9), which was also associated with altered expression levels of MSH6 mRNA in multiple tissues. This study contributes to the growing evidence that DNA repair processes play a key role in ovarian ageing and could be an important therapeutic target for infertility.