Shadyab, Aladdin H

Objective: To evaluate whether effects of oral hormone therapy (HT) on risks of venous and arterial vascular events differ by baseline statin or aspirin use. Methods: We performed time-to-event analysis using data from the Women’s Health Initiative menopausal HT randomized trials to assess risk of thrombotic events. Women were randomized to oral conjugated equine estrogens (CEEs) alone or placebo among women with prior hysterectomy (n = 10,739), and CEE with medroxyprogesterone acetate (MPA) or placebo among women with an intact uterus (n = 16,608), stratified by baseline personal use of statins and aspirin. We evaluated risk of prespecified, adjudicated thrombotic events, including coronary heart disease, stroke, venous thromboembolism, and/or composite major adverse cardiovascular events, at 2 and 5 years. Results: Baseline statin use (n = 827 in CEE-alone trial; n = 1,115 in CEE+MPA trial) or aspirin use (n = 2,212; n = 3,431) was limited. At 5-year follow-up, coronary heart disease risk for CEE-alone versus placebo was hazard ratio (HR) = 0.81 (95% CI: 0.44-1.49) in statin users, similar to nonusers, HR = 1.07 (95% CI: 0.82-1.40). For CEE+MPA, there was also no difference by statin use, HR = 1.02 (95% CI: 0.55-1.89) and HR = 1.47 (95% CI: 1.13-1.90), respectively. Neither statin nor aspirin exposure significantly modified effects of HT on any arterial or venous thrombotic outcome at 2 or 5 years. Conclusions: In this secondary randomized clinical trial analysis, neither statins nor aspirin significantly modified effects of oral HT on key arterial or venous thrombotic outcomes at 2 or 5 years. Results, however, may be underpowered given low baseline exposure prevalence for both statins and aspirin.

Objective: To examine prospective associations of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) test positivity, coronavirus disease 2019 (COVID-2019) symptom severity, and COVID-2019 hospitalization with incident clinical diabetes among aging women. Methods: A cohort study was conducted using data from 34,405 eligible Women’s Health Initiative participants who completed ≥1 COVID-2019 surveys (Survey 1: June–December 2020; Survey 2: June 2021–February 2022) and were followed up for an average of 1.86 (±0.49) years, yielding 399 incident diabetes cases. Results: SARS-CoV-2 test positivity was associated with diabetes risk in the age-adjusted Cox regression model (hazard ratio [HR] = 1.76, 95% confidence interval [CI]: 1.10, 2.82), but not when fully adjusted (HR = 1.43, 95% CI: 0.88, 2.31). Diabetes risk was higher among those with 1–2 COVID-19 symptoms (HR = 1.39, 95% CI: 1.09, 1.77) and those with 3± COVID-2019 symptoms (HR = 1.53, 95% CI: 1.06, 2.22) compared with those without COVID-2019 symptoms in fully-adjusted models, irrespective of self-reported SARS-CoV-2 testing. COVID-2019 hospitalization was associated with 2–3 times the risk of clinical diabetes in age-adjusted (HR = 2.95, 95% CI: 1.52, 5.72) and fully-adjusted (HR = 1.90, 95% CI: 0.97, 3.72) models. Conclusions: Age-adjusted self-reported SARS-CoV-2 test positivity was associated with a higher incidence of diabetes. Reporting of COVID-2019 symptoms and being hospitalized for COVID-2019 were each associated with higher incidence of diabetes in aging women, after controlling for demographic, socioeconomic, lifestyle, and health characteristics.

Abstract There are limited prospective data on whether established risk factors modify breast cancer risk in women with pathogenic variants (PV) in BRCA1/2 and virtually no risk modification data for ATM, CHEK2, or PALB2. We conducted a nested case–control study in the Women’s Health Initiative (WHI), randomly selecting women with and without breast cancer for DNA sequencing. We evaluated breast cancer odds associated with obesity, family cancer history, smoking, alcohol, parity, breastfeeding, oophorectomy, tubal ligation, neighborhood socioeconomic status, and menopausal hormone therapy (MHT) with estrogen and progestin or estrogen only in PV carriers and noncarriers. In exploratory analyses, we grouped genes by established predisposition for estrogen receptor (ER)-positive (ATM and CHEK2) or ER-negative (BRCA1 and PALB2) disease. Multivariable models with interaction terms were used to assess differential risk modification by PVs. Among 12,957 WHI participants, 287 carried PVs. Breastfeeding was modestly associated with reduced risk for PALB2 [OR = 0.08; 95% confidence interval (CI), 0.00–0.92; P value = 0.042]. With one-sided 95% CI, power was sufficient to exclude OR ≥2.0 with obesity for ATM and BRCA2; smoking and alcohol for CHEK2; no breastfeeding for ATM; no oophorectomy for BRCA2 and CHEK2; no tubal ligation for CHEK2; and neighborhood socioeconomic status for all genes. Estrogen + progestin MHT was modestly associated with increased risk for ER-positive PVs (OR = 7.31; 95% CI, 1.14–64.20; P = 0.036). PVs did not modify risk (interaction P ≥ 0.05). BRCA1/2, ATM, CHEK2, and PALB2 PV carriers do not have breast cancer OR ≥2.0 with many established risk factors. However, MHT warrants additional study in PV carriers. Significance: There is limited information on whether established risk factors increase breast cancer risk from PVs. In the WHI, PV carriers had no substantial (≥2-fold) increase with most risk factors, except potentially MHT in ATM or CHEK2 carriers. The results may inform counseling and research on MHT.

BACKGROUND: Premature menopause is a risk factor for accelerated cardiovascular aging, but underlying mechanisms remain incompletely understood. This study investigated the role of leukocyte telomere length (LTL), a marker of cellular aging and genomic instability, in the association of premature menopause with cardiovascular disease. METHODS: Participants from the UK Biobank and Women’s Health Initiative with complete reproductive history and LTL measurements were included. Primary analyses tested the association between age at menopause and LTL using multivariable-adjusted linear regression. Secondary analyses stratified women by history of gynecologic surgery. Mendelian randomization was used to infer causal relationships between LTL and age at natural menopause. Multivariable-adjusted Cox regression and mediation analyses tested the joint associations of premature menopause and LTL with incident coronary artery disease. RESULTS: This study included 130 254 postmenopausal women (UK Biobank: n=122 224; Women’s Health Initiative: n=8030), of whom 4809 (3.7%) had experienced menopause before age 40. Earlier menopause was associated with shorter LTL (meta-analyzed ß=−0.02 SD/5 years of earlier menopause [95% CI, −0.02 to −0.01]; P =7.2×10 -12 ). This association was stronger and significant in both cohorts for women with natural/spontaneous menopause (meta-analyzed ß=−0.04 SD/5 years of earlier menopause [95% CI, −0.04 to −0.03]; P <2.2×10 -16 ) and was independent of hormone therapy use. Mendelian randomization supported a causal association of shorter genetically predicted LTL with earlier age at natural menopause. LTL and age at menopause were independently associated with incident coronary artery disease, and mediation analyses indicated small but significant mediation effects of LTL in the association of menopausal age with coronary artery disease. CONCLUSIONS: Earlier age at menopause is associated with shorter LTL, especially among women with natural menopause. Accelerated telomere shortening may contribute to the heightened cardiovascular risk associated with premature menopause.

Abstract Background Across complex traits, common variants explain only a modest amount of variance, with SNP-heritability consistently below heritability estimates from close relatives. Here, we examined the contribution of rare variant to tobacco use risk in up to 26,000 individuals of European ancestry in the Trans-Omics for Precision Medicine (TOPMed) program with whole genome sequence (WGS;~30X coverage).Method We grouped about 35 million genetic variants by their minor allele frequencies (MAF) and linkage disequilibrium (LD) and estimated SNP-heritability for age of smoking initiation (N = 14,747), cigarettes smoked per day (N = 15,425), smoking cessation (N = 17,871) and initiation (N = 26,340) using linear mixed model. Rare variant population structure is detected and adjusted for by permutation procedure. We estimated an upper bound for narrow-sense heritability for tobacco use using available pedigrees consisting of close relatives in TOPMed.Results Rare variants with MAF 0.1–0.01%, mostly from non-protein altering region, accounted for 26% of variation in age of initiation and 15% for cessation. Follow-up analysis indicated that about one-third of these rare variants contribtion is potentially confounded with rare variants structure even after adjusting for principal components. After further conservative adjustment of population structure, we estimated SNP-based heritability to be 0.21 (SE = 0.08) for age of initiation, 0.15 (0.06) for cigarettes per day, 0.21 (0.09) for cessation, and 0.24 (0.07) for initiation, 1.8–4.5 times higher than previous SNP-based estimates. Our pedigree-based upper-bound for SNP-based heritability ranged from 0.18–0.35.Conclusion The substantial contribution of rare variants for several smoking phenotypes sheds light on the missing heritability and genetic etiology of tobacco use. It also informs fine-mapping strategies since the majority of the rare variant contribution was located in non-coding regulatory regions.