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Genetic variants associated with earlier age at menopause increase the risk of cardiovascular events in women.

ABSTRACT: OBJECTIVE:To better understand the relationship between cardiovascular disease risk and age-at-natural menopause using genetic data. METHODS:Early menopause is associated with cardiovascular disease risk. We constructed a genetic risk score comprising 56 age-at-natural menopause decreasing alleles in men and women from the Framingham Heart Study, the Atherosclerosis Risk in Communities Study, and the Rotterdam Study. If the genetic predisposition to earlier age-at-natural menopause is associated with increased cardiovascular disease risk, it is reasonable to ask whether the risk is shared by men carrying the alleles, despite not experiencing menopause. We estimated the hazard ratio for the score for time to first cardiovascular event. To investigate the possible genetic pleiotropy between age-at-natural menopause and cardiovascular disease, we performed cross-trait linkage disequilibrium score regressions between age-at-natural menopause and cardiovascular disease and risk factors using genome-wide association studies. RESULTS:Twenty-two thousand five hundred and sixty-eight cardiovascular disease-free participants at baseline were analyzed (9,808 men, 12,760 women). Each additional unit of the genetic propensity to earlier age-at-natural menopause increased the hazard of both cardiovascular disease and cardiac death in women (cardiovascular disease: hazard ratio 1.10 [1.04-1.16], P?=?9.7?×?10; cardiac death: 1.12 [1.02-1.24], P?=?0.03), whereas no effect was observed for either outcome in men (hazard ratio 0.99 [0.95-1.04], P?=?0.71; 1.05 [0.94-1.16], P?=?0.34). We found significant negative genetic correlations in women, but not men, between age-at-natural menopause and cardiovascular disease and risk factors. CONCLUSION:Genetic variants associated with earlier age-at-natural menopause are associated with increased cardiovascular disease risk in women, but not men, suggesting sex-specific genetic effects on cardiovascular disease risk.

SUBMITTER: Sarnowski C

PROVIDER: S-EPMC5866156 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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Genetic variants associated with earlier age at menopause increase the risk of cardiovascular events in women.

Sarnowski Chloé C Kavousi Maryam M Isaacs Steve S Demerath Ellen W EW Broer Linda L Muka Taulant T Franco Oscar H OH Ikram Mohammad Arfan MA Uitterlinden André A Franceschini Nora N Lunetta Kathryn L KL Murabito Joanne M JM

Menopause (New York, N.Y.) 20180401 4

<h4>Objective</h4>To better understand the relationship between cardiovascular disease risk and age-at-natural menopause using genetic data.<h4>Methods</h4>Early menopause is associated with cardiovascular disease risk. We constructed a genetic risk score comprising 56 age-at-natural menopause decreasing alleles in men and women from the Framingham Heart Study, the Atherosclerosis Risk in Communities Study, and the Rotterdam Study. If the genetic predisposition to earlier age-at-natural menopaus ...[more]

PMID: 29112599

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Project description:While multiple genetic markers associated with cardiovascular disease have been identified by genome-wide association studies, their aggregate effect on risk beyond traditional factors is uncertain, particularly among women.To test the predictive ability of a literature-based genetic risk score for cardiovascular disease.Prospective cohort of 19,313 initially healthy white women in the Women's Genome Health Study followed up over a median of 12.3 years (interquartile range, 11.6-12.8 years). Genetic risk scores were constructed from the National Human Genome Research Institute's catalog of genome-wide association study results published between 2005 and June 2009.Incident myocardial infarction, stroke, arterial revascularization, and cardiovascular death.A total of 101 single nucleotide polymorphisms reported to be associated with cardiovascular disease or at least 1 intermediate cardiovascular disease phenotype at a published P value of less than 10(-7) were identified and risk alleles were added to create a genetic risk score. During follow-up, 777 cardiovascular disease events occurred (199 myocardial infarctions, 203 strokes, 63 cardiovascular deaths, 312 revascularizations). After adjustment for age, the genetic risk score had a hazard ratio (HR) for cardiovascular disease of 1.02 per risk allele (95% confidence interval [CI], 1.00-1.03/risk allele; P = .006). This corresponds to an absolute cardiovascular disease risk of 3% over 10 years in the lowest tertile of genetic risk (73-99 risk alleles) and 3.7% in the highest tertile (106-125 risk alleles). However, after adjustment for traditional factors, the genetic risk score did not improve discrimination or reclassification (change in c index from Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults [ATP III] risk score, 0; net reclassification improvement, 0.5%; [P = .24]). The genetic risk score was not associated with cardiovascular disease risk (ATP III-adjusted HR/allele, 1.00; 95% CI, 0.99-1.01). In contrast, self-reported family history remained significantly associated with cardiovascular disease in multivariable models.After adjustment for traditional cardiovascular risk factors, a genetic risk score comprising 101 single nucleotide polymorphisms was not significantly associated with the incidence of total cardiovascular disease.

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Genetic variants associated with earlier age at menopause increase the risk of cardiovascular events in women.

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Genetic variants associated with earlier age at menopause increase the risk of cardiovascular events in women.

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