TY - JOUR
T1 - Genetic variants associated with earlier age at menopause increase the risk of cardiovascular events in women
AU - Sarnowski, Chloé
AU - Kavousi, Maryam
AU - Isaacs, Steve
AU - Demerath, Ellen W.
AU - Broer, Linda
AU - Muka, Taulant
AU - Franco, Oscar H.
AU - Ikram, Mohammad Arfan
AU - Uitterlinden, André
AU - Franceschini, Nora
AU - Lunetta, Kathryn L.
AU - Murabito, Joanne M.
N1 - Publisher Copyright:
© 2017 by The North American Menopause Society.
PY - 2018/4/1
Y1 - 2018/4/1
N2 - 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 -4 ; 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.
AB - 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 -4 ; 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.
KW - Age-at-natural menopause
KW - Cardiovascular disease
KW - DNA damage response pathway
KW - Genetic correlation
KW - Genetic risk score
KW - Pleiotropy
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U2 - 10.1097/GME.0000000000001017
DO - 10.1097/GME.0000000000001017
M3 - Article
C2 - 29112599
AN - SCOPUS:85045188440
SN - 1072-3714
VL - 25
SP - 451
EP - 457
JO - Menopause
JF - Menopause
IS - 4
ER -
