Sex‐Specific Reproductive Factors Augment Cardiovascular Disease Risk in Women: A Mendelian Randomization Study

BACKGROUND: Observational studies suggest that reproductive factors are associated with cardiovascular disease, but these are liable to influence by residual confounding. This study explores the causal relevance of reproductive factors on cardiovascular disease in women using Mendelian randomization. METHODS AND RESULTS: Uncorrelated (r (2)<0.001), genome‐wide significant (P<5×10(−8)) single‐nucleotide polymorphisms were extracted from sex‐specific genome‐wide association studies of age at first birth, number of live births, age at menarche, and age at menopause. Inverse‐variance weighted Mendelian randomization was used for primary analyses on outcomes of atrial fibrillation, coronary artery disease, heart failure, ischemic stroke, and stroke. Earlier genetically predicted age at first birth increased risk of coronary artery disease (odds ratio [OR] per year, 1.49 [95% CI, 1.28–1.74], P=3.72×10(−7)) heart failure (OR, 1.27 [95% CI, 1.06–1.53], P=0.009), and stroke (OR, 1.25 [95% CI, 1.00–1.56], P=0.048), with partial mediation through body mass index, type 2 diabetes, blood pressure, and cholesterol traits. Higher genetically predicted number of live births increased risk of atrial fibrillation (OR for <2, versus 2, versus >2 live births, 2.91 [95% CI, 1.16–7.29], P=0.023), heart failure (OR, 1.90 [95% CI, 1.28–2.82], P=0.001), ischemic stroke (OR, 1.86 [95% CI, 1.03–3.37], P=0.039), and stroke (OR, 2.07 [95% CI, 1.22–3.52], P=0.007). Earlier genetically predicted age at menarche increased risk of coronary artery disease (OR per year, 1.10 [95% CI, 1.06–1.14], P=1.68×10(−6)) and heart failure (OR, 1.12 [95% CI, 1.07–1.17], P=5.06×10(−7)); both associations were at least partly mediated by body mass index. CONCLUSIONS: These results support a causal role of a number of reproductive factors on cardiovascular disease in women and identify multiple modifiable mediators amenable to clinical intervention.