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On May 9, 2023, we reported on a study published in the Journal of the American Heart Association that examined the causal relevance of reproductive factors on cardiovascular disease (CVD) in women using a Mendelian randomization framework.
Investigators first extracted uncorrelated, genome-wide significant single nucleotide polymorphisms from sex-specific genome-wide association studies of age at first birth, number of live births, age at menarche, and age at menopause. They then used inverse-variance weighted Mendelian randomization to evaluate outcomes of AF, CAD, HF, ischemic stroke, and stroke.
Results showed that earlier genetically predicted age at first birth increased the risk of CAD (odds ratio [OR] per year 1.49, 95% CI 1.28-1.74; P=3.72x10-7), HF (OR 1.27, 95% CI 1.06-1.53; P=.009), and stroke (OR 1.25, 95% CI 1.00-1.56; P=.048). Odds were partially mediated through BMI, T2D, blood pressure, and cholesterol traits.
Higher genetically predicted number of live births was associated with increased risk of AF (OR per increase in category of <2, 2, or >2 live births 2.91, 95% CI 1.16-7.29; P=.023), HF (OR 1.90, 95% CI 1.28-2.82; P=.001), ischemic stroke (OR 1.86, 95% CI 1.03–3.37; P=.039), and stroke (OR 2.07, 95% CI 1.22–3.52; P=.007). Earlier genetically predicted age at menarche was associated with an increased risk of CAD (OR per year 1.10, 95% CI 1.06-1.14; P=1.68x10-6) and HF (OR 1.12, 95% CI 1.07-1.17; P=5.06x10-7). Both associations were partially mediated by BMI, noted investigators.
"The results support the emerging research focus on female‐specific risk factors, stressing the importance of their routine evaluation in clinical risk stratification. Additionally, the results highlight that close monitoring and early modification of cardiometabolic factors is a key strategy that will at least partly mitigate the increased cardiovascular risk conferred by these reproductive factors."