National Heart and Lung Institute Imperial College London London United Kingdom.
Nuffield Department of Population Health University of Oxford Oxford United Kingdom.
J Am Heart Assoc. 2023 Mar 7;12(5):e027933. doi: 10.1161/JAHA.122.027933. Epub 2023 Feb 27.
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 (<0.001), genome-wide significant (<5×10) 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], =3.72×10) heart failure (OR, 1.27 [95% CI, 1.06-1.53], =0.009), and stroke (OR, 1.25 [95% CI, 1.00-1.56], =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], =0.023), heart failure (OR, 1.90 [95% CI, 1.28-2.82], =0.001), ischemic stroke (OR, 1.86 [95% CI, 1.03-3.37], =0.039), and stroke (OR, 2.07 [95% CI, 1.22-3.52], =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], =1.68×10) and heart failure (OR, 1.12 [95% CI, 1.07-1.17], =5.06×10); 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.
观察性研究表明，生殖因素与心血管疾病有关，但这些因素容易受到残余混杂因素的影响。本研究使用孟德尔随机化方法探讨生殖因素对女性心血管疾病的因果关系。
从性别特异性的初潮年龄、活产数、初潮年龄和绝经年龄的全基因组关联研究中提取出不相关（<0.001）、全基因组显著性（<5×10）的单核苷酸多态性。采用逆方差加权孟德尔随机化方法对心房颤动、冠心病、心力衰竭、缺血性卒中和卒中等结局进行主要分析。遗传预测的初潮年龄较早，会增加患冠心病（每年风险比[OR]，1.49 [95%置信区间，1.28-1.74]，=3.72×10）、心力衰竭（OR，1.27 [95%置信区间，1.06-1.53]，=0.009）和卒中（OR，1.25 [95%置信区间，1.00-1.56]，=0.048）的风险，部分通过体重指数、2 型糖尿病、血压和胆固醇特征进行中介。遗传预测的活产数较高，会增加患心房颤动（<2、2、>2 次活产的 OR，2.91 [95%置信区间，1.16-7.29]，=0.023）、心力衰竭（OR，1.90 [95%置信区间，1.28-2.82]，=0.001）、缺血性卒中和卒中（OR，1.86 [95%置信区间，1.03-3.37]，=0.039）和卒中等风险，这表明生殖因素与女性心血管疾病之间存在因果关系，并确定了多个可通过临床干预来调节的中介因素。
这些结果支持了生殖因素对女性心血管疾病的因果作用，并确定了多个可通过临床干预来调节的中介因素。
