Department of Cardiovascular Surgery, The First Affiliated Hospital of Zhejiang University School of Medicine, Number 79 Qingchun Road, Hangzhou, China.
BMC Med Genomics. 2023 Apr 6;16(1):75. doi: 10.1186/s12920-023-01496-w.
Growing evidence suggests that various reproductive factors, including early menarche, early menopause, and age at first birth, may increase the risk of developing cardiovascular disease (CVD) later in life. However, the associations between reproductive factors and CVDs are inconsistent and controversial. Therefore, we conducted a two-sample Mendelian randomization (MR) analysis to explore the potential links between age at first sex (AFS) and age at first birth (AFB) and several CVDs.
We obtained summary statistics for exposure from the largest genome-wide association studies of AFS and AFB. To serve as instrumental variables, we selected 259 SNPs associated with AFS and 81 SNPs associated with AFB at the genome-wide significance level. We employed a random-effects inverse-variance weighted method to pool estimates, and conducted multivariable MR analysis to determine the direct association between AFS and AFB with CVDs, while accounting for the effects of confounders.
The genetic liability to later AFS was associated with decreased risks of heart failure (odd ratio [OR] 0.700; 95% confidence interval [CI] 0.639-0.767; p = 2.23 × 10), coronary artery disease (OR 0.728; 95% CI 0.657-0.808; p = 1.82 × 10), myocardial infarction (OR 0.731; 95% CI 0.657-0.813; p = 8.33 × 10), stroke (OR 0.747; 95% CI 0.684-0.816; p = 6.89 × 10), and atrial fibrillation (OR 0.871; 95% CI 0.806-0.941; p = 4.48 × 10). The genetic liability to later AFB was also associated with decreased risks of CVDs, including myocardial infarction (OR 0.895; 95% CI 0.852-0.940; p = 8.66 × 10), coronary heart disease (OR 0.901; 95% CI 0.860-0.943; p = 9.02 × 10), heart failure (OR 0.925; 95% CI 0.891-0.961; p = 5.32 × 10), and atrial fibrillation (OR 0.944; 95% CI 0.911-0.978; p = 0.001). However, no association was found between AFB and stroke. The associations remained independent from the effects of AFS and AFB on potential confounders, including smoking, alcohol intake, body mass index, and depression. Mediation analysis suggested that education attainment partly mediates the link from AFS and AFB to CVD outcomes.
Our results observed a causal relationship between later AFS, AFB and lower CVDs risk; it emphasizes the importance of providing sex education since early sex and birth may have undesirable effects. Cardiovascular risk stratification that considers reproductive factors may help address CVD risk.
越来越多的证据表明，多种生殖因素，包括初潮早、绝经早和初产年龄，可能会增加日后患心血管疾病（CVD）的风险。然而，生殖因素与 CVD 的相关性仍存在争议。因此，我们进行了两样本孟德尔随机化（MR）分析，以探讨初潮年龄（AFS）和初产年龄（AFB）与几种 CVD 之间的潜在联系。
我们从最大的 AFS 和 AFB 全基因组关联研究中获取了暴露的汇总统计数据。为了作为工具变量，我们选择了与 AFS 和 AFB 相关的 259 个 SNP 达到全基因组显著性水平。我们采用随机效应逆方差加权法对估计值进行汇总，并进行多变量 MR 分析，以确定 AFS 和 AFB 与 CVD 之间的直接关联，同时考虑到混杂因素的影响。
后期 AFS 的遗传易感性与心力衰竭（比值比 [OR] 0.700；95%置信区间 [CI] 0.639-0.767；p=2.23×10）、冠状动脉疾病（OR 0.728；95%CI 0.657-0.808；p=1.82×10）、心肌梗死（OR 0.731；95%CI 0.657-0.813；p=8.33×10）、中风（OR 0.747；95%CI 0.684-0.816；p=6.89×10）和心房颤动（OR 0.871；95%CI 0.806-0.941；p=4.48×10）的风险降低有关。后期 AFB 的遗传易感性也与 CVD 风险降低有关，包括心肌梗死（OR 0.895；95%CI 0.852-0.940；p=8.66×10）、冠心病（OR 0.901；95%CI 0.860-0.943；p=9.02×10）、心力衰竭（OR 0.925；95%CI 0.891-0.961；p=5.32×10）和心房颤动（OR 0.944；95%CI 0.911-0.978；p=0.001）。然而，AFB 与中风之间没有关联。这些关联仍然独立于 AFS 和 AFB 对包括吸烟、饮酒、体重指数和抑郁在内的潜在混杂因素的影响。中介分析表明，教育程度部分介导了 AFS 和 AFB 与 CVD 结局之间的联系。
我们的研究结果观察到后期 AFS、AFB 与较低 CVD 风险之间存在因果关系；这强调了提供性教育的重要性，因为早期的性行为和生育可能会产生不良影响。考虑生殖因素的心血管风险分层可能有助于解决 CVD 风险。
