Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, GA 3508 Utrecht, the Netherlands.
Netherlands Heart Institute, DG 3501 Utrecht, the Netherlands.
J Clin Endocrinol Metab. 2022 Jun 16;107(7):e2952-e2961. doi: 10.1210/clinem/dgac171.
Accelerated reproductive aging, in women indicated by early natural menopause, is associated with increased coronary heart disease (CHD) risk in observational studies. Conversely, an adverse CHD risk profile has been suggested to accelerate menopause.
To study the direction and evidence for causality of the relationship between reproductive aging and (non-)fatal CHD and CHD risk factors in a bidirectional Mendelian randomization (MR) approach, using age at natural menopause (ANM) genetic variants as a measure for genetically determined reproductive aging in women. We also studied the association of these variants with CHD risk (factors) in men.
Two-sample MR, using both cohort data as well as summary statistics, with 4 methods: simple and weighted median-based, standard inverse-variance weighted (IVW) regression, and MR-Egger regression.
Data from EPIC-CVD and summary statistics from UK Biobank and publicly available genome-wide association studies were pooled for the different analyses.
CHD, CHD risk factors, and ANM.
Across different methods of MR, no association was found between genetically determined reproductive aging and CHD risk in women (relative risk estimateIVW = 0.99; 95% confidence interval (CI), 0.97-1.01), or any of the CHD risk factors. Similarly, no associations were found in men. Neither did the reversed analyses show evidence for an association between CHD (risk factors) and reproductive aging.
Genetically determined reproductive aging is not causally associated with CHD risk (factors) in women, nor were the genetic variants associated in men. We found no evidence for a reverse association in a combined sample of women and men.
在观察性研究中，女性的加速生殖衰老（以自然绝经早为指标）与冠心病（CHD）风险增加有关。相反，不良的 CHD 风险状况被认为会加速绝经。
使用绝经年龄（ANM）的遗传变异作为女性生殖衰老的遗传决定因素的衡量标准，采用双向孟德尔随机化（MR）方法，研究生殖衰老与（非）致命性 CHD 和 CHD 风险因素之间关系的方向和因果关系的证据。我们还研究了这些变体与男性 CHD 风险（因素）的关联。
两样本 MR，使用队列数据和汇总统计数据，共 4 种方法：简单和加权中位数、标准逆方差加权（IVW）回归和 MR-Egger 回归。
来自 EPIC-CVD 的数据和来自 UK Biobank 的汇总统计数据以及公开的全基因组关联研究数据被汇总用于不同的分析。
CHD、CHD 风险因素和 ANM。
在不同的 MR 方法中，遗传决定的生殖衰老与女性 CHD 风险（相对风险估计 IVW=0.99；95%置信区间（CI），0.97-1.01）或任何 CHD 风险因素之间均无关联。同样，在男性中也没有发现关联。反向分析也没有发现 CHD（风险因素）与生殖衰老之间存在关联的证据。
遗传决定的生殖衰老与女性的 CHD 风险（因素）之间没有因果关系，男性的遗传变异也没有关联。我们在女性和男性的综合样本中没有发现反向关联的证据。
