School of Public Health (Shenzhen), Sun Yat-sen University, Shenzhen, Guangdong, 518107, China.
Department of Neurology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, China.
Ann Clin Transl Neurol. 2023 Jan;10(1):70-83. doi: 10.1002/acn3.51702. Epub 2022 Nov 17.
We conducted a Mendelian randomization (MR) study to disentangle causal associations between women's reproductive behaviors and ischemic stroke (IS) and investigate the roles of two modifiable risk factors (body mass index (BMI) and educational attainment (EA)) in these associations.
Using summary-level data from large-scale genome-wide association studies, we performed univariable MR to examine whether there is genetic evidence that women's reproductive traits are causally associated with IS and its subtypes. Multivariable MR and MR mediation analysis were used to investigate whether BMI and EA are common mechanisms or mediators for these associations. A set of sensitivity analyses were conducted to test valid MR assumptions.
We observed consistent and statistically significant associations across female and sex-combined analyses for earlier age at first birth (AFB) and age at first sexual intercourse (AFS) with a higher risk of IS and large-artery atherosclerotic stroke (LAS) risk in the primary analysis. The odds ratios of IS per 1 SD increase in genetically predicted early AFB and AFS were 0.93 (95% CI, 0.86-0.99; p = 0.046) and 0.83 (95% CI, 0.70-0.97, p = 0.020), respectively. Further analyses indicated that BMI played a shared role in AFS and IS/LAS while EA played a shared role in AFS/AFB and IS/LAS as well as a mediator in the path from AFS to IS/LAS.
These findings may inform prevention strategies and interventions directed toward relative women's reproductive behaviors and IS. Future studies are warranted to explore other factors related to EA which are responsible for these causalities.
我们进行了一项孟德尔随机化（MR）研究，以厘清女性生殖行为与缺血性卒中（IS）之间的因果关系，并探讨两个可改变的风险因素（体重指数（BMI）和受教育程度（EA））在这些关联中的作用。
使用来自大规模全基因组关联研究的汇总水平数据，我们进行了单变量 MR 分析，以检验女性生殖特征与 IS 及其亚型是否存在遗传相关性。多变量 MR 和 MR 中介分析用于研究 BMI 和 EA 是否是这些关联的共同机制或中介因素。进行了一系列敏感性分析以检验有效的 MR 假设。
在主要分析中，我们在女性和男女混合分析中观察到一致且具有统计学意义的关联，即初次生育年龄（AFB）和初次性行为年龄（AFS）较早与 IS 和大动脉粥样硬化性卒中（LAS）风险升高相关。每增加一个标准差的遗传预测早期 AFB 和 AFS 与 IS 风险的比值比分别为 0.93（95%CI，0.86-0.99；p=0.046）和 0.83（95%CI，0.70-0.97，p=0.020）。进一步的分析表明，BMI 在 AFS 和 IS/LAS 中发挥共同作用，而 EA 在 AFS/AFB 和 IS/LAS 中发挥共同作用，并在 AFS 到 IS/LAS 的路径中发挥中介作用。
这些发现可能为针对女性生殖行为和 IS 的预防策略和干预措施提供信息。未来的研究需要探索与 EA 相关的其他因素，这些因素可能与这些因果关系有关。
