Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing 100053, China.
Department of Epidemiology and Health Statistics, School of Public Health, Capital Medical University, Beijing 100069, China.
J Stroke Cerebrovasc Dis. 2024 Jun;33(6):107686. doi: 10.1016/j.jstrokecerebrovasdis.2024.107686. Epub 2024 Mar 24.
Cross-sectional and cohort studies have found insufficient evidence of a causal relationship between sex hormone-binding globulin and ischemic stroke, only associations. Here, we performed a sex-stratified, bidirectional, two-sample Mendelian randomization analysis to evaluate whether a causal relationship exists between sex hormone-binding globulin and ischemic stroke.
Single-nucleotide polymorphisms associated with sex hormone-binding globulin and ischemic stroke were screened from genome-wide association studies summary data as instrumental variables to enable a bidirectional, two-sample Mendelian randomization study design. Inverse-variance weighted analysis was used as the main method to evaluate potential causality, and additional methods, including the weighted median and MR-Egger tests, were used to validate the Mendelian randomization results. Cochran's Q statistic, MR-Egger intercept test, and Mendelian Randomization-Pleiotropy Residual Sum and Outlier global test were used as sensitivity analysis techniques to assure the reliability of the results. Multivariable analysis was used to show the robustness of the results with key theorized confounders.
Inverse-variance weighted analysis showed that genetically predicted higher serum sex hormone-binding globulin levels were associated with significantly decreased risk of ischemic stroke in males (odds radio = 0.934, 95 % confidence interval = 0.885-0.985, P = 0.012) and females (odds radio = 0.924, 95 % confidence interval = 0.868-0.983, P = 0.013). In an analysis of ischemic stroke subtypes, genetically predicted higher serum sex hormone-binding globulin levels were also associated with significantly decreased risk of small-vessel occlusion in both males (odds radio = 0.849, 95 % confidence interval = 0.759-0.949, P = 0.004) and females (odds radio = 0.829, 95 % confidence interval = 0.724-0.949, P = 0.006). The association remained in sensitivity analyses and multivariable analyses. The reverse analysis suggested an association between genetically predicted risk of cardioembolism and increased serum sex hormone-binding globulin in females (Beta = 0.029 nmol/L, Standard Error = 0.010, P = 0.003).
Our findings provide new insight into the etiology of ischemic stroke and suggest that modulating serum sex hormone-binding globulin may be a therapeutic strategy to protect against ischemic stroke.
横断面和队列研究发现，性激素结合球蛋白与缺血性卒中之间的因果关系证据不足，仅有相关性。本研究旨在进行性别分层、双向、两样本孟德尔随机化分析，以评估性激素结合球蛋白与缺血性卒中之间是否存在因果关系。
从全基因组关联研究汇总数据中筛选与性激素结合球蛋白和缺血性卒中相关的单核苷酸多态性作为工具变量，以实现双向、两样本孟德尔随机化研究设计。采用逆方差加权分析作为主要方法来评估潜在的因果关系，并采用加权中位数和 MR-Egger 检验等额外方法来验证孟德尔随机化结果。Cochran's Q 统计量、MR-Egger 截距检验和 Mendelian Randomization-Pleiotropy Residual Sum and Outlier 全局检验用于敏感性分析技术，以确保结果的可靠性。多变量分析用于显示关键理论混杂因素下结果的稳健性。
逆方差加权分析表明，遗传预测的血清性激素结合球蛋白水平升高与男性（比值比=0.934，95%置信区间=0.885-0.985，P=0.012）和女性（比值比=0.924，95%置信区间=0.868-0.983，P=0.013）缺血性卒中风险显著降低相关。在缺血性卒中亚型分析中，遗传预测的血清性激素结合球蛋白水平升高与男性（比值比=0.849，95%置信区间=0.759-0.949，P=0.004）和女性（比值比=0.829，95%置信区间=0.724-0.949，P=0.006）小血管闭塞风险显著降低也相关。该关联在敏感性分析和多变量分析中仍然存在。反向分析表明，女性中遗传预测的心源性栓塞风险与血清性激素结合球蛋白升高之间存在关联（Beta=0.029 nmol/L，标准误差=0.010，P=0.003）。
本研究结果为缺血性卒中的病因学提供了新的见解，并提示调节血清性激素结合球蛋白可能是预防缺血性卒中的一种治疗策略。
