Wu Zhi-Ping, Wei Wei, Liu Shan, Hu Meng-Die, Zhao Heng, Li Xiao-Feng, Chen Xin
Department of Epidemiology, School of Public Health, Dalian Medical University, Dalian, China.
Department of Neurosurgery, Central Hospital of Dalian University of Technology, Dalian, China.
Nutr Metab Cardiovasc Dis. 2025 Jun;35(6):103974. doi: 10.1016/j.numecd.2025.103974. Epub 2025 Mar 13.
Previous studies have reported an association of lacunar stroke with hypertension, obesity, and type 2 diabetes (T2D). The aim of this study was to investigate whether the association was causal and whether body mass index mediated the effect of hypertension on lacunar stroke.
The independence and causal association of hypertension, obesity, and T2D with lacunar stroke were assessed by multivariate Mendelian randomization (MVMR) and network Mendelian randomization (NMR) with inverse variance weighting (IVW). The reliability of the results was increased by sensitivity analyses including MR-Egger, Cochrane's Q test, Mendelian Randomization Pleiotropy RESidual Sum and Outlier (MR-PRESSO), and leave-one-out. MVMR analysis found that genetically predicted hypertension had a 42 % higher lacunar stroke risk (OR: 1.42, 95 % CI: 1.29-1.56, P < 0.001) when adjusted for obesity and T2D, genetically predicted T2D had a 9 % higher lacunar stroke risk (OR: 1.09, 95 % CI: 1.03-1.16, P < 0.004) when adjusted for hypertension and obesity, and genetically predicted obesity had a 15 % lower lacunar stroke risk (OR: 0.85, 95 % CI: 0.77-0.93, P < 0.001) when adjusted for hypertension and T2D. NMR found that 44 % of the association between hypertension and lacunar stroke risk was mediated by obesity.
This genetic association study found novel independent genetic associations between hypertension and T2D with high risk of lacunar stroke, whereas obesity attenuated the risk of lacunar stroke. The findings emphasize the importance of individualized lacunar stroke prevention strategies rather than uniform weight management optimize medical care in high-risk populations.
既往研究报道腔隙性卒中与高血压、肥胖及2型糖尿病（T2D）有关联。本研究旨在调查这种关联是否为因果关系，以及体重指数是否介导了高血压对腔隙性卒中的影响。
采用多变量孟德尔随机化（MVMR）和网络孟德尔随机化（NMR）并结合逆方差加权（IVW）法评估高血压、肥胖及T2D与腔隙性卒中的独立性及因果关联。通过包括MR-Egger、Cochrane's Q检验、孟德尔随机化多效性残差和离群值（MR-PRESSO）以及逐一剔除分析在内的敏感性分析提高结果的可靠性。MVMR分析发现，校正肥胖和T2D后，基因预测的高血压使腔隙性卒中风险升高42%（比值比：1.42，95%置信区间：1.29 - 1.56，P < 0.001）；校正高血压和肥胖后，基因预测的T2D使腔隙性卒中风险升高9%（比值比：1.09，95%置信区间：1.03 - 1.16，P < 0.004）；校正高血压和T2D后，基因预测的肥胖使腔隙性卒中风险降低15%（比值比：0.85，95%置信区间：0.77 - 0.93，P < 0.001）。NMR发现，高血压与腔隙性卒中风险之间44%的关联由肥胖介导。
这项基因关联研究发现高血压和T2D与腔隙性卒中高风险之间存在新的独立基因关联，而肥胖可降低腔隙性卒中风险。这些发现强调了个体化腔隙性卒中预防策略的重要性，而非统一的体重管理，以优化高危人群的医疗护理。
