Division of Neurocritical Care and Emergency Neurology, Department of Neurology (J.N.A., N.S., C.P.B., K.V., R.B.N., K.N.S., G.J.F.), Yale School of Medicine, New Haven, CT.
Department of Neurology (N.S.), Medical University of Warsaw, Poland.
Stroke. 2021 Jan;52(2):582-587. doi: 10.1161/STROKEAHA.120.031622. Epub 2021 Jan 14.
Animal and observational studies indicate that smoking is a risk factor for aneurysm formation and rupture, leading to nontraumatic subarachnoid hemorrhage (SAH). However, a definitive causal relationship between smoking and the risk of SAH has not been established. Using Mendelian randomization (MR) analyses, we tested the hypothesis that smoking is causally linked to the risk of SAH.
We conducted a 1-sample MR study using data from the UK Biobank, a large cohort study that enrolled over 500 000 Britons aged 40 to 69 from 2006 to 2010. Participants of European descent were included. SAH cases were ascertained using a combination of self-reported, electronic medical record, and death registry data. As the instrument, we built a polygenic risk score using independent genetic variants known to associate (<5) with smoking behavior. This polygenic risk score represents the genetic susceptibility to smoking initiation. The primary MR analysis utilized the ratio method. Secondary MR analyses included the inverse variance weighted and weighted median methods.
A total of 408 609 study participants were evaluated (mean age, 57 [SD 8], female sex, 220 937 [54%]). Among these, 132 566 (32%) ever smoked regularly, and 904 (0.22%) had a SAH. Each additional SD of the smoking polygenic risk score was associated with 21% increased risk of smoking (odds ratio [OR], 1.21 [95% CI, 1.20-1.21]; <0.001) and a 10% increased risk of SAH (OR, 1.10 [95% CI, 1.03-1.17]; =0.006). In the primary MR analysis, genetic susceptibility to smoking was associated with a 63% increase in the risk of SAH (OR, 1.63 [95% CI, 1.15-2.31]; =0.006). Secondary analyses using the inverse variance weighted method (OR, 1.57 [95% CI, 1.13-2.17]; =0.007) and the weighted median method (OR, 1.74 [95% CI, 1.06-2.86]; =0.03) yielded similar results. There was no significant pleiotropy (MR-Egger intercept =0.39; MR Pleiotropy Residual Sum and Outlier global test =0.69).
These findings provide evidence for a causal link between smoking and the risk of SAH.
动物研究和观察性研究表明，吸烟是动脉瘤形成和破裂的危险因素，导致非创伤性蛛网膜下腔出血（SAH）。然而，吸烟与 SAH 风险之间的明确因果关系尚未建立。本研究使用孟德尔随机化（MR）分析，检验了吸烟与 SAH 风险之间存在因果关系的假设。
我们使用 UK Biobank 的数据进行了一项单样本 MR 研究，该研究是一项大型队列研究，于 2006 年至 2010 年招募了超过 50 万 40 至 69 岁的英国人。纳入了欧洲血统的参与者。SAH 病例通过结合自我报告、电子病历和死亡登记数据确定。作为工具，我们使用与吸烟行为独立相关的独立遗传变异（<5）构建了一个多基因风险评分。该多基因风险评分代表了吸烟起始的遗传易感性。主要 MR 分析采用比值法。次要 MR 分析包括逆方差加权和加权中位数方法。
共评估了 408609 名研究参与者（平均年龄为 57[8]岁，女性 220937[54%]）。其中，32%的人经常吸烟，904 人（0.22%）患有 SAH。吸烟多基因风险评分每增加一个标准差，吸烟风险增加 21%（优势比[OR]，1.21[95%置信区间，1.20-1.21]；<0.001），SAH 风险增加 10%（OR，1.10[95%置信区间，1.03-1.17]；=0.006）。在主要 MR 分析中，吸烟的遗传易感性与 SAH 风险增加 63%相关（OR，1.63[95%置信区间，1.15-2.31]；=0.006）。使用逆方差加权法（OR，1.57[95%置信区间，1.13-2.17]；=0.007）和加权中位数法（OR，1.74[95%置信区间，1.06-2.86]；=0.03）的二次分析得出了类似的结果。没有显著的异质性（MR-Egger 截距=0.39；MR 异质性残差总和和异常值全局检验=0.69）。
这些发现为吸烟与 SAH 风险之间存在因果关系提供了证据。
