评估二氧化氮（NO₂）、氮氧化物（NO_x）、细颗粒物（PM_2.5）和可吸入颗粒物（PM₁₀）4种空气污染物与缺血性脑卒中、脑出血、蛛网膜下腔出血的风险之间是否存在因果关联。

采用双样本孟德尔随机化（MR）设计。将NO₂、NO_x、PM_2.5和PM₁₀等空气污染物相关的单核苷酸多态性（SNP）作为工具变量，摘要数据均来自英国生物银行（UKB）数据库。缺血性脑卒中、脑出血、蛛网膜下腔出血的数据分别来自MEGASTROKE项目、国际卒中遗传学联盟、全基因组关联研究2020年发表的欧洲人群动脉瘤破裂导致蛛网膜下腔出血部分。主要分析方法为逆方差加权法（IVW），并采用简单中位数法、加权中位数法、MR-Egger回归、留一法及MR-PRESSO法进行敏感性分析。

随机效应IVW分析结果显示：PM_2.5与蛛网膜下腔出血存在名义上的关联，但置信区间较宽（OR=5.75，95%CI：1.13~29.20，P=0.035）；经Bonferroni校正后，该名义相关信号不再具有统计学意义。进一步敏感性分析结果显示，留一法及MR-PRESSO法识别出离群SNP，在校正离群值后，效应量大幅降低且差异无统计学意义（OR=2.05，95%CI：0.98~4.29，P=0.069）。未发现其他空气污染物（NO₂、NO_x、PM₁₀）与蛛网膜下腔出血存在显著关联，也未发现空气污染物（NO₂、NO_x、PM_2.5、PM₁₀）与脑出血、缺血性脑卒中存在显著关联。

本研究未发现遗传预测的常见空气污染物（NO₂、NO_x、PM_2.5、PM₁₀）暴露与缺血性脑卒中、脑出血及蛛网膜下腔出血存在稳健的整体人群因果关联，但PM_2.5与蛛网膜下腔出血存在名义相关信号，该信号主要由一个离群SNP驱动，提示该遗传变异可能作为效应修饰因子参与基因-环境交互作用。

To assess whether there are causal associations between four air pollutants [nitrogen dioxide (NO₂), nitrogen oxides (NO_x), fine particulate matter (PM_2.5), and inhalable particulate matter (PM₁₀)] and the risk of ischemic stroke, intracerebral hemorrhage, and subarachnoid hemorrhage.

A two-sample Mendelian randomization (MR) approach was employed. Single nucleotide polymorphisms associated with air pollutants such as NO₂, NO_x, PM_2.5, and PM₁₀ were used as instrumental variables, with summary data sourced from the UK Biobank database. Data for ischemic stroke, intracerebral hemorrhage, and subarachnoid hemorrhage were obtained from the MEGASTROKE project, the International Stroke Genetics Consortium, and the dataset of aneurysmal subarachnoid hemorrhage with European populations in the 2020 genome-wide association study, respectively. The primary analysis method was the inverse variance weighting (IVW) method, with sensitivity analyses conducted using the simple median, weighted median, MR-Egger regression, leave-one-out and MR-PRESSO methods.

The random-effects IVW analysis showed a nominal association between PM_2.5 and subarachnoid hemorrhage, but the confidence interval was wide (OR=5.75, 95%CI: 1.13 – 29.20, P=0.035). After Bonferroni correction, this nominal association was no longer statistically significant. Further sensitivity analyses using MR-PRESSO and leave-one-out methods identified an outlier SNP; after correction for this outlier, the effect estimate substantially decreased and lost statistical significance (OR=2.05, 95%CI: 0.98 – 4.29, P=0.069). No associations were observed between subarachnoid hemorrhage and other air pollutants (NO₂, NO_x, and PM₁₀), and no significant associations were found between any air pollutants and intracerebral hemorrhage or ischemic stroke.

This study found no robust causal association between genetically predicted exposure to common air pollutants (NO₂, NO_x, PM_2.5, and PM₁₀) and the risk of ischemic stroke, intracerebral hemorrhage, or subarachnoid hemorrhage. The nominally significant association between PM_2.5 and subarachnoid hemorrhage was largely driven by an outlier SNP, the signal was mainly driven by an outlier SNP, suggesting hat this genetic variant may act as an effect modifier in gene-environment interactions.