Liu Renjie, Shi Xin, Feng Jiahui, Piao Jianmin, Yang Zhongxi, Zhao Yuhao, Yin Haoyuan, Chen Xuan
Department of Neurovascular Surgery, The First Hospital of Jilin University, Changchun, 130021, Jilin, China.
Department of Radiology, The First Hospital of Jilin University, Changchun, 130021, Jilin, China.
Neurol Ther. 2023 Aug;12(4):1299-1308. doi: 10.1007/s40120-023-00500-w. Epub 2023 Jun 3.
Recent observational studies have reported the association between ischemic stroke (IS) and cerebral microbleeds (CMBs). Whether this reflects a causal association remains to be established. Herein, we adopted a two-sample bidirectional Mendelian randomization (MR) analysis to comprehensively evaluate the causal association of IS and CMBs.
The summary-level genome-wide association studies (GWASs) data of IS were obtained from the GIGASTROKE consortium (62,100 European ancestry cases and 1,234,808 European ancestry controls). All IS cases could be further divided into large-vessel atherosclerosis stroke (LVS, n = 6399), cardio-embolic stroke (CES, n = 10,804) and small-vessel occlusion stroke (SVS, n = 6811). Meanwhile, we used publicly available summary statistics from published GWASs of CMBs (3556 of the 25,862 European participants across 2 large initiatives). A bidirectional MR analysis was conducted using inverse-variance weighting (IVW) as the major outcome, whereas MR-Egger and weighted median (WM) were used to complement the IVW estimates as they can provide more robust estimates in a broader set of scenarios but are less efficient (wider CIs). A Bonferroni-corrected threshold of p < 0.0125 was considered significant, and p values between 0.0125 and 0.05 were considered suggestive of evidence for a potential association.
We detected that higher risk of IS [IVW odds ratio (OR) 1.47, 95% confidence interval (CI) 1.04-2.07, p = 0.03] and SVS (IVW OR 1.62, 95% CI 1.07-2.47, p = 0.02) were significantly associated with CMBs. Reverse MR analyses found no significant evidence for a causal effect of CMBs on IS and its subtypes.
Our study provides potential evidence that IS and SVS are causally linked to increased risk of CMBs. Further research is needed to determine the mechanisms of association between IS and CMBs.
近期的观察性研究报告了缺血性卒中（IS）与脑微出血（CMBs）之间的关联。这是否反映了因果关系仍有待确定。在此，我们采用两样本双向孟德尔随机化（MR）分析来全面评估IS与CMBs之间的因果关联。
IS的汇总水平全基因组关联研究（GWAS）数据来自GIGASTROKE联盟（62100例欧洲血统病例和1234808例欧洲血统对照）。所有IS病例可进一步分为大动脉粥样硬化性卒中（LVS，n = 6399）、心源性栓塞性卒中（CES，n = 10804）和小血管闭塞性卒中（SVS，n = 6811）。同时，我们使用了已发表的CMBs的GWAS的公开汇总统计数据（来自2项大型研究的25862名欧洲参与者中的3556名）。以逆方差加权（IVW）作为主要结果进行双向MR分析，而MR-Egger和加权中位数（WM）用于补充IVW估计值，因为它们可以在更广泛的情况下提供更稳健的估计值，但效率较低（置信区间更宽）。经Bonferroni校正的p < 0.0125的阈值被认为具有显著性，0.0125至0.05之间的p值被认为提示可能存在关联的证据。
我们发现，IS的较高风险[IVW比值比（OR）1.47，95%置信区间（CI）1.04 - 2.07，p = 0.03]和SVS（IVW OR 1.62，95% CI 1.07 - 2.47，p = 0.02）与CMBs显著相关。反向MR分析未发现CMBs对IS及其亚型有因果效应的显著证据。
我们的研究提供了潜在证据，表明IS和SVS与CMBs风险增加存在因果联系。需要进一步研究以确定IS与CMBs之间的关联机制。
