Inflammatory Cytokines and Risk of Ischemic Stroke: A Mendelian Randomization Study

Yalan Li; Jun Lu; Jie Wang; Peizhi Deng; Changjiang Meng; Haibo Tang

doi:10.3389/fphar.2021.779899

Inflammatory Cytokines and Risk of Ischemic Stroke: A Mendelian Randomization Study

Front Pharmacol. 2022 Jan 17:12:779899. doi: 10.3389/fphar.2021.779899. eCollection 2021.

Authors

Yalan Li^{1

2}, Jun Lu³, Jie Wang^{1

2}, Peizhi Deng^{1

2}, Changjiang Meng^{1

2}, Haibo Tang⁴

Affiliations

¹ Center of Clinical Pharmacology, The Third Xiangya Hospital, Central South University, Changsha, China.
² Department of Cardiology, The Third Xiangya Hospital, Central South University, Changsha, China.
³ School of Medicine, Hunan Normal University, Changsha, China.
⁴ Department of Metabolic and Bariatric Surgery, The Third Xiangya Hospital, Central South University, Changsha, China.

Abstract

Background: Observational studies have revealed the association between some inflammatory cytokines and the occurrence of ischemic stroke, but the causal relationships remain unclear. Methods: We conducted a two-sample Mendelian randomization (MR) analysis to assess the causal effects of thirty inflammatory cytokines and the risk of ischemic stroke. For exposure data, we collected genetic variants associated with inflammatory cytokines as instrumental variables (IVs) from a genome-wide association study (GWAS) meta-analysis from Finland (sample size up to 8,293). For the outcome data, we collected summary data of ischemic stroke from a large-scale GWAS meta-analysis involved 17 studies (34,217 cases and 406,111 controls). We further performed a series of sensitivity analyses as validation of primary MR results. Results: According to the primary MR estimations and further sensitivity analyses, we established one robust association after Bonferroni correction: the odds ratio (95% CI) per unit change in genetically increased IL-4 was 0.84 (0.89-0.95) for ischemic stroke. The chemokine MCP3 showed a nominally significant association with ischemic stroke risk (OR: 0.93, 95% CI: 0.88-0.99, unadjusted p < 0.05). There was no evidence of a causal effect of other inflammatory cytokines and the risk of ischemic stroke. Conclusions: Our study suggested that genetically increased IL-4 levels showed a protective effect on the risk of ischemic stroke, which provides important new insights into the potential therapeutic target for preventing ischemic stroke.

Keywords: Mendelian randomization; causal inference; inflammatory cytokines; instrumental variable (IV); ischemic stroke.