Inflammatory factors mediated the effect of air pollution on ischemic stroke: a two-step, mediation Mendelian randomization study

Z.-L. Huang, Z.-H. Huang, Y. Xie, Y.-D. Li, Z.-D. Pi, C. Jiang, A.-M. Chen, X.-Y. Gao, J. Wen, J.-M. Zhu

Department of Neurology, Changde Hospital, Xiangya School of Medicine, Central South University, Changde, China. zhujm0718@126.com

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• Neurology

OBJECTIVE: Numerous investigations have indicated a correlation between air pollution (AP) and an elevated ischemic stroke (IS) likelihood. The existing literature does not provide a consensus about the possible link between AP and IS. A two-sample Mendelian randomization (MR) analysis was utilized to systematically measure the causal link between AP and ischemic stroke. Furthermore, the mediating impact of inflammatory factors was also performed by a two-step MR.

MATERIALS AND METHODS: A two-sample MR analysis was utilized to examine the AP impact on the incidence of IS. Additionally, a two-step MR approach was carried out to account for possible mediating variables. The indirect impact was determined by employing the product approach, which included multiplying the AP impact on inflammatory factors by the inflammatory factors’ impacts on IS. The MR effect was identified through inverse variance-weighted (IVW) meta-analysis of each Wald Ratio. Additionally, complementary studies were conducted using the weighted median and MR-egger approaches.

RESULTS: The IVW method with random effects showed that the per unit increase in genetically predicted PM2.5 was linked to the 0.362-fold elevated ischemic stroke risk (OR: 1.362, 95% CI: 1.032-1.796, p=0.029). Furthermore, the IVM technique, incorporating random effects, demonstrated that the per unit increase in genetically predicted PM2.5 was related to an elevated Interleukin (IL)-1β risk (OR: 1.529, 95% CI: 1.191-1.963, p=0.001), IL-6 (OR: 1.498, 95% CI: 1.094-2.052, p=0.012) and IL-17 (OR: 1.478, 95% CI: 1.021-2.139, p=0.038). IL-1β, IL-6, and IL-17 modulated the PM2.5 impact on ischemic stroke, while the proportion mediated by them was 59.5%.

CONCLUSIONS: A positive correlation between genetically predicted PM2.5 levels and elevated ischemic stroke risk is mediated by IL-1β, IL-6, and IL-17.

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