Plasma proteome mediate the impact of PM_2.5 on stroke: A 2-step Mendelian randomization study

The objectives of this study were to measure the mediation effect of plasma proteins and to clarify their mediating role in the relationship between stroke risk and particulate matter 2.5 (PM_2.5) exposure. The possible mediating role of plasma proteins on the causative link between PM_2.5 exposure and stroke incidence were examined using a two-step Mendelian randomization (MR) approach based on two-sample Mendelian randomization (TSMR). The findings revealed a significant positive causal relationship between PM_2.5 exposure and stroke, with an inverse variance weighted odds ratio of 1.219 (95 % CI: 1.002 - 1.482, P < 0.05). Additionally, a positive causal association was identified between PM_2.5 exposure and several plasma proteins, including FAM134B, SAP, ITGB7, Elafin, and DCLK3. Among these, FAM134B, ITGB7, Elafin, and DCLK3 also demonstrated a positive causal association with stroke, whereas only SAP was found to be negatively causally associated with stroke. Remarkably, four plasma proteins, namely DCLK3, FAM134B, Elafin, and ITGB7, were identified as mediators, accounting for substantial proportions (14.5 %, 13.6 %, 11.1 %, and 9.9 %) of the causal association between PM_2.5 and stroke. These results remained robust across various sensitivity analyses. Consequently, the study highlights the significant and independent impact of PM_2.5 on stroke risk and identifies specific plasma proteins as potential targets for preventive interventions against PM_2.5-induced stroke.