Immune cell-mediated CETP gene and the causal relationship with ischemic stroke disease risk: Mendelian randomization analysis with mediation effect assessment

Background: The advancement of cholesterol ester transfer protein inhibitors in the treatment of coronary heart disease (CHD) has thus far failed to produce approved therapeutic agents, despite Mendelian randomization (MR) studies establishing CETP gene as a viable target for CHD prevention. However, there is currently no empirical evidence supporting the role of CETP-related genes as potential therapeutic targets for ischemic stroke. Our study aims to delineate CETP gene as a novel key player in ischemic stroke pathogenesis, establish its causal association with ischemic stroke, and assess the potential mediating effect of immune cells in this process. Methods Using the expression quantitative trait loci (eQTL) database and a cross-ethnic cohort of 688807 Europeans and Asians, we conducted MR analysis to investigate the causal relationship between key genes and ischemic stroke. Additionally, we performed mediation analysis to examine the involvement of 731 immune phenotypes in these relationships. Result We confirmed that an increase in CETP gene expression is associated with an increased risk of ischemic stroke (OR 1.090, 95% CI : 1.033 to 1.151, p = 0.002), and 11 types of immune cells including IgD + CD24 + B cells mediate this causal relationship. Conclusion Increased CETP gene expression is closely associated with a high risk of ischemic stroke, and CETP inhibitors may serve as the next generation of drugs for ischemic stroke therapy.