Dissecting the causal association between perturbational responses of human blood cells and ischemic stroke: A Mendelian randomization analysis

This study explores the causal relationship between perturbational responses of human blood cells and ischemic stroke (IS) using Mendelian randomization (MR) analysis and assesses the potential impact of these blood cell perturbations on IS risk. We utilized human blood cell perturbation phenotype data from a large-scale genome-wide association study published in Nature Genetics (January 2024), involving over 4700 participants exposed to 36 perturbations from peripheral blood samples. Genetic determinants of IS were sourced from the IEU OpenGWAS database, encompassing data from 11,929 cases and 472,192 controls of European descent. The primary analytical approach employed was inverse variance weighting, supplemented by alternative methods including weighted median estimation, MR-Egger, simple model, and weighted model. These analyses were integrated with Benjamini-Hochberg false discovery rate (FDR) correction to evaluate the significance of causal associations. Our analysis identified a significant protective causal relationship between platelet perturbational response (odds ratio [OR] = 0.956, 95% confidence interval [CI] = 0.932-0.980, P < .001, PFDR = .036) and IS. Additionally, we found 2 potential causal factors: monocyte perturbational response (OR = 0.941, 95% CI = 0.893-0.991, P = .021, PFDR = .646), which is also protective, and eosinophil perturbational response (OR = 1.010, 95% CI = 1.001-1.018, P = .026, PFDR = .646), identified as a risk factor for IS. Additionally, reliability tests of this MR, including MR-Egger intercept and MR pleiotropy residual sum and outlier tests, revealed no evidence of pleiotropy, and Cochran Q test also confirmed the reliability of our results. Our findings highlight the platelet perturbational response as a significant protective factor against IS. In contrast, the eosinophil perturbational response indicated potential risk effects, while the monocyte perturbational response suggested protective effects; however, these associations did not remain significant after FDR correction. These insights lay the groundwork for future research focused on elucidating the underlying mechanisms and identifying potential therapeutic targets for stroke prevention and treatment.