Causal effects of circulating immune cells on coronary atherosclerosis: Evidence from Mendelian randomization

The role of circulating immune cells in coronary atherosclerosis remains unclear. This study aimed to assess the causal effects of various immune cells on coronary atherosclerosis using Mendelian randomization (MR). Circulating immune cell datasets were obtained from genome-wide association studies, and coronary atherosclerosis datasets were obtained from FinnGen. Single-nucleotide polymorphisms satisfying the assumptions of association, independence, and exclusivity were screened in the datasets and analyzed using MR, with inverse-variance weighted as the main method. Horizontal pleiotropy, heterogeneity, and sensitivity analyses were performed using the MR-Egger, Cochran Q, and leave-one-out analyses, respectively. The MR analysis showed that effector memory double negative (DN) (cluster of differentiation [CD]4-CD8-) %DN (odds ratio [OR]: 1.042, 95% confidence interval [CI]: 1.008-1.077, P = .014), CD4 on CD39+ CD4+ (OR: 1.027, 95% CI: 1.001-1.054, P = .040), C-X3-C motif chemokine receptor 1 on CD14+ CD16- monocytes (OR: 1.035, 95% CI: 1.010-1.060, P = .006), C-C chemokine receptor 7 on naive CD4+ (OR: 1.035, 95% CI: 1.006-1.076, P = .023), and immunoglobulin D- CD38- %lymphocytes (OR: 1.098, 95% CI: 1.016-1.187, P = .019) were associated with an increased genetic susceptibility to coronary atherosclerosis, with no horizontal pleiotropy (P ≥ .05). Cochran Q showed no heterogeneity (P ≥ .05), and the sensitivity analysis indicated that the results were robust. The MR analysis revealed various markers and immune cell subsets, including effector memory DN (CD4-CD8-) %DN, CD4 on CD39+ CD4+, C-X3-C motif chemokine receptor on CD14+ CD16- monocytes, C-C chemokine receptor 7 on naive CD4+, and IgD- CD38- %lymphocytes, associated with increased genetic susceptibility to coronary atherosclerosis. This provides a genetic explanation for the role of specific immune cells in inducing and exacerbating coronary artery disease and offers new ideas for the exploration of immune markers and immune-targeted drugs.