Large-scale and comprehensive analysis of the associations between immune cell traits and cardiovascular disease risks

Background Immune cells are associated with multiple cardiovascular diseases (CVDs); however, the relationships and mechanisms remain poorly understood. This study aimed to investigate the immune cell-CVD associations at a large-scale level comprehensively. Methods Using GWAS summary statistics of immune cell traits from 3757 participants and CVD data from a meta-analysis of FinnGen and UK Biobank, we estimated the genetic overlap and causality between the 731 immune cell traits and ten kinds of CVDs. Gene function, tissue-specific, and pathway enrichment analysis were subsequently performed, targeting the top 10 pleiotropic genes in each pairwise correlation. Utilizing approximately 600 thousand Single RNA sequencing data from dilated cardiopathy, hypertrophic cardiopathy, and healthy control, the expression of immune cell markers was investigated at the single-cell level between the three groups to verify the MR results. Results A total of 93 pairwise significant genetic overlaps were found between immune cells and CVDs after adjustment (FDR <0.05), with identified 930 pleiotropic genes that shared the most genetic influences. Gene function, tissue-specific, and pathway enrichment analysis targeting the top 3 pleiotropic genes of each pair revealed possible underlying mechanisms. In the univariate MR analysis, 20 immune cell traits were identified to have a significant causal association with 7 CVDs. In the multivariate, the causal effect of 6 immunocyte traits on CVDs were confirmed, including CD20 on IgD- CD38br (odd ratio (OR), 0.970; 95% confidence interval (CI), 0.943-0.999, p<0.05) for valvular heart disease, IgD- CD38- %lymphocyte (OR, 1.030; 95% CI, 1.009-1.052, p<0.05) and CD80 on CD62L+ plasmacytoid DC (OR, 0.975; 95% CI, 0.963-0.988, p<0.05) for heart failure, Naive-mature B cell %B cell (OR, 1.050; 95% CI, 1.009-1.093, p<0.05), CD28 on CD45RA- CD4 not Treg (OR, 0.946; 95% CI, 0.906-0.988, p<0.05), and IgD- CD38dim %lymphocyte (OR, 1.026; 95% CI, 1.003-1.051, p<0.05) for diastolic blood pressure. What’s more, single-cell analysis showed that infiltration of immune cells was significantly different between the dilated cardiopathy and hypertrophic cardiopathy groups. Conclusion Collectively, we first described a comprehensive and large-scale atlas of genetic correlation and causality between immune cell traits and CVDs, which were further validated at gene, cell, and tissue levels.