Genome-wide cross-trait analysis reveals immunogenetic pleiotropy between autoimmune diseases and myocardial infarction and prioritizes therapeutic targets.
TL;DR
Specific ADs and MI share an immunogenetic architecture involving immune and vascular pathways involving immune and vascular pathways that warrant further mechanistic investigation.
Abstract
Background
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Aims
Autoimmune diseases (ADs) are associated with increased myocardial infarction (MI) risk, suggesting shared genetic susceptibility. We systematically investigated the shared genetic architecture, pleiotropic loci, and candidate therapeutic targets linking ADs and MI.
Methods
We analyzed genome-wide association study summary statistics for 10 ADs and MI, primarily from European-ancestry populations. Linkage disequilibrium score regression, high-definition likelihood, stratified linkage disequilibrium score regression, pleiotropy analysis, Bayesian colocalization, and immune-trait colocalization were performed. Candidate genes were prioritized using summary-data-based Mendelian randomization and followed up using quantitative polymerase chain reaction in hypoxia-treated HL-1 cardiomyocytes and by descriptive expression profiling in single-cell RNA sequencing datasets from human atherosclerotic plaques and cardiac resident immune cells.
Results
MI showed significant positive genetic correlations with Crohn's disease, rheumatoid arthritis (RA), and primary biliary cholangitis (PBC) after false discovery rate correction. We identified 49 pleiotropic loci, including 7 with colocalization evidence compatible with a shared causal variant. Integrative analyses prioritized 12 candidate genes, with SH2B3, TMEM116, and ACAD10 highlighted across multiple disease pairs. Immune-trait colocalization highlighted activated monocyte- and T-cell-related features in RA-MI and PBC-MI. In HL-1 cardiomyocytes, hypoxia increased Acad10, Sh2b3, and Tmem116 expression over time. In single-cell datasets, SH2B3 showed prominent expression in plaque macrophages, endothelial cells, and cardiac resident macrophages.
Conclusions
Specific ADs and MI share an immunogenetic architecture involving immune and vascular pathways. These findings prioritize pleiotropic loci, candidate genes, and immune-cell contexts that warrant further mechanistic investigation.