Genetic Prioritization of BTN3A2 Reveals an Interferon‐Responsive T‐Cell Program in Dermatomyositis Through Single‐Cell Mendelian Randomization and Multi‐Omics Integration

ABSTRACT Dermatomyositis (DM) is a complex autoimmune disorder characterized by genetic susceptibility and dysregulated immune activation. However, the relationship between genetic variation and specific immune cell states remains poorly understood. We aimed to identify genetically supported immune‐cell‐specific molecular programs underlying DM and investigate their biological relevance. We integrated immune‐cell‐specific single‐cell expression quantitative trait loci (sc‐eQTLs) from the OneK1K cohort with DM genome‐wide association study (GWAS) summary statistics using two‐sample Mendelian randomization (MR). Candidate genes were replicated using an independent sc‐eQTL dataset and prioritized by Bayesian colocalization. Multi‐tissue validation was performed using skeletal muscle transcriptomics, peripheral blood mononuclear cells (PBMC), and skin single‐cell RNA sequencing, protein expression data, clinical phenotypes, virtual knockout analysis, and gain‐of‐function analyses of BTN3A2. We identified 204 immune cell‐specific eGenes associated with DM and prioritized four high‐confidence genes, including HLA‐DRB1, HLA‐C, Lnc‐HLA‐B‐2, and BTN3A2. BTN3A2 showed robust colocalization across multiple CD4 + and CD8 + T‐cell subsets and was further supported by muscle transcriptomic data. BTN3A2 was consistently upregulated in both DM muscle tissues and PBMCs and was broadly expressed across T‐cell, NK‐cell, and B‐cell populations. BTN3A2 + T cells exhibited enhanced cytotoxic, activation, antigen‐presentation, and interferon‐responsive programs, which were reproduced in circulating PBMCs and lesional skin T cells. BTN3A2 expression was negatively correlated with MMT8 scores, while in silico knockout analysis implicated interferon‐stimulated and antiviral pathways. Integrating cell‐type‐specific genetic evidence with multi‐tissue immune profiling identified BTN3A2 as a genetically supported candidate associated with DM and an interferon‐responsive T‐cell state, providing novel insights for future mechanistic investigation.