Genome‐Wide Association Analysis and Multi‐Omic Mendelian Randomization Insight Into the Molecular Network of Immune‐Related Dysfunction in the Pathogenesis of Rheumatoid Arthritis

Nov 25, 2025International journal of rheumatic diseases

Genetic and Molecular Links to Immune System Problems in Rheumatoid Arthritis

AI simplified

Abstract

A total of 29 independent risk loci associated with rheumatoid arthritis (RA) were identified, including 7 that are new.

ERAP2 was classified as a high-confidence causal gene for RA, while SWAP70 and LTBR were considered moderate-confidence causal genes.
SWAP70 is linked to a lower risk of RA, whereas ERAP2 and LTBR are associated with increased risk.
Single-cell RNA sequencing showed that SWAP70 is mostly found in B cells, while LTBR is more common in dendritic cells.
RNA sequencing of RA synovial tissue confirmed higher levels of SWAP70, RASGRP1, and RHOH in patients.
The findings suggest that immune regulatory genes like ERAP2, SWAP70, and LTBR could be important targets for new RA treatments.

AI simplified

BACKGROUND: Rheumatoid arthritis (RA) is a complex autoimmune disease influenced by genetic and immune dysregulation. The causal roles of specific immune-related genes in RA pathogenesis remain incompletely understood.

METHODS: We conducted a large-scale genome-wide association study (GWAS) meta-analysis across three RA cohorts to identify genome-wide significant risk loci. Causal genes and proteins were prioritized by integrating these results with cis-eQTL and pQTL datasets using two-sample Mendelian randomization (MR) and summary-data-based MR (SMR). Cell-type-specific expression was assessed using single-cell RNA sequencing (scRNA-seq), and gene expression in RA synovial tissue was validated via bulk RNA-seq.

RESULTS: We identified 29 independent RA-associated loci, including 7 novel associations. Integrated MR and SMR analyses classified ERAP2 as a high-confidence causal gene, while SWAP70 and LTBR were deemed moderate-confidence causal genes. SWAP70 showed a protective association, whereas ERAP2 and LTBR were positively associated with RA risk. Single-cell transcriptomic analysis revealed cell-type-specific enrichment, with SWAP70 prevalent in B cells and LTBR in dendritic cells. Bulk RNA-seq confirmed the upregulation of SWAP70, RASGRP1, and RHOH in RA patients.

CONCLUSION: Our integrative multi-omics framework reveals immune regulatory genes with potential causal roles in RA pathogenesis, highlighting ERAP2, SWAP70, LTBR, and other candidates as promising therapeutic targets.

Full Text

Full text is available at the source.

View full text ↗

Abstract

Full Text

Related papers

what lands in your inbox each week: