Integrating chromatin accessibility and genome-wide association study identifies <i>RUNX3</i> and <i>TRAF1</i> as susceptibility genes for rheumatoid arthritis

Genome-wide association studies (GWAS) have identified numerous rheumatoid arthritis (RA) associated genetic variants, most of which localize to non-coding regulatory regions (eg, enhancers), but their functional annotation remains a barrier to translating GWAS findings into mechanistic insights. This study hypothesized that these enhancer single nucleotide polymorphisms (SNPs) reside in the accessible chromatin domains of RA's target tissue (synovium) and modulate target gene expression by altering transcription factor (TF) binding affinity. Thus, leveraging prospectively collected RA synovial tissues, it aimed to identify key regulatory TFs and their roles in RA pathogenesis. The study integrated assay for transposase-accessible chromatin sequencing (ATAC-seq) data from synovial tissues of 7 RA patients with GWAS-derived RA-associated enhancer SNPs to prioritize TFs that bind these enhancers, with functional validation performed using primary fibroblast-like synoviocytes (FLSs) from RA synovial tissues and MH7A cell lines. Results showed that 1006 GWAS SNPs localized to enhancer regions and were significantly enriched in the open chromatin domains of RA synovium; TF enrichment analysis identified RUNX3 as the top candidate TF, which regulates FLS migration and invasion. Mechanistically, the G allele of rs1930785 binds RUNX3 in an allele-specific manner, upregulating the expression of its target gene TRAF1, which in turn exerts a protective effect on FLS homeostasis. The study confirms RUNX3 as a key TF regulating the activity of RA-associated enhancers, highlights the value of patient-derived synovial tissue data and the dual validation system, and lays a foundation for mechanistic research and targeted therapy for RA.