rs7579944

This functional study integrates epigenomic datasets (ATAC-seq, Hi-C, ChIP-seq, RNA-seq) from fibroblast-like synoviocytes (FLS) to map the functional relevance of 101 fine-mapped rheumatoid arthritis GWAS associations. FLS regulatory elements account for 24% of RA heritability, and the study assigns putative target genes to RA risk loci, identifying TNFAIP3, IFNAR1, CDK6, RBPJ and others as disease-relevant genes. TNF stimulation reveals dynamic chromatin interactions and differential gene expression at RA-associated regulatory regions.

This functional study identified a novel LBH enhancer containing the RA-risk variant rs906868 (G/T) located 6kb upstream of the LBH transcription start site. Using luciferase reporter assays and RA fibroblast-like synoviocytes (FLS), the authors demonstrated that the RA-risk G allele (Ref) significantly reduced enhancer activity compared to the protective T allele (SNP: 2.9±0.6 vs Ref: 1.6±0.3, p<0.0001), and this was associated with lower LBH expression in homozygous Ref FLS lines (SNP: 1.2±0.13 vs Ref: 0.65±0.08, p=0.01). DNA methylation of the enhancer decreased transcriptional activity for both alleles, indicating that LBH regulation depends on the interplay between the rs906868 SNP and epigenetic methylation status.