Expression quantitative trait loci analysis in rheumatoid arthritis identifies tissue specific variants associated with severity and outcome.

Objective: Genome-wide association studies have successfully identified more than 100 loci associated with susceptibility to rheumatoid arthritis (RA). However, our understanding of the functional effects of genetic variants in causing RA and their effects on disease severity and response to treatment remains limited.

Methods: In this study, we conducted expression quantitative trait locus (eQTL) analysis to dissect the link between genetic variants and gene expression comparing the disease tissue against blood using RNA-Sequencing of synovial biopsies (n=85) and blood samples (n=51) from treatment-naïve patients with RA from the Pathobiology of Early Arthritis Cohort.

Results: This identified 898 eQTL genes in synovium and genes loci in blood, with 232 genes in common to both synovium and blood, although notably many eQTL were tissue specific. Examining the HLA region, we uncovered a specific eQTL at with the critical triad of single-nucleotide polymorphisms (SNPs) rs3128921 driving synovial expression, and both rs3128921 and gene expression correlating with clinical severity and increasing probability of the lympho-myeloid pathotype.

Conclusions: This analysis highlights the need to explore functional consequences of genetic associations in disease tissue. SNP rs3128921 could potentially be used to stratify patients to more aggressive treatment immediately at diagnosis.