The role of rare protein-coding variants to anti-TNF treatment response in rheumatoid arthritis

Objective Many rheumatoid arthritis (RA) patients have their disease controlled with anti-tumor necrosis factor alpha (anti-TNF) biologic therapies. However, a significant number of RA patients fail to respond to anti-TNF therapy. Here, we hypothesized that rare and low-frequency variants might influence anti-TNF treatment response. Methods We sequenced the coding region of 750 genes in 1,094 RA patients of European ancestry treated with anti-TNF medications. After quality control, we included 690 genes in the analysis. We applied single variants association and gene-based association tests to identify variants associated with anti-TNF treatment response. We also performed gene set analyses of 27 TNF pathway genes, considering TNF's key mechanistic role. Results We identified 14,420 functional variants, of which 6,934 were predicted as non-synonymous where 2,136 were further predicted to be damaging. Despite being a well-powered study, no single variant or gene showed study-wide significant association with change in disease activity outcome or EULAR response outcome. Intriguingly, we observed 3 genes, out of 27 with nominal signals of association (P