Identification of rare coding variants in TYK2 protective for rheumatoid arthritis in the Japanese population and their effects on cytokine signalling

Objective Although genome-wide association studies (GWAS) have identified approximately 100 loci for rheumatoid arthritis (RA), the disease mechanisms are not completely understood. We evaluated the pathogenesis of RA by focusing on rare coding variants. Methods The coding regions of 98 candidate genes identified by GWAS were sequenced in 2294 patients with RA and 4461 controls in Japan. An association analysis was performed using cases and controls for variants, genes and domains of TYK2. Cytokine responses for two associated variants (R231W, rs201917359; and R703W, rs55882956) in TYK2 as well as a previously reported risk variant (P1004A, rs34536443) for multiple autoimmune diseases were evaluated by reporter assays. Results A variant in TYK2 (R703W) showed a suggestive association (p=5.47x10(-8), OR=0.48). We observed more accumulation of rare coding variants in controls in TYK2 (p=3.94x10(-12)-OR=0.56). The four-point-one, ezrin, radixin, moesin (FERM; 2.14x 10(-3), OR=0.66) and pseudokinase domains (1.63x10(-8), OR=0.52) of TYK2 also showed enrichment of variants in controls. R231W in FERM domain especially reduced interleukin (IL)-6 and interferon (IFN)-gamma signalling, whereas P11044 in kinase domain reduced IL-12, IL-23 and IFN-alpha signalling. R703W in pseudokinase domain reduced cytokine signals similarly to P1104A, but the effects were weaker than those of P1104A. Conclusions The FERM and pseudokinase domains in TYK2 were associated with the risk of RA in the Japanese population. Variants in TYK2 had different effects on cytokine signalling, suggesting that the regulation of selective cytokine signalling is a target for RA treatment.