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=5.47×10−8, OR=0.48). We observed more accumulation of rare coding variants in controls in TYK2 (p=3.94×10−12, OR=0.56). The four-point-one, ezrin, radixin, moesin (FERM; 2.14×10−3, OR=0.66) and pseudokinase domains (1.63×10−8, OR=0.52) of TYK2 also showed enrichment of variants in controls. R231W in FERM domain especially reduced interleukin (IL)-6 and interferon (IFN)-γ signalling, whereas P1104A in kinase domain reduced IL-12, IL-23 and IFN-α 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.
- rheumatoid arthritis
- rare variant
- cytokine signaling
- target sequencing
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Handling editor Josef S Smolen
Contributors TM and YM designed the study and drafted the manuscript. TM and YM performed the resequencing and analysed these data. YK conducted the reporter assays and revised the manuscript. MK, KM and KY critically reviewed the manuscript.
Funding This work was conducted as part of the BioBank Japan Project supported by the Japan Agency for Medical Research and Development and by the Ministry of Education, Culture, Sports, Science and Technology of the Japanese government.
Competing interests None declared.
Patient consent for publication Not required.
Ethics approval All subjects provided written informed consent for participation in the study as approved by the ethical committee of each institutional review board. The study was approved by the ethics committee at the RIKEN Center for Integrative Medical Sciences (accession number 17-17-16(3)).
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement Data are available upon reasonable request.
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