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

Tomoki Motegi, Yuta Kochi, Koichi Matsuda, Michiaki Kubo, Kazuhiko Yamamoto, Yukihide Momozawa

Research output: Contribution to journalArticle

Abstract

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)-γsignalling, 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.

Original languageEnglish
JournalAnnals of the Rheumatic Diseases
DOIs
Publication statusPublished - 01-01-2019

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Rheumatoid Arthritis
Genes
Association reactions
Cytokines
Interferons
Population
Genome-Wide Association Study
Interleukin-23
Interleukin-12
Interleukin-6
Assays
Phosphotransferases
Autoimmune Diseases
Japan
Therapeutics

All Science Journal Classification (ASJC) codes

  • Rheumatology
  • Immunology and Allergy
  • Immunology
  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

@article{91948d01e62a4a7f838da32cc462467d,
title = "Identification of rare coding variants in TYK2 protective for rheumatoid arthritis in the Japanese population and their effects on cytokine signalling",
abstract = "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)-γsignalling, 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.",
author = "Tomoki Motegi and Yuta Kochi and Koichi Matsuda and Michiaki Kubo and Kazuhiko Yamamoto and Yukihide Momozawa",
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month = "1",
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doi = "10.1136/annrheumdis-2019-215062",
language = "English",
journal = "Annals of the Rheumatic Diseases",
issn = "0003-4967",
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Identification of rare coding variants in TYK2 protective for rheumatoid arthritis in the Japanese population and their effects on cytokine signalling. / Motegi, Tomoki; Kochi, Yuta; Matsuda, Koichi; Kubo, Michiaki; Yamamoto, Kazuhiko; Momozawa, Yukihide.

In: Annals of the Rheumatic Diseases, 01.01.2019.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Identification of rare coding variants in TYK2 protective for rheumatoid arthritis in the Japanese population and their effects on cytokine signalling

AU - Motegi, Tomoki

AU - Kochi, Yuta

AU - Matsuda, Koichi

AU - Kubo, Michiaki

AU - Yamamoto, Kazuhiko

AU - Momozawa, Yukihide

PY - 2019/1/1

Y1 - 2019/1/1

N2 - 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)-γsignalling, 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.

AB - 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)-γsignalling, 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.

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