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Rheumatoid arthritis
Association of the RPA3-UMAD1 locus with interstitial lung diseases complicated with rheumatoid arthritis in Japanese
  1. Yuya Shirai1,2,
  2. Suguru Honda3,
  3. Katsunori Ikari3,
  4. Masahiro Kanai1,4,
  5. Yoshito Takeda2,
  6. Yoichiro Kamatani5,6,
  7. Takayuki Morisaki7,8,
  8. Eiichi Tanaka3,
  9. Atsushi Kumanogoh2,9,10,
  10. Masayoshi Harigai3,
  11. Yukinori Okada1,6,10,11
  1. 1 Department of Statistical Genetics, Osaka University Graduate School of Medicine, Suita, Japan
  2. 2 Department of Respiratory Medicine and Clinical Immunology, Osaka University Graduate School of Medicine, Suita City, Japan
  3. 3 Department of Rheumatology, Tokyo Women’s Medical University School of Medicine, Shinjuku-ku, Japan
  4. 4 Department of Biomedical Informatics, Harvard Medical School, Boston, Massachusetts, USA
  5. 5 Laboratory of Complex Trait Genomics, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, the University of Tokyo, Minato-ku, Japan
  6. 6 Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
  7. 7 Division of Molecular Pathology, The Institute of Medical Science, The University of Tokyo, Minato-ku, Japan
  8. 8 BioBank Japan, The Institute of Medical Science, The University of Tokyo, Minato-ku, Japan
  9. 9 Department of Immunopathology, Immunology Frontier Research Center (WPI-IFReC), Osaka University, Suita, Japan
  10. 10 Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives, Osaka University, Suita, Japan
  11. 11 Laboratory of Statistical Immunology, Immunology Frontier Research Center (WPI-IFReC), Osaka University, Suita, Japan
  1. Correspondence to Dr Yukinori Okada, Department of Statistical Genetics, Osaka University Graduate School of Medicine, Suita 565-0871, Japan; yokada{at}sg.med.osaka-u.ac.jp

Abstract

Objectives The genetic background of rheumatoid arthritis–interstitial lung disease (RA-ILD) has been evaluated in Europeans, but little knowledge has been obtained in non-Europeans. This study aimed to elucidate genome-wide risk of RA-ILD in non-Europeans.

Methods We performed an initial genome-wide association study (GWAS) of RA-ILD in the Japanese population. By conducting the meta-analysis of the three GWAS datasets of the RA cohorts and biobank of Japanese, our study included 358 RA-ILD cases and 4550 RA subjects without ILD. We then conducted the stratified analysis of the effect of the GWAS risk allele in each CT image pattern.

Results We identified one novel RA-ILD risk locus at 7p21 that satisfied the genome-wide significance threshold (rs12702634 at RPA3-UMAD1, OR=2.04, 95% CI 1.59 to 2.60, p=1.5×10−8). Subsequent stratified analysis based on the CT image patterns demonstrated that the effect size of the RA-ILD risk allele (rs12702634-C) was large with the UIP pattern (OR=1.86, 95% CI 0.97 to 3.58, p=0.062) and the probable UIP pattern (OR=2.26, 95% CI 1.36 to 3.73, p=0.0015).

Conclusion We revealed one novel genetic association with RA-ILD in Japanese. The RA-ILD risk of the identified variant at RPA3-UMAD1 was relatively high in the CT image patterns related to fibrosis. Our study should contribute to elucidation of the complicated aetiology of RA-ILD.

  • pulmonary fibrosis
  • rheumatoid arthritis
  • gene polymorphism
https://creativecommons.org/licenses/by/4.0/

This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See: https://creativecommons.org/licenses/by/4.0/.

https://doi.org/10.1136/annrheumdis-2020-217256

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    Footnotes

    • Handling editor Josef S Smolen

    • YS and SH contributed equally.

    • Contributors YS and YO designed the study and wrote the manuscripts. YS, MK and YK performed the analysis. SH, KI, TM, ET and MH constructed the clinical and genotype data. YT, AK and YO supervised the study.

    • Funding This research was supported by AMED under Grant Numbers JP19ek0410041 and JP20ek0410075, Takeda Science Foundation and Bioinformatics Initiative of Osaka University Graduate School of Medicine, Osaka University. MK was supported by a Nakajima Foundation Fellowship and the Masason Foundation.

    • Competing interests None declared.

    • Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

    • Patient consent for publication Not required.

    • Ethics approval This study was approved by the ethical committee of Osaka University.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Data availability statement Data are available upon reasonable request. GWAS genotype data from the BBJ subjects are deposited at National Bioscience Database Center Human Database (Research ID: hum0014).