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  • Genetic landscape of interactive effects of HLA-DRB1 alleles on susceptibility to ACPA(+) rheumatoid arthritis and ACPA levels in Japanese population

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Immunogenetics
Original article
Genetic landscape of interactive effects of HLA-DRB1 alleles on susceptibility to ACPA(+) rheumatoid arthritis and ACPA levels in Japanese population
  1. Chikashi Terao1,2,3,4,5,
  2. Yukinori Okada6,7,8,
  3. Katsunori Ikari9,10,
  4. Yuta Kochi11,
  5. Akari Suzuki11,
  6. Koichiro Ohmura12,
  7. Keitaro Matsuo13,
  8. Atsuo Taniguchi9,
  9. Michiaki Kubo14,
  10. Soumya Raychaudhuri3,4,5,15,
  11. Kazuhiko Yamamoto11,
  12. Hisashi Yamanaka9,
  13. Yoichiro Kamatani7,
  14. Tsuneyo Mimori12,
  15. Fumihiko Matsuda1
  1. 1 Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan
  2. 2 Center for the Promotion of Interdisciplinary Education and Research, Kyoto University, Kyoto, Japan
  3. 3 Division of Rheumatology, Immunology, and Allergy, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA
  4. 4 Division of Genetics, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA
  5. 5 Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, USA
  6. 6 Department of Statistical Genetics, Osaka University Graduate School of Medicine, Osaka, Japan
  7. 7 Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
  8. 8 Laboratory of Statistical Immunology, Immunology, Frontier Research Center (WPI-IFReC), Osaka University, Suita, Japan
  9. 9 Institute of Rheumatology, Tokyo Women’s Medical University, Tokyo, Japan
  10. 10 Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Kyoto, Japan
  11. 11 Laboratory for Autoimmune Diseases, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
  12. 12 Department of Rheumatology and Clinical Immunology, Kyoto University Graduate School of Medicine, Kyoto, Japan
  13. 13 Division of Molecular and Clinical Epidemiology, Aichi Cancer Center Research Institute, Nagoya, Japan
  14. 14 Laboratory for Genotyping Development, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
  15. 15 Arthritis Research UK Epidemiology Unit, Musculoskeletal Research Group, University of Manchester, Manchester Academic Health Sciences Centre, Manchester, UK
  1. Correspondence to Dr Chikashi Terao, Division of Rheumatology, Immunology, and Allergy, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA; a0001101{at}kuhp.kyoto-u.ac.jp

Abstract

Background HLA-DRB1 is the strongest susceptibility gene to rheumatoid arthritis (RA). HLA-DRB1 alleles showed significant non-additive and interactive effects on susceptibility to RA in the European population, but these effects on RA susceptibility should vary between populations due to the difference in allelic distribution. Furthermore, non-additive or interactive effects on the phenotypes of RA are not fully known. We evaluated the non-additive and interactive effects of HLA-DRB1 alleles on RA susceptibility and anticitrullinated protein/peptide antibody (ACPA) levels in Japanese patients.

Methods A total of 5581 ACPA(+) RA and 19 170 controls were genotyped or imputed for HLA-DRB1 alleles. Logistic regression analysis was performed for both allelic non-additive effects and interactive effects of allelic combinations. The significant levels were set by Bonferroni’s correction. A total of 4371 ACPA(+) RA were analysed for ACPA levels.

Results We obtained evidence of non-additive and interactive effects of HLA-DRB1 on ACPA(+) RA susceptibility (p=2.5×10−5 and 1.5×10−17, respectively). Multiple HLA-DRB1 alleles including HLA-DRB1*04:05, the most common susceptibility allele in the Japanese, showed significant non-additive effects (p≤0.0043). We identified multiple allelic combinations with significant interactive effects including a common combination with the European population as well as novel combinations. Additional variance of ACPA(+) RA susceptibility could be explained substantially by heterozygote dominance or interactive effects. We did not find evidence of non-additive and interactive effects on levels of ACPA.

Conclusion HLA allelic non-additive and interactive effects on ACPA(+) RA susceptibility were observed in the Japanese population. The allelic non-additive and interactive effects depend on allelic distribution in populations.

  • rheumatoid arthritis
  • genetics

https://doi.org/10.1136/jmedgenet-2017-104779

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    Footnotes

    • Contributors Wrote the paper: CT. Conceived and designed the study: CT. Analysed the data: CT, YO, YK. Substantial contribution to acquired samples and creation of data in genome-wide association study: CT, YO, KI, YK, AS, KO, KM, AT, MK, SR, KY, HY, YK, TM, FM. All authors revised and approved the manuscript to be published.

    • Funding This study was supported by JSPS KAKENHI (grant nos JP16H06251 and JP16K15513), KANAE foundation for the promotion of medical science, The Uehara Memorial Foundation, The John Mung Advanced Program, Kyoto University.

    • Competing interests None declared.

    • Patient consent Detail has been removed from this case description/these case descriptions to ensure anonymity. The editors and reviewers have seen the detailed information available and are satisfied that the information backs up the case the authors are making.

    • Ethics approval This study was approved by the ethical review board in each institution.

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