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A large-scale association study identified multiple HLA-DRB1 alleles associated with ACPA-negative rheumatoid arthritis in Japanese subjects
  1. Chikashi Terao1,2,
  2. Koichiro Ohmura1,
  3. Yuta Kochi3,
  4. Katsunori Ikari4,
  5. Etsuko Maruya5,
  6. Masaki Katayama1,
  7. Kota Shimada6,
  8. Akira Murasawa7,
  9. Shigeru Honjo8,
  10. Kiyoshi Takasugi9,
  11. Keitaro Matsuo10,
  12. Kazuo Tajima10,
  13. Akari Suzuki3,
  14. Kazuhiko Yamamoto11,
  15. Shigeki Momohara4,
  16. Hisashi Yamanaka4,
  17. Ryo Yamada2,
  18. Hiroo Saji5,
  19. Fumihiko Matsuda2,12,13,
  20. Tsuneyo Mimori1
  1. 1Department of Rheumatology and Clinical Immunology, Kyoto University Graduate School of Medicine, Kyoto, Japan
  2. 2Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan
  3. 3Laboratory for Autoimmune Diseases, Center for Genomic Medicine, RIKEN, Yokohama, Japan
  4. 4Institute of Rheumatology, Tokyo Women's Medical University, Tokyo, Japan
  5. 5HLA Laboratory, Kyoto, Japan
  6. 6Department of Rheumatology, Sagamihara National Hospital, National Hospital Organization, Sagamihara, Japan
  7. 7Department of Rheumatology, Niigata Rheumatic Center, Niigata, Japan
  8. 8Saiseikai Takaoka Hospital, Toyama, Japan
  9. 9Dohgo Spa Hospital, Matsuyama, Japan
  10. 10Aichi Cancer Center Hospital and Research Institute, Nagoya, Japan
  11. 11Department of Allergy and Rheumatology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
  12. 12CREST program, Japan Science and Technology Agency, Kawaguchi, Japan
  13. 13Institut National de la Sante et de la Recherche Medicale (INSERM) Unite U852, Kyoto University Graduate School of Medicine, Kyoto, Japan
  1. Correspondence to Koichiro Ohmura, Department of Rheumatology and Clinical Immunology, Graduate School of Medicine, Kyoto University, 54 Shogoin-Kawahara-cho Sakyo-ku, Kyoto 606–8507, Japan; ohmurako{at}


Background HLA-DRB1 is associated with rheumatoid arthritis (RA). However, it has recently been suggested that HLA-DRB1 is only associated with patients with RA who have anticitrullinated peptide/protein antibodies (ACPA), which are specific to RA.

Objective To elucidate whether specific HLA-DR alleles are associated with ACPA-negative RA development.

Methods HLA-DRB1 typing was carried out in 368 Japanese ACPA-negative patients with RA and 1508 healthy volunteers as the first set, followed by HLA-DRB1 typing of 501 cases and 500 controls as the second set. The HLA-DRB1 allele frequency and diplotype frequency were compared in each group, and the results of the two studies were combined to detect HLA-DRB1 alleles or diplotypes associated with ACPA-negative RA.

Results HLA-DRB1*12:01 was identified as a novel susceptibility allele for ACPA-negative RA (p=0.000088, OR=1.72, 95% CI 1.31 to 2.26). HLA-DRB1*04:05 and *14:03 showed moderate associations with ACPA-negative RA (p=0.0063, OR=1.26, 95% CI 1.07 to 1.49 and p=0.0043, OR=1.81, 95% CI 1.20 to 2.73, respectively). The shared epitope was weakly associated with ACPA-negative RA, but no dosage effect was detected (p=0.016, OR=1.17, 95% CI 1.03 to 1.34). A combination of HLA-DRB1*12:01 and DRB1*09:01 showed a strong association with susceptibility to ACPA-negative RA (p=0.00013, OR=3.62, 95% CI 1.79 to 7.30). Homozygosity for HLA-DR8 was significantly associated with ACPA-negative RA (p=0.0070, OR=2.16, 95% CI 1.22 to 3.82). It was also found that HLA-DRB1*15:02 and *13:02 were protective against ACPA-negative RA (p=0.00010, OR=0.68, 95% CI 0.56 to 0.83 and p=0.00059, OR=0.66, 95% CI 0.52 to 0.84, respectively).

Conclusions In this large-scale association study multiple alleles and diplotypes were found to be associated with susceptibility to, or protection against, ACPA-negative RA.

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  • Funding CT is an associate fellow of the global COE program supported by the Ministry of Education, Culture, Sports, Science and Technology (MEXT), Japan. This work was supported by grants-in-aid from the Ministry of Health, Labor and Welfare of Japan and from the Ministry of Education, Culture, Sports, Science and Technology of Japan as well as by research grants from the Japan Rheumatism Foundation, the Waksman Foundation and the Mitsubishi Pharma Research Foundation.

  • Competing interests None.

  • Patient consent Obtained.

  • Ethics approval This study was approved by the local ethical committees at each institution.

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