Protective effect of the HLA-DRB1*13:02 allele in Japanese rheumatoid arthritis patients

Shomi Oka; Hiroshi Furukawa; Aya Kawasaki; Kota Shimada; Shoji Sugii; Atsushi Hashimoto; Akiko Komiya; Naoshi Fukui; Satoshi Ito; Tadashi Nakamura; Koichiro Saisho; Masao Katayama; Shinichiro Tsunoda; Hajime Sano; Kiyoshi Migita; Akiko Suda; Shouhei Nagaoka; Naoyuki Tsuchiya; Shigeto Tohma

doi:10.1371/journal.pone.0099453

Protective effect of the HLA-DRB1*13:02 allele in Japanese rheumatoid arthritis patients

PLoS One. 2014 Jun 9;9(6):e99453. doi: 10.1371/journal.pone.0099453. eCollection 2014.

Authors

Shomi Oka¹, Hiroshi Furukawa¹, Aya Kawasaki², Kota Shimada³, Shoji Sugii⁴, Atsushi Hashimoto⁵, Akiko Komiya¹, Naoshi Fukui¹, Satoshi Ito⁶, Tadashi Nakamura⁷, Koichiro Saisho⁸, Masao Katayama⁹, Shinichiro Tsunoda¹⁰, Hajime Sano¹⁰, Kiyoshi Migita¹¹, Akiko Suda¹², Shouhei Nagaoka¹³, Naoyuki Tsuchiya², Shigeto Tohma¹

Affiliations

¹ Clinical Research Center for Allergy and Rheumatology, Sagamihara Hospital, National Hospital Organization, Sagamihara, Japan.
² Molecular and Genetic Epidemiology Laboratory, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.
³ Department of Rheumatology, Sagamihara Hospital, National Hospital Organization, Sagamihara, Japan; Department of Rheumatology, Tokyo Metropolitan Tama Medical Center, Fuchu, Japan.
⁴ Department of Rheumatology, Tokyo Metropolitan Tama Medical Center, Fuchu, Japan.
⁵ Department of Rheumatology, Sagamihara Hospital, National Hospital Organization, Sagamihara, Japan.
⁶ Department of Rheumatology, Niigata Rheumatic Center, Shibata, Japan.
⁷ Department of Rheumatology, Kumamoto Shinto General Hospital, Kumamoto, Japan.
⁸ Department of Orthopedics/Rheumatology, Miyakonojo Hospital, National Hospital Organization, Miyakonojo, Japan.
⁹ Department of Internal Medicine, Nagoya Medical Center, National Hospital Organization, Nagoya, Japan.
¹⁰ Division of Rheumatology, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan.
¹¹ Clinical Research Center, Nagasaki Medical Center, National Hospital Organization, Omura, Japan.
¹² Department of Rheumatology, Yokohama Minami Kyosai Hospital, Yokohama, Japan; Center for Rheumatic Diseases, Yokohama City University Medical Center, Yokohama, Japan.
¹³ Department of Rheumatology, Yokohama Minami Kyosai Hospital, Yokohama, Japan.

Abstract

Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease. Certain HLA-DRB1 "shared-epitope" alleles are reported to be positively associated with increased RA susceptibility, whereas some of the other alleles may be negatively associated. However, studies on the latter are rare. Here, we focus on the protective effects of DRB1 alleles in Japanese RA patients in an association study. Relative predispositional effects (RPE) were analyzed by sequential elimination of carriers of each allele with the strongest association. The protective effects of DRB1 alleles were investigated in patients stratified according to whether they possessed anti-citrullinated peptide antibodies (ACPA). The DRB1*13:02 allele was found to be negatively associated with RA (P = 4.59×10(-10), corrected P (Pc) = 1.42×10(-8), odds ratio [OR] 0.42, 95% CI 0.32-0.55, P [RPE] = 1.27×10(-6)); the genotypes DRB1*04:05/*13:02 and *09:01/*13:02 were also negatively associated with RA. The protective effect of *13:02 was also present in ACPA-positive patients (P = 3.95×10(-8), Pc = 1.22×10(-6), OR 0.42, 95%CI 0.31-0.58) whereas *15:02 was negatively associated only with ACPA-negative RA (P = 8.87×10(-5), Pc = 0.0026, OR 0.26, 95%CI 0.12-0.56). Thus, this study identified a negative association of DRB1*13:02 with Japanese RA; our findings support the protective role of DRB1*13:02 in the pathogenesis of ACPA-positive RA.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adult
Alleles*
Amino Acids
Arthritis, Rheumatoid / genetics*
Arthritis, Rheumatoid / immunology
Asian People / genetics*
Autoantibodies / immunology
Case-Control Studies
Epitopes / immunology
Female
Gene Frequency
Genetic Predisposition to Disease*
Genotype
HLA-DRB1 Chains / chemistry
HLA-DRB1 Chains / genetics*
HLA-DRB1 Chains / immunology
Heterozygote
Humans
Japan
Male
Middle Aged
Odds Ratio

Substances

Amino Acids
Autoantibodies
Epitopes
HLA-DRB1 Chains

Grants and funding

This work was supported by Grants-in-Aid for Scientific Research (B, C) (22390199, 22591090), for Exploratory Research (25670458) and for Young Scientists (B) (24791018) from the Japan Society for the Promotion of Science, Health and Labour Science Research Grants from the Ministry of Health, Labour and Welfare of Japan, Grants-in-Aid for Clinical Research from National Hospital Organization, Research Grants from Daiwa Securities Health Foundation, Research Grants from Japan Research Foundation for Clinical Pharmacology, Research Grants from The Nakatomi Foundation, Research Grants from Takeda Science Foundation, Research Grants from Mitsui Sumitomo Insurance Welfare Foundation, Research Grants from SENSHIN Medical Research Foundation and research grants from pharmaceutical companies: Abbott Japan Co., Ltd., Astellas Pharma Inc., Chugai Pharmaceutical Co., Ltd., Eisai Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Merck Sharp and Dohme Inc., Pfizer Japan Inc., Takeda Pharmaceutical Company Limited, Teijin Pharma Limited. The funders had no role in study design, data collection and analysis, decision to publish or preparing the manuscript.