Human Leukocyte Antigen and Systemic Sclerosis in Japanese: The Sign of the Four Independent Protective Alleles, DRB1*13:02, DRB1*14:06, DQB1*03:01, and DPB1*02:01

Hiroshi Furukawa; Shomi Oka; Aya Kawasaki; Kota Shimada; Shoji Sugii; Takashi Matsushita; Atsushi Hashimoto; Akiko Komiya; Naoshi Fukui; Kouji Kobayashi; Atsumu Osada; Atsushi Ihata; Yuya Kondo; Tatsuo Nagai; Keigo Setoguchi; Akiko Okamoto; Akira Okamoto; Noriyuki Chiba; Eiichi Suematsu; Hajime Kono; Masao Katayama; Shunsei Hirohata; Takayuki Sumida; Kiyoshi Migita; Minoru Hasegawa; Manabu Fujimoto; Shinichi Sato; Shouhei Nagaoka; Kazuhiko Takehara; Shigeto Tohma; Naoyuki Tsuchiya

doi:10.1371/journal.pone.0154255

Human Leukocyte Antigen and Systemic Sclerosis in Japanese: The Sign of the Four Independent Protective Alleles, DRB113:02, DRB114:06, DQB103:01, and DPB102:01

PLoS One. 2016 Apr 26;11(4):e0154255. doi: 10.1371/journal.pone.0154255. eCollection 2016.

Authors

Hiroshi Furukawa^{1

2}, Shomi Oka^{1

2}, Aya Kawasaki¹, Kota Shimada^{3

4}, Shoji Sugii⁴, Takashi Matsushita⁵, Atsushi Hashimoto³, Akiko Komiya², Naoshi Fukui², Kouji Kobayashi⁶, Atsumu Osada⁶, Atsushi Ihata⁶, Yuya Kondo⁷, Tatsuo Nagai⁸, Keigo Setoguchi⁹, Akiko Okamoto¹⁰, Akira Okamoto¹¹, Noriyuki Chiba¹², Eiichi Suematsu¹³, Hajime Kono¹⁰, Masao Katayama¹⁴, Shunsei Hirohata⁸, Takayuki Sumida⁷, Kiyoshi Migita¹⁵, Minoru Hasegawa¹⁶, Manabu Fujimoto¹⁷, Shinichi Sato¹⁸, Shouhei Nagaoka⁶, Kazuhiko Takehara⁵, Shigeto Tohma², Naoyuki Tsuchiya¹

Affiliations

¹ Molecular and Genetic Epidemiology Laboratory, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Japan.
² Clinical Research Center for Allergy and Rheumatology, Sagamihara Hospital, National Hospital Organization, 18-1 Sakuradai, Minami-ku, Sagamihara, Japan.
³ Department of Rheumatology, Sagamihara Hospital, National Hospital Organization, 18-1 Sakuradai, Minami-ku, Sagamihara, Japan.
⁴ Department of Rheumatic Diseases, Tokyo Metropolitan Tama Medical Center, 2-8-29 Musashi-dai, Fuchu, Japan.
⁵ Department of Dermatology, Faculty of Medicine, Institute of Medical, Pharmaceutical, and Health Sciences, Kanazawa University, 13-1 Takaramachi, Kanazawa, Japan.
⁶ Department of Rheumatology, Yokohama Minami Kyosai Hospital, 1-21-1 Rokuura-higashi, Kanazawa-ku, Yokohama, Japan.
⁷ Department of Internal Medicine, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Japan.
⁸ Department of Rheumatology and Infectious Diseases, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Sagamihara, Japan.
⁹ Department of Allergy and Immunological Diseases, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, 3-18-22 Hon-komagome, Bunkyo-ku, Tokyo, Japan.
¹⁰ Department of Internal Medicine, Teikyo University, 2-11-1 Kaga, Itabashi-ku, Tokyo, Japan.
¹¹ Department of Rheumatology, Himeji Medical Center, National Hospital Organization, 68 Hon-machi, Himeji, Japan.
¹² Department of Rheumatology, Morioka Hospital, National Hospital Organization, 1-25-1 Aoyama, Morioka, Japan.
¹³ Department of Internal Medicine and Rheumatology, Clinical Research Institute, Kyushu Medical Center, National Hospital Organization, 1-8-1 Jigyohama, Chuo-ku, Fukuoka, Japan.
¹⁴ Department of Internal Medicine, Nagoya Medical Center, National Hospital Organization, 4-1-1 Sannomaru, Naka-ku, Nagoya, Japan.
¹⁵ Clinical Research Center, Nagasaki Medical Center, National Hospital Organization, 2-1001-1 Kubara, Omura, Japan.
¹⁶ Department of Dermatology, School of Medicine, Faculty of Medical Sciences, University of Fukui, 23-3 Matsuokashimoaizuki, Eiheiji, Japan.
¹⁷ Department of Dermatology, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Japan.
¹⁸ Department of Dermatology, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, Japan.

Abstract

Objective: Several studies on associations between human leukocyte antigen (HLA) allele frequencies and susceptibility to systemic sclerosis (SSc) have been reported. Anti-centromere antibodies (ACA) and anti-topoisomerase I antibodies (ATA) are found in SSc patients. Here, we sought to identify HLA alleles associated with SSc in Japanese, and explored their associations with SSc phenotypes including the presence of autoantibodies.

Methods: Associations of HLA-DRB1, DQB1, and DPB1 were analyzed in 463 Japanese SSc patients and 413 controls.

Results: We found that DRB1*13:02 (P = 0.0011, Pc = 0.0319, odds ratio [OR] 0.46, 95% confidence interval [CI] 0.29-0.73), DRB1*14:06 (P = 6.60X10-5, Pc = 0.0020, OR 0.05, 95%CI 0.01-0.41), DQB1*03:01 (P = 0.0009, Pc = 0.0150, OR 0.56, 95%CI 0.40-0.79), and DPB1*02:01 (P = 5.16X10-6, Pc = 8.77X10-5, OR 0.52, 95%CI 0.39-0.69) were protectively associated with SSc. In addition, these four alleles seemed to be independently associated with the protection against the susceptibility of SSc. On the other hand, we could not find predisposing alleles for overall SSc. With respect to SSc subsets, a tendency for these four alleles to be protectively associated was observed. However, there was a significant association between DRB1*01:01, DRB1*10:01, DQB1*05:01, and DPB1*04:02 and the susceptibility to SSc with ACA. On the other hand, the presence of DRB1*15:02, DQB1*06:01, DPB1*03:01, and DPB1*09:01 was associated with SSc with ATA.

Conclusion: Thus, the present study has identified protective associations of the four HLA class II alleles with overall Japanese SSc and predisposing associations of HLA class II alleles with Japanese SSc subsets.

Publication types

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

MeSH terms

Adult
Alleles
Asian People / genetics
Female
Genetic Predisposition to Disease
HLA-DP beta-Chains / genetics*
HLA-DQ beta-Chains / genetics*
HLA-DRB1 Chains / genetics*
Humans
Japan / epidemiology
Male
Middle Aged
Protective Factors
Scleroderma, Systemic / epidemiology
Scleroderma, Systemic / genetics*

Substances

HLA-DP beta-Chains
HLA-DPB1*02:01 antigen
HLA-DQ beta-Chains
HLA-DQB1 antigen
HLA-DRB1 Chains
HLA-DRB1*13 antigen

Grants and funding

The study was supported by Grants-in-Aid for Scientific Research (B, C) (26293123, 22591090) 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 Kato Memorial Trust for Nambyo Research, and research grants from the following pharmaceutical companies: Abbott Japan Co., Ltd., Astellas Pharma Inc., Chugai Pharmaceutical Co., Ltd., Eisai Co., Ltd., Mitsuibishi 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.