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.
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.



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



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.



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.
Molecular and Genetic Epidemiology Laboratory, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Japan.|Clinical Research Center for Allergy and Rheumatology, Sagamihara Hospital, National Hospital Organization, 18-1 Sakuradai, Minami-ku, Sagamihara, Japan.
Hiroshi
H
Furukawa
Molecular and Genetic Epidemiology Laboratory, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Japan.|Clinical Research Center for Allergy and Rheumatology, Sagamihara Hospital, National Hospital Organization, 18-1 Sakuradai, Minami-ku, Sagamihara, Japan.
Shomi
S
Oka
Molecular and Genetic Epidemiology Laboratory, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Japan.
Aya
A
Kawasaki
Department of Rheumatology, Sagamihara Hospital, National Hospital Organization, 18-1 Sakuradai, Minami-ku, Sagamihara, Japan.|Department of Rheumatic Diseases, Tokyo Metropolitan Tama Medical Center, 2-8-29 Musashi-dai, Fuchu, Japan.
Kota
K
Shimada
Department of Rheumatic Diseases, Tokyo Metropolitan Tama Medical Center, 2-8-29 Musashi-dai, Fuchu, Japan.
Shoji
S
Sugii
Department of Dermatology, Faculty of Medicine, Institute of Medical, Pharmaceutical, and Health Sciences, Kanazawa University, 13-1 Takaramachi, Kanazawa, Japan.
Takashi
T
Matsushita
Department of Rheumatology, Sagamihara Hospital, National Hospital Organization, 18-1 Sakuradai, Minami-ku, Sagamihara, Japan.
Atsushi
A
Hashimoto
Clinical Research Center for Allergy and Rheumatology, Sagamihara Hospital, National Hospital Organization, 18-1 Sakuradai, Minami-ku, Sagamihara, Japan.
Akiko
A
Komiya
Clinical Research Center for Allergy and Rheumatology, Sagamihara Hospital, National Hospital Organization, 18-1 Sakuradai, Minami-ku, Sagamihara, Japan.
Naoshi
N
Fukui
Department of Rheumatology, Yokohama Minami Kyosai Hospital, 1-21-1 Rokuura-higashi, Kanazawa-ku, Yokohama, Japan.
Kouji
K
Kobayashi
Department of Rheumatology, Yokohama Minami Kyosai Hospital, 1-21-1 Rokuura-higashi, Kanazawa-ku, Yokohama, Japan.
Atsumu
A
Osada
Department of Rheumatology, Yokohama Minami Kyosai Hospital, 1-21-1 Rokuura-higashi, Kanazawa-ku, Yokohama, Japan.
Atsushi
A
Ihata
Department of Internal Medicine, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Japan.
Yuya
Y
Kondo
Department of Rheumatology and Infectious Diseases, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Sagamihara, Japan.
Tatsuo
T
Nagai
Department of Allergy and Immunological Diseases, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, 3-18-22 Hon-komagome, Bunkyo-ku, Tokyo, Japan.
Keigo
K
Setoguchi
Department of Internal Medicine, Teikyo University, 2-11-1 Kaga, Itabashi-ku, Tokyo, Japan.
Akiko
A
Okamoto
Department of Rheumatology, Himeji Medical Center, National Hospital Organization, 68 Hon-machi, Himeji, Japan.
Akira
A
Okamoto
Department of Rheumatology, Morioka Hospital, National Hospital Organization, 1-25-1 Aoyama, Morioka, Japan.
Noriyuki
N
Chiba
Department of Internal Medicine and Rheumatology, Clinical Research Institute, Kyushu Medical Center, National Hospital Organization, 1-8-1 Jigyohama, Chuo-ku, Fukuoka, Japan.
Eiichi
E
Suematsu
Department of Internal Medicine, Teikyo University, 2-11-1 Kaga, Itabashi-ku, Tokyo, Japan.
Hajime
H
Kono
Department of Internal Medicine, Nagoya Medical Center, National Hospital Organization, 4-1-1 Sannomaru, Naka-ku, Nagoya, Japan.
Masao
M
Katayama
Department of Rheumatology and Infectious Diseases, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Sagamihara, Japan.
Shunsei
S
Hirohata
Department of Internal Medicine, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Japan.
Takayuki
T
Sumida
Clinical Research Center, Nagasaki Medical Center, National Hospital Organization, 2-1001-1 Kubara, Omura, Japan.
Kiyoshi
K
Migita
Department of Dermatology, School of Medicine, Faculty of Medical Sciences, University of Fukui, 23-3 Matsuokashimoaizuki, Eiheiji, Japan.
Minoru
M
Hasegawa
Department of Dermatology, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Japan.
Manabu
M
Fujimoto
Department of Dermatology, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, Japan.
Shinichi
S
Sato
Department of Rheumatology, Yokohama Minami Kyosai Hospital, 1-21-1 Rokuura-higashi, Kanazawa-ku, Yokohama, Japan.
Shouhei
S
Nagaoka
Department of Dermatology, Faculty of Medicine, Institute of Medical, Pharmaceutical, and Health Sciences, Kanazawa University, 13-1 Takaramachi, Kanazawa, Japan.
Kazuhiko
K
Takehara
Clinical Research Center for Allergy and Rheumatology, Sagamihara Hospital, National Hospital Organization, 18-1 Sakuradai, Minami-ku, Sagamihara, Japan.
Shigeto
S
Tohma
Molecular and Genetic Epidemiology Laboratory, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Japan.
Naoyuki
N
Tsuchiya
D000328:Adult; D000483:Alleles; D044466:Asian People / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D059868:HLA-DP beta-Chains / Q000235:genetics*; D059866:HLA-DQ beta-Chains / Q000235:genetics*; D059811:HLA-DRB1 Chains / Q000235:genetics*; D006801:Humans; D007564:Japan / Q000453:epidemiology; D008297:Male; D008875:Middle Aged; D065840:Protective Factors; D012595:Scleroderma, Systemic / Q000453:epidemiology / Q000235:genetics*
D059868:HLA-DP beta-Chains; C500433:HLA-DPB1*02:01 antigen; D059866:HLA-DQ beta-Chains; C069051:HLA-DQB1 antigen; D059811:HLA-DRB1 Chains; C506473:HLA-DRB1*13 antigen