Human leukocyte antigens and systemic lupus erythematosus: a protective role for the HLA-DR6 alleles DRB1*13:02 and *14:03.
Many studies on associations between human leukocyte antigen (HLA) allele frequencies and susceptibility to systemic lupus erythematosus (SLE) have been performed. However, few protective associations with HLA-DRB1 alleles have been reported. Here, we sought protective, as well as predispositional, alleles of HLA-DRB1 in Japanese SLE patients. An association study was conducted for HLA-DRB1 in Japanese SLE patients. Relative predispositional effects were analyzed by sequential elimination of carriers of each allele with the strongest association. We also explored the association of DRB1 alleles with SLE phenotypes including the presence of autoantibody and clinical manifestations. Significantly different carrier frequencies of certain DRB1 alleles were found to be associated with SLE as follows: increased DRB1*15:01 (P = 5.48×10⁻¹⁰, corrected P (Pc) = 1.59×10⁻⁸, odds ratio [OR] 2.17, 95% confidence interval [CI] 1.69-2.79), decreased DRB1*13:02 (P = 7.17×10⁻⁵, Pc = 0.0020, OR 0.46, 95% CI 0.34-0.63) and decreased DRB1*14:03 (P = 0.0010, Pc = 0.0272, OR 0.34, 95% CI 0.18-0.63). Additionally, the "*15:01/*13:02 or *14:03" genotype tended to be negatively associated with SLE (P = 0.4209, OR 0.66), despite there being significant positive associations with *15:01 when present together with alleles other than *13:02 or *14:03 (P = 1.79×10⁻¹¹, OR 2.39, 95% CI 1.84-3.10). This protective effect of *13:02 and *14:03 was also confirmed in SLE patients with different clinical phenotypes. To the best of our knowledge, this is the first report of a protective association between the carrier frequencies of HLA-DRB1*13:02 and *14:03 and SLE in the Japanese population.
Clinical Research Center for Allergy and Rheumatology, Sagamihara Hospital, National Hospital Organization, Sagamihara, Japan.
Hiroshi
H
Furukawa
Molecular and Genetic Epidemiology Laboratory, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.
Aya
A
Kawasaki
Clinical Research Center for Allergy and Rheumatology, Sagamihara Hospital, National Hospital Organization, Sagamihara, Japan.
Shomi
S
Oka
Molecular and Genetic Epidemiology Laboratory, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.
Ikue
I
Ito
Department of Rheumatology, Tokyo Metropolitan Tama Medical Center, Fuchu, Japan ; Department of Rheumatology, Sagamihara Hospital, National Hospital Organization, Sagamihara, Japan.
Kota
K
Shimada
Department of Rheumatology, Tokyo Metropolitan Tama Medical Center, Fuchu, Japan.
Shoji
S
Sugii
Department of Rheumatology, Sagamihara Hospital, National Hospital Organization, Sagamihara, Japan.
Atsushi
A
Hashimoto
Clinical Research Center for Allergy and Rheumatology, Sagamihara Hospital, National Hospital Organization, Sagamihara, Japan.
Akiko
A
Komiya
Clinical Research Center for Allergy and Rheumatology, Sagamihara Hospital, National Hospital Organization, Sagamihara, Japan.
Naoshi
N
Fukui
Department of Internal Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.
Yuya
Y
Kondo
Department of Rheumatology, Niigata Rheumatic Center, Shibata, Japan.
Satoshi
S
Ito
Department of Internal Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.
Taichi
T
Hayashi
Department of Internal Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.
Isao
I
Matsumoto
Department of Internal Medicine and Rheumatology, Juntendo University School of Medicine, Tokyo, Japan.
Makio
M
Kusaoi
Department of Internal Medicine and Rheumatology, Juntendo University School of Medicine, Tokyo, Japan.
Hirofumi
H
Amano
Department of Rheumatology and Infectious Disease, Kitasato University School of Medicine, Sagamihara, Japan.
Tatsuo
T
Nagai
Department of Rheumatology and Infectious Disease, Kitasato University School of Medicine, Sagamihara, Japan.
Shunsei
S
Hirohata
Department of Allergy and Immunological Diseases, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Tokyo, Japan.
Keigo
K
Setoguchi
Department of Internal Medicine, Teikyo University, Tokyo, Japan.
Hajime
H
Kono
Department of Rheumatology, Himeji Medical Center, National Hospital Organization, Himeji, Japan.
Akira
A
Okamoto
Department of Rheumatology, Morioka Hospital, National Hospital Organization, Morioka, Japan.
Noriyuki
N
Chiba
Department of Internal Medicine and Rheumatology, Clinical Research Institute, Kyushu Medical Center, National Hospital Organization, Fukuoka, Japan.
Eiichi
E
Suematsu
Department of Internal Medicine, Nagoya Medical Center, National Hospital Organization, Nagoya, Japan.
Masao
M
Katayama
Clinical Research Center, Nagasaki Medical Center, National Hospital Organization, Omura, Japan.
Kiyoshi
K
Migita
Center for Rheumatic Diseases, Yokohama City University Medical Center, Yokohama, Japan ; Department of Rheumatology, Yokohama Minami Kyosai Hospital, Yokohama, Japan.
Akiko
A
Suda
Center for Rheumatic Diseases, Yokohama City University Medical Center, Yokohama, Japan.
Shigeru
S
Ohno
Juntendo University School of Medicine, Tokyo, Japan.
Hiroshi
H
Hashimoto
Department of Internal Medicine and Rheumatology, Juntendo University School of Medicine, Tokyo, Japan.
Yoshinari
Y
Takasaki
Department of Internal Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.
Takayuki
T
Sumida
Department of Rheumatology, Yokohama Minami Kyosai Hospital, Yokohama, Japan.
Shouhei
S
Nagaoka
Molecular and Genetic Epidemiology Laboratory, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.
Naoyuki
N
Tsuchiya
Clinical Research Center for Allergy and Rheumatology, Sagamihara Hospital, National Hospital Organization, Sagamihara, Japan.
Shigeto
S
Tohma
D000328:Adult; D000483:Alleles; D044466:Asian People / Q000235:genetics*; D016022:Case-Control Studies; D004247:DNA / Q000032:analysis; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D015808:HLA-DR6 Antigen / Q000235:genetics* / Q000276:immunology; D059811:HLA-DRB1 Chains / Q000235:genetics* / Q000276:immunology; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000235:genetics* / Q000276:immunology* / Q000517:prevention & control; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D016133:Polymerase Chain Reaction
D015808:HLA-DR6 Antigen; D059811:HLA-DRB1 Chains; D004247:DNA