title: Protective Role of HLA-DRB1*13:02 against Microscopic Polyangiitis and MPO-ANCA-Positive Vasculitides in a Japanese Population: A Case-Control Study.
abstract: Among antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV), granulomatosis with polyangiitis (GPA) and proteinase 3-ANCA-positive AAV (PR3-AAV) are prevalent in European populations, while microscopic polyangiitis (MPA) and myeloperoxidase-ANCA-positive AAV (MPO-AAV) are predominant in the Japanese. We previously demonstrated association of DRB1*09:01-DQB1*03:03 haplotype, a haplotype common in East Asians but rare in the European populations, with MPA/MPO-AAV, suggesting that a population difference in HLA-class II plays a role in the epidemiology of this disease. To gain further insights, we increased the sample size and performed an extended association study of DRB1 and DPB1 with AAV subsets in 468 Japanese patients with AAV classified according to the European Medicines Agency algorithm (MPA: 285, GPA: 92, eosinophilic GPA [EGPA]: 56, unclassifiable: 35) and 596 healthy controls. Among these patients, 377 were positive for MPO-ANCA and 62 for PR3-ANCA. The significance level was set at α = 3.3x10-4 by applying Bonferroni correction. The association of DRB1*09:01 with MPO-AAV was confirmed (allele model, P = 2.1x10-4, odds ratio [OR] = 1.57). Protective association of DRB1*13:02 was detected against MPO-AAV (allele model, P = 2.3x10-5, OR = 0.42) and MPA (dominant model, P = 2.7x10-4, OR = 0.43). A trend toward increased frequency of DPB1*04:01, the risk allele for GPA in European populations, was observed among Japanese patients with PR3-AAV when conditioned on DRB1*13:02 (Padjusted = 0.0021, ORadjusted = 3.48). In contrast, the frequency of DPB1*04:01 was decreased among Japanese patients with MPO-AAV, and this effect lost significance when conditioned on DRB1*13:02 (Padjusted = 0.16), suggesting that DRB1*13:02 or other allele(s) in linkage disequilibrium may be responsible for the protection. The differential association of DPB1*04:01 with PR3-AAV and MPO-AAV and difference in DPB1*04:01 allele frequencies between populations supported the hypothesis that the HLA-class II population difference may account in part for these epidemiologic characteristics. Furthermore, taken together with our previous observations, the haplotype carrying DRB1*13:02 was suggested to be a shared protective factor against multiple autoimmune diseases.
authors.affiliation: Molecular and Genetic Epidemiology Laboratory, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.|Doctoral Program in Biomedical Sciences, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Japan.|Master's Program in Medical Sciences, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Japan.
authors.forename: Aya
authors.initials: A
authors.lastname: Kawasaki
authors.affiliation: Molecular and Genetic Epidemiology Laboratory, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.|Doctoral Program in Biomedical Sciences, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Japan.
authors.forename: Narumi
authors.initials: N
authors.lastname: Hasebe
authors.affiliation: Molecular and Genetic Epidemiology Laboratory, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.|Master's Program in Medical Sciences, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Japan.
authors.forename: Misaki
authors.initials: M
authors.lastname: Hidaka
authors.affiliation: Department of Pharmacovigilance, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.|Department of Rheumatology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Fumio
authors.initials: F
authors.lastname: Hirano
authors.affiliation: Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
authors.forename: Ken-Ei
authors.initials: KE
authors.lastname: Sada
authors.affiliation: Department of Internal Medicine, Juntendo University Koshigaya Hospital, Koshigaya, Japan.
authors.forename: Shigeto
authors.initials: S
authors.lastname: Kobayashi
authors.affiliation: Department of Internal Medicine, St. Marianna University School of Medicine, Kawasaki, Japan.
authors.forename: Hidehiro
authors.initials: H
authors.lastname: Yamada
authors.affiliation: Molecular and Genetic Epidemiology Laboratory, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.|Doctoral Program in Biomedical Sciences, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Japan.|Master's Program in Medical Sciences, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Japan.|Clinical Research Center for Allergy and Rheumatology, Sagamihara Hospital, National Hospital Organization, Sagamihara, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Furukawa
authors.affiliation: Department of Nephrology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.
authors.forename: Kunihiro
authors.initials: K
authors.lastname: Yamagata
authors.affiliation: Department of Internal Medicine (Rheumatology), Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Sumida
authors.affiliation: Department of Rheumatology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Miyasaka
authors.affiliation: Clinical Research Center for Allergy and Rheumatology, Sagamihara Hospital, National Hospital Organization, Sagamihara, Japan.
authors.forename: Shigeto
authors.initials: S
authors.lastname: Tohma
authors.affiliation: Department of Internal Medicine, St. Marianna University School of Medicine, Kawasaki, Japan.
authors.forename: Shoichi
authors.initials: S
authors.lastname: Ozaki
authors.affiliation: Department of Nephrology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Seiichi
authors.initials: S
authors.lastname: Matsuo
authors.affiliation: Juntendo University School of Medicine, Tokyo, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Hashimoto
authors.affiliation: Okayama University Hospital, Okayama, Japan.
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Makino
authors.affiliation: First Department of Internal Medicine, Kyorin University School of Medicine, Tokyo, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Arimura
authors.affiliation: Department of Pharmacovigilance, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.|Institute of Rheumatology, Tokyo Women's Medical University, Tokyo, Japan.
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Harigai
authors.affiliation: Molecular and Genetic Epidemiology Laboratory, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.|Doctoral Program in Biomedical Sciences, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Japan.|Master's Program in Medical Sciences, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Japan.
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Tsuchiya
mesh_terms: D000328:Adult; D000368:Aged; D000483:Alleles; D056648:Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis / Q000097:blood / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D019268:Antibodies, Antineutrophil Cytoplasmic / Q000097:blood*; D016022:Case-Control Studies; D005260:Female; D015870:Gene Expression; D005787:Gene Frequency; D059811:HLA-DRB1 Chains / Q000235:genetics* / Q000276:immunology; D006239:Haplotypes; D006801:Humans; D007564:Japan; D015810:Linkage Disequilibrium; D008297:Male; D055953:Microscopic Polyangiitis / Q000097:blood / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D008875:Middle Aged; D016017:Odds Ratio; D009195:Peroxidase / Q000097:blood*; D065840:Protective Factors
chemical_list: D019268:Antibodies, Antineutrophil Cytoplasmic; D059811:HLA-DRB1 Chains; C506473:HLA-DRB1*13 antigen; D009195:Peroxidase