Protective Role of HLA-DRB1*13:02 against Microscopic Polyangiitis and MPO-ANCA-Positive Vasculitides in a Japanese Population: A Case-Control Study.

Hirofumi Makino,Shigeto Kobayashi,Hiroshi Furukawa,Ken-Ei Sada,Yoshihiro Arimura,Seiichi Matsuo,Narumi Hasebe,Shigeto Tohma,Fumio Hirano,Shoichi Ozaki,Naoyuki Tsuchiya,Aya Kawasaki,Kunihiro Yamagata,Hiroshi Hashimoto,Masayoshi Harigai,Hidehiro Yamada,Nobuyuki Miyasaka,Misaki Hidaka,Takayuki Sumida

doi:10.1371/journal.pone.0154393

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.

Highlights

An epidemiologic difference is clearly observed in antineutrophil cytoplasmic antibody (ANCA) -associated vasculitides (AAV) between European and East Asian populations
Four hundred and sixty-eight Japanese patients with AAV and 596 healthy controls, including the 116 patients with myeloperoxidase-ANCA-positive AAV (MPO-AAV) and 265 controls reported in our previous study [11], were recruited at the institutes participating in the Research Committee on Intractable Vasculitides and in the Research Group on Progressive Renal Diseases, both organized by the Ministry of Health, Labour, and Welfare of Japan, research groups organized by Sagamihara Hospital, National Hospital Organization, and the Tokyo Medical and Dental University
Association of DRB1 alleles with AAV was tested using clinical disease classification according to the European Medicines Agency (EMEA) algorithm (Table 1 and S3 Table) as well as by ANCA specificity (Table 2 and S4 Table)

Summary

Introduction

An epidemiologic difference is clearly observed in antineutrophil cytoplasmic antibody (ANCA) -associated vasculitides (AAV) between European and East Asian populations. With respect to AAV in the populations of European ancestry, candidate gene studies with relatively small sample sizes suggested an association of the DR4-DQ7 haplotype with the predisposition to both GPA and MPA in the UK [2], of the DR1-DQ1 haplotype with GPA in the UK [3], and of DRB1Ã04 with end-stage renal disease accompanied by GPA in Germany [4]. Protective association of DRB1Ã13 has been detected for GPA in Germany [4] and in the Netherlands [5]. Association of DPB1Ã04:01 with GPA has been reported in a moderately powered study in Germany [6]

Methods

Results

Conclusion