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

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

<i>HLA-DRB1</i> allele frequencies in Japanese patients with MPO-AAV or PR3-AAV or in healthy controls.

<p><i>HLA-DRB1</i> allele frequencies in Japanese patients with MPO-AAV or PR3-AAV or in healthy controls.</p

<i>HLA-DRB1</i> allele frequencies in Japanese patients with MPA, EGPA, or GPA or in healthy controls.

<p><i>HLA-DRB1</i> allele frequencies in Japanese patients with MPA, EGPA, or GPA or in healthy controls.</p

<i>HLA-DPB1</i> allele frequencies in Japanese patients with MPO-AAV or PR3-AAV or in healthy controls.

<p><i>HLA-DPB1</i> allele frequencies in Japanese patients with MPO-AAV or PR3-AAV or in healthy controls.</p

Conditional logistic regression analysis between <i>DRB1*13</i>:<i>02</i> and <i>DPB1*04</i>:<i>01</i> in AAV subsets.

<p>Conditional logistic regression analysis between <i>DRB1*13</i>:<i>02</i> and <i>DPB1*04</i>:<i>01</i> in AAV subsets.</p

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

<div><p>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 <i>DRB1*09</i>:<i>01-DQB1*03</i>:<i>03</i> haplotype, a haplotype common in East Asians but rare in the European populations, with MPA/MPO-AAV, suggesting that a population difference in <i>HLA-class II</i> 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 <i>DRB1</i> and <i>DPB1</i> 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 <i>DRB1*09</i>:<i>01</i> with MPO-AAV was confirmed (allele model, P = 2.1x10^-4, odds ratio [OR] = 1.57). Protective association of <i>DRB1*13</i>:<i>02</i> 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 <i>DPB1*04</i>:<i>01</i>, the risk allele for GPA in European populations, was observed among Japanese patients with PR3-AAV when conditioned on <i>DRB1*13</i>:<i>02</i> (P_adjusted = 0.0021, OR_adjusted = 3.48). In contrast, the frequency of <i>DPB1*04</i>:<i>01</i> was decreased among Japanese patients with MPO-AAV, and this effect lost significance when conditioned on <i>DRB1*13</i>:<i>02</i> (P_adjusted = 0.16), suggesting that <i>DRB1*13</i>:<i>02</i> or other allele(s) in linkage disequilibrium may be responsible for the protection. The differential association of <i>DPB1*04</i>:<i>01</i> with PR3-AAV and MPO-AAV and difference in <i>DPB1*04</i>:<i>01</i> allele frequencies between populations supported the hypothesis that the <i>HLA-class II</i> population difference may account in part for these epidemiologic characteristics. Furthermore, taken together with our previous observations, the haplotype carrying <i>DRB1*13</i>:<i>02</i> was suggested to be a shared protective factor against multiple autoimmune diseases.</p></div

<i>HLA-DPB1</i> allele frequencies in Japanese patients with MPA, EGPA, or GPA or in healthy controls.

<p><i>HLA-DPB1</i> allele frequencies in Japanese patients with MPA, EGPA, or GPA or in healthy controls.</p