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Genetics of microscopic polyangiitis in the Japanese population.

ABSTRACT: The epidemiology of ANCA-associated vasculitis is substantially different between Caucasians and Japanese, which may be related to differences in genetic backgrounds. In this review, I discussed our findings on the genetics of microscopic polyangiitis (MPA) in Japanese. Analysis of HLA genes revealed a significant increase in the HLA-DRB1*09:01-DQB1*03:03 haplotype MPA. This is one of the most frequent haplotypes in Japanese, but is nearly absent in Caucasians, and has been shown to be associated with multiple autoimmune diseases. Analysis of KIR genes revealed significant decreases in the carrier frequency of an activating receptor KIR2DS3 in MPA. When KIRs were analyzed in combination with HLA ligands, the proportion of individuals carrying KIR3DL1 and HLA-Bw4 but not KIR3DS1, the most inhibitory of all KIR3DS1/3DL1/HLA-B combinations, was significantly increased in MPA. These results suggested that decreased activation of NK and/or T cells may cause a predisposition to MPA. LILRA2 is an activating receptor involved in granulocyte and macrophage activation. LILRA2 SNP rs2241524 G >A, which disrupts the intron 6 splice acceptor site, was significantly associated with MPA. The risk allele produces an LILRA2 isoform lacking three amino acids in the linker region. These findings, when confirmed by larger-scale studies, will shed light on the molecular mechanisms of MPA. (*English Translation of J Jpn Coll Angiol 2009; 49: 31-37.).

SUBMITTER: Tsuchiya N

PROVIDER: S-EPMC3595849 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Genetics of microscopic polyangiitis in the Japanese population.

Tsuchiya Naoyuki N

Annals of vascular diseases 20120101 3

The epidemiology of ANCA-associated vasculitis is substantially different between Caucasians and Japanese, which may be related to differences in genetic backgrounds. In this review, I discussed our findings on the genetics of microscopic polyangiitis (MPA) in Japanese. Analysis of HLA genes revealed a significant increase in the HLA-DRB1*09:01-DQB1*03:03 haplotype MPA. This is one of the most frequent haplotypes in Japanese, but is nearly absent in Caucasians, and has been shown to be associate ...[more]

PMID: 23555527

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Project description:BackgroundInterstitial lung disease (ILD) is a severe complication with poor prognosis in anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). Prevalence of AAV-associated ILD (AAV-ILD) in Japan is considerably higher than that in Europe. Recently, we reported that a MUC5B variant rs35705950, the strongest susceptibility variant to idiopathic pulmonary fibrosis (IPF), was strikingly increased in AAV-ILD patients but not in AAV patients without ILD; however, due to the low allele frequency in the Japanese population, the MUC5B variant alone cannot account for the high prevalence of AAV-ILD in Japan. In this study, we examined whether other IPF susceptibility alleles in TERT and DSP genes are associated with susceptibility to AAV subsets and AAV-ILD.MethodsFive hundred and forty-four Japanese patients with AAV and 5558 controls were analyzed. Among the AAV patients, 432 were positive for myeloperoxidase (MPO)-ANCA (MPO-AAV). A total of 176 MPO-AAV patients were positive and 216 were negative for ILD based on CT or high-resolution CT. Genotypes of TERT and DSP variants were determined by TaqMan SNP Genotyping Assay, and their association was tested by chi-square test.ResultsWhen the frequencies of the IPF risk alleles TERT rs2736100A and DSP rs2076295G were compared between AAV subsets and healthy controls, both alleles were significantly increased in microscopic polyangiitis (MPA) (TERT P = 2.3 × 10-4, Pc = 0.0023, odds ratio [OR] 1.38; DSP P = 6.9 × 10-4, Pc = 0.0069, OR 1.32) and MPO-AAV (TERT P = 1.5 × 10-4, Pc = 0.0015, OR 1.33; DSP P = 0.0011, Pc = 0.011, OR 1.26). On the other hand, no significant association was detected when the allele frequencies were compared between MPO-AAV patients with and without ILD.ConclusionsUnexpectedly, TERT and DSP IPF risk alleles were found to be associated with MPA and MPO-AAV, regardless of the presence of ILD. These findings suggest that TERT and DSP may be novel susceptibility genes to MPA/MPO-AAV and also that some susceptibility genes may be shared between IPF and MPA/MPO-AAV.

Project description: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 ? = 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.

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Genetics of microscopic polyangiitis in the Japanese population.

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Genetics of microscopic polyangiitis in the Japanese population.

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