Association Oftertanddspvariants With Microscopic Polyangiitis And Myeloperoxidase-Anca Positive Vasculitis In A Japanese Population: A Genetic Association Study

Background Interstitial 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 aMUC5Bvariant 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, theMUC5Bvariant alone cannot account for the high prevalence of AAV-ILD in Japan. In this study, we examined whether other IPF susceptibility alleles inTERTandDSPgenes are associated with susceptibility to AAV subsets and AAV-ILD. Methods Five 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 ofTERTandDSPvariants were determined by TaqMan SNP Genotyping Assay, and their association was tested by chi-square test. Results When the frequencies of the IPF risk allelesTERTrs2736100A andDSPrs2076295G were compared between AAV subsets and healthy controls, both alleles were significantly increased in microscopic polyangiitis (MPA) (TERT P = 2.3 x 10(-4),P-c = 0.0023, odds ratio [OR] 1.38;DSP P = 6.9 x 10(-4),P-c = 0.0069, OR 1.32) and MPO-AAV (TERT P = 1.5 x 10(-4),P-c = 0.0015, OR 1.33;DSP P = 0.0011,P-c = 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. Conclusions Unexpectedly,TERTandDSPIPF risk alleles were found to be associated with MPA and MPO-AAV, regardless of the presence of ILD. These findings suggest thatTERTandDSPmay be novel susceptibility genes to MPA/MPO-AAV and also that some susceptibility genes may be shared between IPF and MPA/MPO-AAV.