AUTHOR=Kawasaki Aya , Sada Ken-ei , Kusumawati Premita Ari , Hirano Fumio , Kobayashi Shigeto , Nagasaka Kenji , Sugihara Takahiko , Ono Nobuyuki , Fujimoto Takashi , Kusaoi Makio , Tamura Naoto , Kusanagi Yasuyoshi , Itoh Kenji , Sumida Takayuki , Yamagata Kunihiro , Hashimoto Hiroshi , Makino Hirofumi , Arimura Yoshihiro , Harigai Masayoshi , Tsuchiya Naoyuki 

TITLE=Association of HLA-class II alleles with risk of relapse in myeloperoxidase-antineutrophil cytoplasmic antibody positive vasculitis in the Japanese population

JOURNAL=Frontiers in Immunology

VOLUME=14

YEAR=2023

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2023.1119064

DOI=10.3389/fimmu.2023.1119064

ISSN=1664-3224

ABSTRACT=<sec><title>Background</title><p>Disease relapse remains a major problem in the management of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). In European populations, <italic>HLA-DPB1*04:01</italic> is associated with both susceptibility and relapse risk in proteinase 3-ANCA positive AAV. In a Japanese population, we previously reported an association between <italic>HLA-DRB1*09:01</italic> and <italic>DQB1*03:03</italic> with susceptibility to, and <italic>DRB1*13:02</italic> with protection from, myeloperoxidase-ANCA positive AAV (MPO-AAV). Subsequently, the association of <italic>DQA1*03:02</italic>, which is in strong linkage disequilibrium with <italic>DRB1*09:01</italic> and <italic>DQB1*03:03</italic>, with MPO-AAV susceptibility was reported in a Chinese population. However, an association between these alleles and risk of relapse has not yet been reported. Here, we examined whether <italic>HLA-class II</italic> is associated with the risk of relapse in MPO-AAV.</p></sec><sec><title>Methods</title><p>First, the association of <italic>HLA-DQA1*03:02</italic> with susceptibility to MPO-AAV and microscopic polyangiitis (MPA) and its relationship with previously reported <italic>DRB1*09:01</italic> and <italic>DQB1*03:03</italic> were examined in 440 Japanese patients and 779 healthy controls. Next, the association with risk of relapse was analyzed in 199 MPO-ANCA positive, PR3-ANCA negative patients enrolled in previously reported cohort studies on remission induction therapy. Uncorrected P values (P<sub>uncorr</sub>) were corrected for multiple comparisons in each analysis using the false discovery rate method.</p></sec><sec><title>Results</title><p>The association of <italic>DQA1*03:02</italic> with susceptibility to MPO-AAV and MPA was confirmed in a Japanese population (MPO-AAV: P<sub>uncorr</sub>=5.8x10<sup>-7</sup>, odds ratio [OR] 1.74, 95% confidence interval [CI] 1.40–2.16, MPA: P<sub>uncorr</sub>=1.1x10<sup>-5</sup>, OR 1.71, 95%CI 1.34–2.17). <italic>DQA1*03:02</italic> was in strong linkage disequilibrium with <italic>DRB1*09:01</italic> and <italic>DQB1*03:03</italic>, and the causal allele could not be determined using conditional logistic regression analysis. Relapse-free survival was shorter with nominal significance in carriers of <italic>DRB1*09:01</italic> (P<sub>uncorr</sub>=0.049, Q=0.42, hazard ratio [HR]:1.87), <italic>DQA1*03:02</italic> (P<sub>uncorr</sub>=0.020, Q=0.22, HR:2.11) and <italic>DQB1*03:03</italic> (P<sub>uncorr</sub>=0.043, Q=0.48, HR:1.91) than in non-carriers in the log-rank test. Conversely, serine carriers at position 13 of HLA-DRβ1 (HLA-DRβ1_13S), including <italic>DRB1*13:02</italic> carriers, showed longer relapse-free survival with nominal significance (P<sub>uncorr</sub>=0.010, Q=0.42, HR:0.31). By combining <italic>DQA1*03:02</italic> and HLA-DRβ1_13S, a significant difference was detected between groups with the highest and lowest risk for relapse (P<sub>uncorr</sub>=0.0055, Q=0.033, HR:4.02).</p></sec><sec><title>Conclusion</title><p><italic>HLA-class II</italic> is associated not only with susceptibility to MPO-AAV but also with risk of relapse in the Japanese population.</p></sec>