Association ofHLA-class IIalleles with risk of relapse in myeloperoxidase-antineutrophil cytoplasmic antibody positive vasculitis in the Japanese population

Abstract

AbstractBackgroundDisease relapse remains a major problem in the management of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). In European populations,HLA-DPB1*04:01is associated with both susceptibility and relapse risk in proteinase 3-ANCA positive AAV. In a Japanese population, we previously reported an association betweenHLA-DRB1*09:01andDQB1*03:03with susceptibility to, andDRB1*13:02with protection from, myeloperoxidase-ANCA positive AAV (MPO-AAV). Subsequently, the association ofDQA1*03:02, which is in strong linkage disequilibrium withDRB1*09:01andDQB1*03:03, 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 whetherHLA-class IIis associated with the risk of relapse in MPO-AAV.MethodsFirst, the association ofHLA-DQA1*03:02with susceptibility to MPO-AAV and microscopic polyangiitis (MPA) and its relationship with previously reportedDRB1*09:01andDQB1*03:03were 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 (Puncorr) were corrected for multiple comparisons in each analysis using the false discovery rate method.ResultsThe association ofDQA1*03:02with susceptibility to MPO-AAV and MPA was confirmed in a Japanese population (MPO-AAV: Puncorr=5.8×10−7, odds ratio [OR] 1.74, 95% confidence interval [CI] 1.40–2.16, MPA: Puncorr=1.1×10−5, OR 1.71, 95%CI 1.34–2.17).DQA1*03:02was in strong linkage disequilibrium withDRB1*09:01andDQB1*03:03, and the causal allele could not be determined using conditional logistic regression analysis. Relapse-free survival was shorter with nominal significance in carriers ofDRB1*09:01(Puncorr=0.049, Q=0.42, hazard ratio [HR]:1.87),DQA1*03:02(Puncorr=0.020, Q=0.22, HR:2.11) andDQB1*03:03(Puncorr=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), includingDRB1*13:02carriers, showed longer relapse-free survival with nominal significance (Puncorr=0.010, Q=0.42, HR:0.31). By combiningDQA1*03:02and HLA-DRβ1_13S, a significant difference was detected between groups with the highest and lowest risk for relapse (Puncorr=0.0055, Q=0.033, HR:4.02).ConclusionHLA-class IIis associated not only with susceptibility to MPO-AAV but also with risk of relapse in the Japanese population.