Association of<i>HLA-class II</i>alleles with risk of relapse in myeloperoxidase-antineutrophil cytoplasmic antibody positive vasculitis in the Japanese population

Abstract Background Disease 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.Methods First, 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.Results The 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).Conclusion HLA-class IIis associated not only with susceptibility to MPO-AAV but also with risk of relapse in the Japanese population..

Medienart:	Preprint

Erscheinungsjahr:	2024
Erschienen:	2024

Enthalten in:	bioRxiv.org - (2024) vom: 23. Apr. Zur Gesamtaufnahme - year:2024

Sprache:	Englisch

Beteiligte Personen:

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

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Themen:	570 Biology

doi:	10.1101/2022.12.28.22283983

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PPN (Katalog-ID):	XBI038291681