Meta-analysis revealed HLA susceptibility markers in ANCA-associated vasculitis and its clinical subtypes

ANCA-associated vasculitis (AAV) is a group of systemic autoimmune diseases affecting small blood-vessels. Class-II human leukocyte antigen (HLA) genes are often reported as major genetic determinants. We conducted a systematic review and meta-analysis to evaluate the susceptibility conferred by HLA genes to AAV and five of its clinical subtypes [PR3+AAV, MPO+AAV, granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA) and eosinophilic granulomatosis with polyangiitis (EGPA)].

Relevant articles published March 2024 or previously were retrieved from electronic databases using appropriate keywords. Eligible studies were included according to inclusion/exclusion criteria. Funnel plots, the Newcastle-Ottawa Scale and GRADE tools were used to evaluate the quality of the evidence and the research findings. Statistical analyses were performed using RevMan 5.4.1. The meta-odds ratio and the Z test P-value were considered to check the HLA associations.

This meta-analysis of associations between HLA alleles and AAV and its subtypes identified 30 significant associations, of which 17 withstood Bonferroni corrections. rs9277554-C from HLA-DPB1 [meta-analysis overall odds ratio (Meta-OR) = 3.92 (3.27-4.69)], rs1049072-A from HLA-DQB1 [Meta-OR = 1.39 (1.27-1.52)] and rs9277341-C from HLA-DPA1 [Meta-OR = 0.41 (0.03-0.57)] were found to be significantly associated (P < 0.00001) with AAV and GPA, respectively. HLA-DRB1*09:01 was found to be significantly associated with (P < 0.00001) (i.e. a predisposing allele for) AAV [Meta-OR = 1.72 (1.46-2.03)], MPO+AAV [Meta-OR = 1.65 (1.41-1.93)] and MPA [Meta-OR = 1.75 (1.41-2.19)]. Significant association (P ≤ 0.0005) was also observed between HLA-DPB1*01:01 and AAV [Meta-OR = 0.38 (0.24-0.62)] and between HLA-DRB1*11:01 and MPA [Meta-OR = 2.11 (1.39-3.20)]. Sensitivity analysis identified additional significant (P ≤ 0.001) alleles HLA-DPB1*04:01 and HLA-DPB1*02:01 predisposing patients to AAV and to more than one subtype of AAV.

Multiple alleles of HLA-DRB1 and HLA-DPB1 were found to be associated with predisposition to AAV and its subtypes. Predisposition to AAV, PR3+AAV and GPA was found to be associated with HLA-DPB1*04:01, and protection against AAV, PR3+AAV and GPA was found to be associated with HLA-DPB1*02:01. Predisposition to AAV, MPO+AAV and MPA was found to be associated with HLA-DRB1*09:01.