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

Abstract Objectives ANCA-associated vasculitis (AAV) is a group of systemic autoimmune diseases affecting small blood-vessels. Class-II HLA genes often reported as major genetic determinants. We conducted a systematic review and meta-analysis to evaluate the susceptibility conferred by HLA genes in AAV and five sub-types i.e. PR3+AAV, MPO+AAV, Granulomatosis with polyangiitis (GPA), Microscopic polyangiitis (MPA) and Eosinophilic granulomatosis with polyangiitis (EGPA). Methods Relevant articles were retrieved until March 2024, from electronic databases using appropriate keywords. Eligible studies were included following inclusion-exclusion criteria. Funnel plots, Newcastle-Ottawa Scale and GRADE tools were used to evaluate the quality of evidence and research findings. Statistical analyses were performed by RevMan 5.4.1. The meta-odds ratio and Z test p-value were considered to check the HLA associations. Results Meta-analysis of HLA-alleles identified 30 significant associations with AAV and its sub-types of which 17 withstood Bonferroni corrections. rs9277554-C from HLA-DPB1 (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 significantly associated (p < 0.00001) with AAV and GPA respectively. DRB1*09:01 was significantly (p < 0.00001) predisposing allele in AAV (Meta-OR = 1.72(1.46–2.03)) and 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 for DPB1*01:01 (Meta-OR = 0.38(0.24–0.62)) and DRB1*11:01 (Meta-OR = 2.11(1.39–3.20)) for AAV and MPA respectively. Sensitivity analysis identified additional significant (p ≤ 0.001) predisposing alleles DPB1*04:01 and DPB1*02:01 in AAV and more than one sub-types. Conclusion Multiple alleles from HLA-DRB1 and DPB1 were found to provide predisposition to AAV and sub-types. Predisposition by DPB1*04:01 and protection by DPB1*02:01 were specific for AAV, PR3+AAV and GPA. Predisposition by DRB1*09:01 was observed among AAV, MPO+AAV and MPA.