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