Meta-analysis confirmed genetic susceptibility conferred by multiple risk variants from CTLA4 and SERPINA1 in granulomatosis with polyangiitis

Background Granulomatosis with polyangiitis (GPA) is a rare systemic autoimmune disease. Smaller sample size and complex nature of the disease pathogenesis has made it challenging to perform well-powered genetic investigations. We performed a systematic review based meta-analysis in GPA to investigate the genetic susceptibility conferred by non-human leukocyte antigen (non-HLA) candidate genes. Methods A systematic review was performed using web-based literature search and eligible studies were included following inclusion-exclusion criteria. Studies were evaluated for their quality of evidence and study outcome was assessed using the Newcastle-Ottawa Scale and Grades of Research, Assessment, Development and Evaluation tools. Reviewer's agreement was accessed through Cohen's kappa value. Meta-analyses were performed using RevMan 5 tool. Meta-odds ratio (meta-OR) and Z test P value were evaluated to estimate the genetic susceptibility for each of the variants. Results Eighteen studies were found eligible and 7 genetic variants from only 4 genes, namely CTLA4, PRTN3, SERPINA1 and PTPN22 could be studied for meta-analysis. rs231775-G (49-G) (Meta-OR = 1.42 [1.14-1.76]; P = .001) of CTLA4 and rs7151526-A (Meta-OR = 2.70 [1.51-4.85]; P = .0008) of SERPINA1 were confirmed to be predisposing alleles, and rs5742909-C (318-C) (Meta-OR = 0.65 [0.44-0.97]; P =.03) of CTLA4 was found to be protective for GPA. In concordance with the genetic association of rs7151526-A, serological marker for the same variant "Z" allele of SERPINA1 was found to be predisposing (Meta-OR = 12.60 [5.01-31.68]; P < .00001) for GPA. Conclusion Genetic variants confirmed in this study play critical roles in T-cell mediated immune function and could be significantly implicated in GPA. Molecular pathology studies are warranted to confirm their role. These markers could be used for efficient patient classification and disease management.