Distinct HLA and non‐HLA associations in different subtypes of ANCA‐associated vasculitides in North India

Abstract

Aim: Antineutrophil cytoplasmic antibody-associated vasculitis (AAV) is an autoimmune disease characterized by necrotizing small vessel vasculitis that can affect various organs and present multiple symptoms. Susceptibility to AAV is multifactorial and most likely caused by an amalgamation of genetic and environmental factors. The aim of the present study was to explore the distribution of human leukocyte antigen (HLA)-DRB1/DQB1, protein tyrosine phosphatase non-receptor type 22 (PTPN22) and cytotoxic T-Lymphocyte-associated protein 4 (CTLA-4) polymorphisms in North Indian AAV patients and their associations with clinical and pathological characteristics associated with the disease. Methods: A total of 150 AAV patients and 150 healthy controls were recruited. The clinical classification showed 128 as granulomatosis with polyangiitis (GPA) and 21 as microscopic polyangiitis. Only 1 case of eosinophilic granulomatosis with polyangiitis was encountered, which was excluded from analysis. HLA-DRB1/DQB1 alleles were determined by polymerase chain reaction-sequence-specific primer (PCR-SSP) method and single nucleotide variant genotyping for CTLA-4 and PTPN22 was done by simple probe-based SNP arrays. Results: A significant predispositional association of DRB1*03 and DQB1*02 alleles, were confirmed in proteinase 3 (PR3)-AAV patients, whereas DRB1*10, DRB1*14 and DQB1*05 were protective alleles in AAV, PR3-AAV and GPA patients. GG genotype of CTLA-4 + 49A/G was increased in patients as compared to controls and showed an association with AAV, PR3-AAV and GPA patients. Conclusion: The study indicated strong genetic associations were linked with PR3 antineutrophil cytoplasmic antibody specificity and it appears that PR3-AAV and MPO-AAV have distinct genetic backgrounds.

An immunogenetic perspective of ANCA-associated vasculitides

“…Another study demonstrated that the CTLA-4-318 SNP was associated with GPA susceptibility [27]. The GG genotype of CTLA-4 + 49A/G was found to be correlated with AAV (PR3-AAV and GPA) in an Indian cohort [18]. The A allele of rs3087243 CTLA has been found to be a protective factor against AAV [28].…”

“…Also, the HLA-DRB4 alleles were found to be related to symptoms of vasculitis in German patients [17]. In a recent study, the DRB1*03 and DQB1*02 alleles were associated with confirmed in proteinase 3 (PR3)-AAV patients, whereas the DRB1*10, DRB1*14, and DQB1*05 were found to be protective alleles in AAV [18].…”

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

“…Three studies were found eligible for the meta-analysis and were evaluated. 8,15,33 A allele of rs2476601 was identified to provide borderline risk (Meta-OR = 1.17 [0.55-2.48]; P = .69) with nonsignificant association (Figure 2H).…”

“…14 Although not consistently observed in candidate gene studies, the significant association of −1858 C/T, rs2476601 with GPA/MPA was reported in Caucasians but was not replicated among Indians. 6,15 An association of PRTN3 promoter polymorphisms rs231775-G and A564G was observed in Germans, which was not replicated among European Americans. 16,17 These genetic variants from CTLA4, PRTN3, SERPINA1 and PTPN22 have been studied in distinctly different ethnic populations and association heterogeneity was observed.…”

Unraveling the Immunopathogenesis and Genetic Variants in Vasculitis Toward Development of Personalized Medicine

“…With regards to the HLA region, the alleles DPA1, DPB1 * 04:01, DPB1 * 04:02, DPB1 * 23:01, DQB1 * 02 , and DRB1 * 03 were associated with the development of PR3-ANCAs, whereas DQA1 * 03:02, DQB1 * 03:03 , and DRB1 * 09:01 were associated with the MPO-ANCAs ( 38 , 53 ). These risk factors were identified based on previous association studies ( 35 , 37 , 38 , 53 , 54 ).…”