Association of Granulomatosis With Polyangiitis (Wegener's) With HLA–DPB1*04 and SEMA6A Gene Variants: Evidence From Genome‐Wide Analysis

Abstract

Objective To identify genetic determinants of granulomatosis with polyangiitis (Wegener’s) (GPA). Methods We carried out a genome-wide association study (GWAS) of 492 GPA cases and 1,506 healthy controls (white subjects of European descent), followed by replication analysis of the most strongly associated signals in an independent cohort of 528 GPA cases and 1,228 controls. Results Genome-wide significant associations were identified in 32 single-nucleotide polymorphic (SNP) markers across the HLA region, the majority of which were located in the HLA–DPB1 and HLA–DPA1 genes encoding the class II major histocompatibility complex (MHC) DPβ chain 1 and DPα chain 1 proteins, respectively. Peak association signals in these 2 genes, emanating from SNPs rs9277554 (for DPβ chain 1) and rs9277341 (DPα chain 1) were strongly replicated in an independent cohort (in the combined analysis of the initial cohort and the replication cohort, P = 1.92 × 10−50 and 2.18 × 10−39, respectively). Imputation of classic HLA alleles and conditional analyses revealed that the SNP association signal was fully accounted for by the classic HLA–DPB1*04 allele. An independent single SNP, rs26595, near SEMA6A (the gene for semaphorin 6A) on chromosome 5, was also associated with GPA, reaching genome-wide significance in a combined analysis of the GWAS and replication cohorts (P = 2.09 × 10−8). Conclusion We identified the SEMA6A and HLA–DP loci as significant contributors to risk for GPA, with the HLA–DPB1*04 allele almost completely accounting for the MHC association. These two associations confirm the critical role of immunogenetic factors in the development of GPA.

Human Leukocyte Antigen Class II Haplotypes Affect Clinical Characteristics and Progression of Type 1 Autoimmune Hepatitis in Japan

“…It was recently proposed that associations with specific HLA-C and HLA-B alleles in autoimmune diseases might result from combinations of these ligands and their corresponding killer cell immunoglobulin-like receptors (KIR) that were expressed by natural killer (NK) cells and a subset of T-lymphocytes [12], [13]. Moreover, the importance of HLA-DP alleles was highlighted in genome-wide association studies (GWAS) and comprehensive HLA analyses of patients with autoimmune diseases, which demonstrated HLA-DP gene variations having a strong association with systemic lupus erythematosus, antineutrophil cytoplasmic antibody-associated vasculitis, and granulomatosis with polyangiitis [14]–[16]. Based on the above reports, we searched for associations of particular HLA alleles, including HLA class I (A, B, and C) and HLA class II (DRB1, DQB1, and DPB1), and haplotypes with susceptibility, clinical manifestations, and outcome of patients with AIH.…”

Identification of Functional and Expression Polymorphisms Associated With Risk for Antineutrophil Cytoplasmic Autoantibody–Associated Vasculitis

“…Although often considered a single disease, GPA and MPA diverge in important respects, such as in the extent of their association with PR3‐reactive ANCAs compared to MPO‐reactive ANCAs, the risk of relapsing disease, and the association of GPA with granulomatous inflammation. The etiology of AAV remains unknown; however, genome‐wide association studies (GWAS) performed in a North American GPA cohort and a European GPA/MPA cohort confirmed the findings from candidate gene analyses identifying strong associations of these diseases with major histocompatibility complex (MHC) class II region alleles 1, 2. A genome‐wide significant association at the SERPINA1 locus was also identified in the European cohort study, with both this and several associations with MHC alleles being differentially detected between patient subsets defined by the presence of PR3‐ANCAs or MPO‐ANCAs 2.…”

The immunopathology of ANCA-associated vasculitis

“…Thus, different HLA genes confer varying degrees of genetic risk across the three subtypes of AAV. A further GWAS analysis of 492 GPA patients and 1,506 healthy controls performed by the Vasculitis Clinical Research Consortium (VCRC) also identified association with HLA-DP, replicating in a further cohort of 528 cases and 1,228 controls [57]. …”