The HLA region in ANCA-associated vasculitis: characterisation of genetic associations in a Scandinavian patient population

Abstract

ObjectiveThe antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) are inflammatory disorders with ANCA autoantibodies recognising either proteinase 3 (PR3-AAV) or myeloperoxidase (MPO-AAV). PR3-AAV and MPO-AAV have been associated with distinct loci in the human leucocyte antigen (HLA) region. While the association between MPO-AAV and HLA has been well characterised in East Asian populations where MPO-AAV is more common, studies in populations of European descent are limited. The aim of this study was to thoroughly characterise associations to the HLA region in Scandinavian patients with PR3-AAV as well as MPO-AAV.MethodsGenotypes of single-nucleotide polymorphisms (SNPs) located in the HLA region were extracted from a targeted exome-sequencing dataset comprising Scandinavian AAV cases and controls. Classical HLA alleles were called using xHLA. After quality control, association analyses were performed of a joint SNP/classical HLA allele dataset for cases with PR3-AAV (n=411) and MPO-AAV (n=162) versus controls (n=1595). Disease-associated genetic variants were analysed for association with organ involvement, age at diagnosis and relapse, respectively.ResultsPR3-AAV was significantly associated with both HLA-DPB1*04:01 and rs1042335 at theHLA-DPB1locus, also after stepwise conditional analysis. MPO-AAV was significantly associated with HLA-DRB1*04:04. Neither carriage of HLA-DPB1*04:01 alleles in PR3-AAV nor of HLA-DRB1*04:04 alleles in MPO-AAV were associated with organ involvement, age at diagnosis or relapse.ConclusionsThe association to the HLA region was distinct in Scandinavian cases with MPO-AAV compared with cases of East Asian descent. In PR3-AAV, the two separate signals of association to theHLD-DPB1region mediate potentially different functional effects.

Evaluating Single-Nucleotide Polymorphisms in Inflammasome Proteins and Serum Levels of IL-18 and IL-1β in Kidney Interstitial Damage in Anti-Neutrophilic Cytoplasmic Antibody-Associated Vasculitis

“…Genotypes of SNPs located in different genes involved in the function of the immune system have been evaluated as risk factors for susceptibility and clinical outcomes of AAV. Several authors studied the association of certain SNPs in the human leukocyte antigen (HLA) regions and found differences in frequency according to ANCA specificity (myeloperoxidase (MPO) or proteinase-3 (PR3)) [ 14 , 15 ]. Casal Moura et al found an association of rs351111, located in the PR3 gene, with a higher frequency of severe relapses in a cohort of 188 patients [ 16 ].…”