Risk HLA class II alleles and amino acid residues in myeloperoxidase-ANCA-associated vasculitis.

Abstract

A genome-wide association study (GWAS) indicated that myeloperoxidase-ANCA associated vasculitis (AAV) is associated with HLA-DQ. However, susceptibility alleles in these loci have been under-investigated. Here we genotyped 258 Chinese patients with myeloperoxidase-AAV and 597 healthy control individuals at HLA DRB1, DQA1, DQB1 and DPB1, and extracted the encoded amino acid sequences from the IMGT/HLA database. The replication cohort included 97 cases and 107 controls. T cell epitopes of myeloperoxidase were predicted and docked to the HLA molecules. We found DQA1∗0302 (odds ratio 2.34 (95% confidence interval 1.75-3.14)) and DQB1∗0303 (odds ratio 1.89 (1.45-2.48)) were risk alleles for myeloperoxidase-AAV. They are in overt linkage disequilibrium (r2 0.69) and the haplotype DQA1∗0302-DQB1∗0303 presents a significant risk (haplotype score 6.39) as well. Aspartate160 on the DQ α chain (odds ratio 2.06 (1.60-2.67)), encoded by DQA1∗0302, and isoleucine185 on the DQ β chain (odds ratio 1.73 (1.38-2.18)), encoded by DQB1∗0303, both located in the α2β2 domains, conferred significant risk for myeloperoxidase-AAV. Homologous modeling showed that DQα∗160D may confer susceptibility to myeloperoxidase-AAV by altering dimerization of the HLA molecules. Thus, more attention should be paid to the roles of amino acids in the α2β2 domains in addition to the α1β1 binding groove of HLA class II molecules.