Disease relevant HLA class II alleles isolated by genotypic, haplotypic, and sequence analysis in North American Caucasians with pemphigus vulgaris.

Early studies of genetic susceptibility to pemphigus vulgaris (PV) showed associations between human leukocyte antigen (HLA) DR4 and DR6 and disease. The emergence of DNA sequencing techniques has implicated numerous DRB1 and DQB1 loci in various populations, leading to confusion regarding which exact alleles confer susceptibility. The strong linkage disequilibrium among DR and DQ HLA alleles further complicates the investigation of the true susceptibility loci. In this study, we report genotyping data for the largest sampling of North American Caucasian non-Jewish and Ashkenazi Jewish PV patients studied to date and compare our data with other population studies. To pinpoint true susceptibility, alleles among overrepresented sequences, we applied a step-wise reductionist analysis through (1) determination of the degree of linkage disequilibrium (LD) between purportedly associated alleles, (2) haplotype frequencies comparisons, and (3) primary sequence comparisons of disease-associated versus non-disease-associated alleles to identify crucial differences in amino acid residues in putative peptide binding pockets. Collectively, our data provide extended support for the hypothesis that the HLA associations in Caucasian PV patients map to DRB1*0402 and DQB1*0503 alone. Further structure-function studies will be required to define the exact mechanisms of HLA-mediated control of susceptibility and resistance to disease.