Linkage disequilibrium analysis of familial psoriasis: identification of multiple disease-associated MHC haplotypes

Although psoriasis vulgaris (PsV) is strongly associated with certain human leukocyte antigens, the pathogenetic nature of these associations remains elusive. The objectives of this study were: (i) to determine whether HLA loci directly determine susceptibility or merely serve as markers for the susceptibility allele; and (ii) to identify additional disease-associated haplotypes. By applying maximum likelihood linkage disequilibrium analysis (LDA) in cases vs. controls, we found the susceptibility gene to be more strongly associated with specific HLA haplotypes than with their component alleles. Stronger linkage disequilibrium between PsV and HLA alleles was detected at HLA-C and HLA-B than at DRB1 and DQB1. Parametric linkage analysis accounting for marker-trait disequilibrium in psoriasis vulgaris pedigrees yielded most significant results for a locus close to HLA-B and -C. Furthermore, we found that susceptibility is linked to at least three different ancestral HLA haplotypes; among them, HLA-Cw7-B8-DRB1*0301-DQB1*02 is linked to PsV for the first time. These results identify a major PsV susceptibility locus in the immediate vicinity of, but distinct from HLA-B or HLA-C, and suggest that multiple disease alleles have arisen during human evolution.