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 lo ci directly determine susceptibility or merely sen-e as markers for the sus ceptibility allele: and (ii) to identify additional disease-associated hapl otypes. By applying maximum likelihood linkage disequilibrium analysis (LDA ) in cases vs. controls, we found the susceptibility gene io be more strong ly associated with specific HLA haplotypes than with their component allele s. Stronger linkage disequilibrium bt tween PsV and HLA alleles was detecte d at HLA-C and HLA-B than at DRB1 and DQB1. Parametric linkage analysis acc ounting for marker-trail disequilibrium in psoriasis vulgaris pedigrees yie lded most significant results for a locus close to HLA-B and -C. Furthermor e, we found that susceptibility is linked to at least three different ances tral 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 l ocus in the immediate vicinity of, but distinct from HLA-B or HLA-C, and su ggest that multiple disease alleles have arisen during human evolution.