The MHC Genes in Psoriasis

Psoriasis is a common, immunologically-mediated, inflammatory and hyperproliferative disease of the skin and joints. Available evidence indicates that a major psoriasis gene (PSORS1) resides in the major histocompatibility complex (MHC), and that several additional psoriasis susceptibility genes reside elsewhere. Identification of the PSORS1 gene has been hampered by the existence of strong linkage disequilibrium (LD) in the MHC. Because it is not possible to rely on pvalues associated with single alleles or short haplotypes, we and others have addressed this problem by assessing the risk associated with long “ancestral haplotypes” vs. their recombinant descendant haplotypes (recombinant ancestral haplotype mapping). Utilizing this technique, two different groups have identified a haplotype containing HLA-Cw6, “allele 5” of corneodesmosin (CDSN), and specific alleles at six intervening genes as the most likely location for PSORS1. Recently, a multicenter collaboration has been formed to identify which of the genes (or regulatory elements) on this haplotype is the “true” susceptibility allele. This collaboration is essential, as the number of informative recombinants is small due to the proximity of the genes in question. It will also be important to entertain the possibilities that multiple genes on the same haplotype influence risk, and that multiple distinct MHC alleles / haplotypes can influence risk (allelic heterogeneity). A collaborative approach involving very large numbers of families and / or cases and controls is the best way to address both of these critical questions.