Novel genetic association between the corneodesmosin (MHC S) gene and susceptibility to psoriasis

Psoriasis is an inflammatory skin disease of unknown origin, but with a cle ar genetic component, The strongest genetic association has been found with the major histocompatibility complex (MHC) region, and specifically betwee n susceptibility to familial early onset psoriasis and human leukocyte anti gen (HLA)-Cw6, The basis of this association of the HLA-C locus with diseas e pathogenesis is, however, not clear, and it is possible that other genes, or a combination of genes, in the HLA region are of functional importance. The MHC S gene is expressed specifically in keratinocyte differentiation a nd, being located 10 kb telomeric of HLA-C, is a plausible candidate gene, We analysed the allelic distribution of two polymorphisms: in the MHC S gen e (at +619 and +1243) in a case-control association study. We could confirm a significant association between psoriasis and HLA-Cw6 [odds ratio (OR) = 7.5]. No association was found between disease (or any subtypes) and the M HC S gene polymorphism at position +619, despite its close proximity to HLA -C and the strong linkage disequilibrium between the loci, However, a signi ficant trend with the rarer allele at MHC S (+1243) and psoriasis was detec ted in the overall data set (OR = 2.66; P = 2 x 10(-9)), This effect was mo st pronounced in the type la (early onset) psoriatics (OR = 3.43). Furtherm ore, homozygosity for the associated allele at MHC S (+1243) increased the risk of disease over that for carriage of HLA-Cw6 alone (OR = 9.38), sugges ting that allele 2 of MHC S (+1243) provides an additional risk in psoriasi s susceptibility. The strong association found here, coupled with the biolo gical involvement of the MHC S gene product corneodesmosin in skin physiolo gy, implicates this locus (or a haplotype across HLA-C and MHC S) in the im paired desquamation characteristic of psoriasis.