Searching for the major histocompatibility complex psoriasis susceptibility gene.

Psoriasis, a common skin disorder, is widely regarded to be multifactorial in origin including gene-gene and gene-environment interactions. Genetic and allelic heterogeneity, multifactorial inheritance, and low penetrance of susceptibility alleles substantially complicate both study design and interpretation of results. Notwithstanding these difficulties, genome-wide scans for psoriasis susceptibility have generated robust evidence for a major locus lying within the major histocompatibility complex (PSORS1, Psoriasis Susceptibility 1), on the short arm of chromosome 6. Subsequent studies have sought to refine the PSORS1 boundaries by means of linkage disequilibrium fine mapping. Studies of positional candidate genes have also been undertaken, focusing on HLA-C, corneodesmosin, and alpha-helix coiled-coil rod homolog genes. Methodologic approaches, results, and interpretations of these studies are discussed, as well as future research objectives. In particular, we emphasize the importance of characterizing PSORS1 linkage disequilibrium patterns and developing functional assays for disease-associated alleles.

Genetic analysis of PSORS1 distinguishes guttate psoriasis and palmoplantar pustulosis.

The PSORS1 locus in the major histocompatibility complex region is the major genetic determinant for psoriasis vulgaris. Within the PSORS1 region reside at least three potential candidate genes for psoriasis susceptibility. Specific allelic variants of the genes HLA-Cw*6, HCR*WWCC, and CDSN*5 are strongly associated with psoriasis vulgaris and are in strong linkage disequilibrium with each other. We have genotyped the three psoriasis vulgaris susceptibility alleles of the PSORS1 locus in two clinical variants of psoriasis (guttate psoriasis and palmoplantar pustulosis) to study whether PSORS1 is also involved in the pathogenesis of these variants. We also asked whether these two clinical subgroups could help us to distinguish the causative gene within the high-risk PSORS1 haplotype. The association of guttate psoriasis with the three PSORS1 susceptibility alleles was similar and even stronger than seen with psoriasis vulgaris. Palmoplantar pustulosis, however, did not show association with any of the three candidate genes at this locus. Finally, no correlation with the age of onset for disease was observed. Our results show conclusively that psoriasis vulgaris and guttate psoriasis have a similar genetic basis for their association to PSORS1, whereas palmoplantar pustulosis appears to be a distinct disorder.