S gene (Corneodesmosin) diversity and its relationship to psoriasis; High content of cSNP in the HLA-linked S gene

Psoriasis is a heterogeneous disease in which several reports suggest the p resence of a susceptibility gene in or in the proximity of the human leukoc yte antigen complex in chromosome 6p. There is an association between HLA-C w6 and young onset of the disease. The S gene (corneodesmosin), located 160 kb telomeric of HLA-C, is a strong candidate for psoriasis due to its repo rtedly exclusive expression in differentiating keratinocytes. We have studi ed this gene in a large Swedish psoriasis population and we report a striki ngly high degree of polymorphism in the coding parts of the gene, 1 every 1 00 base pairs. We used a stratified approach to compare the polymorphic var iants in patients and controls. A single nucleotide polymorphism in the cod ing region leading to an amino acid exchange (Ser-->Phe) that differed sign ificantly between patients and controls was identified (position 619). Owin g to a high allele frequency in a larger control group, however, and an ins ignificant influence of the variant on the age at onset distribution curve based on a large psoriasis population, we could not confirm that this codin g single nucleotide polymorphism was involved in disease etiology. We also examined the single nucleotide polymorphism in position 1243, recently prop osed to have an influence on the pathogenesis of the disease. This polymorp hism showed less association to the disease as compared with the single nuc leotide polymorphism at positions 619 and 722. Such a high degree of variat ion present also in an HLA gene which is not involved in immune response in dicates the difficulty involved in assessing the role of a specific allele in the pathogenesis of a complex disease in this region. A strong associati on effect due to linkage disequilibrium in an extended region in the HLA co mplex is also a complicating factor.