Genetic basis of psoriasis

Abstract

Psoriasis manifests between the ages of 20 and 40 and is characterized by plaque-like hyperproliferative skin lesions, particularly at sites of trauma. It affects around 1–2% of the population and can be associated with other inflammatory diseases. Disease can be triggered by climate, stress and, of course, genetic factors. Like many other complex genetic diseases, no specific susceptibility mutations have been identified as yet, although linkage to a number chromosome regions has been demonstrated, such as 17q25. The strongest genetic association for psoriasis is with the human leukocyte antigen (HLA) gene cluster on 6p21, and specifically linkage with the HLA-Cw6 allele. Genomic sequence of the chromosome region harbouring the psoriasis-susceptibility locus PSORS1 is available, which should greatly facilitate the identification of disease genes. One such candidate, CORNEO-DESMOSIN, is genetically linked to PSORS1 (mapping 160 kb distal to HLA-C) and is expressed in the skin with a proposed role in keratinocyte differentiation and desquamation. However, Nair et al.1xLocalisation of psoriasis-susceptibility locus PSORS1 to a 60-kb interval telomeric to HLA-C. Nair, R.P. et al. Am. J. Hum. Genet. 2000; 66: 1833–1844Abstract | Full Text | Full Text PDF | PubMed | Scopus (198)See all References1 now provide convincing evidence to exclude HLA-C and CORNEODESMOSIN as candidates for PSORS1.Using published genomic sequence and genome databases, the authors identified 62 polymorphic markers mapping to 6p21, which were then used to genotype families with at least one psoriatic individual. After analysis, the authors were able to identify an ancestral chromosome haplotype spanning 60 kb that is likely to harbour the same PSORS1 disease-associated mutation. This high-risk psoriasis haplotype was found in nearly two-thirds of all psoriasis-affected individuals in this study, suggesting that it is a major disease-associated mutation. Affected individuals that do not carry this high-risk haplotype might still carry the same mutation, but they might have inherited too little of the haplotype to be identified with this marker set. Alternatively, they might have inherited a distinct PSORS1 mutation or none at all.Nair et al. have defined a very small genetic interval that contains PSORS1, but which excludes HLA-C and CORNEODESMOSIN. This raises the questions of which gene does encode for PSORS1, what exactly is the high-risk mutation and why does it give an elevated risk of psoriasis? According to the gene map of this region, there are three genes that, although they are annotated as pseudogenes, need to be assessed. It might be that the entire 60 kb sequence of affected and multiple unaffected individuals needs to be compared before PSORS1 will be revealed. It is plausible that PSORS1 might not be a coding mutation but, instead, occurs within a promoter or long-range enhancer sequence that effects gene regulation and expression, for example, that of CORNEODESMOSIN. At present, PSORS1 remains elusive.