Advances in the search for psoriasis susceptibility genes

Psoriasis (PS) is a common skin disorder affecting approximately 2% of the Caucasian population. Despite the established influence of several environmental factors, epidemiological data and twin studies have long demonstrated a genetic basis for psoriasis susceptibility. Moreover an association between PS and HLA-Cw6 has been reported in different ethnic groups. In recent years, the availability of statistical methods for complex disease linkage analysis has prompted many researchers to carry out genome-wide scans. Their results have been conflicting and linkage replication has seldom been documented. However, a few chromosome regions have been confirmed in independent studies. In particular, compelling evidence supports the existence of a susceptibility locus within the HLA region. Moreover, loci on chromosomes 17q and 1q have been reported in at least two independent genome scans. Several groups have undertaken the refinement of regions identified during genome scans, using linkage disequilibrium data. This approach has allowed the fine mapping of the 6p21 locus, now restricted to a 60-kb genomic segment. As critical regions get smaller, candidate gene analysis becomes an attractive approach. So far, three genes have been extensively investigated: S100A7 on chromosome 1q and CDSN and HCR on chromosome 6p21. Even though several SNPs have been identified within these genes, none of them seems to meet the requirement needed to prove an involvement in PS pathogenesis. These criteria include association replication in different populations and functional studies of SNP biological significance. Thus, only a collaborative and multidisciplinary approach will allow the identification of PS susceptibility genes.