The genetics of psoriasis: a complex disorder of the skin and immune system

Abstract

In the last few years, molecular genetics analyses have permitted novel insights into psoriasis, a disease characterized by uncontrolled proliferation of keratinocytes and recruitment of T cells into the skin. The disease affects approximately 1-2% of the Caucasian population and can occur in association with other inflammatory diseases such as Crohn's disease and in association with human immunodeficiency virus (HIV) infection. Given that psoriasis has characteristics of an autoimmune disease, it is not surprising that HLA studies revealed an association with certain alleles, notably HLA-Cw6. Despite this HLA component, psoriasis in some families is inherited as an autosomal dominant trait with high penetrance. Loci at chromosome 17q25 and 4q have been identified following genome-wide linkage scans of large, multiply affected families. In the case of at least the susceptibility locus at 17q25, the development of psoriasis does not require the presence of HLA-Cw6. Sib-pair analyses have confirmed the association with HLA-Cw6, confirmed the existence of a locus at 17q25 and identified other possible susceptibility loci. Two independent groups have reported a third region on chromosome 20p. Despite these findings, the extent of genetic heterogeneity and the role of environmental triggers and modifier genes is still not clear. The precise role of HLA also still needs to be defined. The isolation of novel susceptibility genes will provide insights into the precise biochemical pathways that control this disease. Such pathways will also reveal additional candidate genes that can be tested for molecular alterations resulting in disease susceptibility.

Psoriasis: genetic associations and immune system changes

“…Linkage to chromosome 1q21 was first described in Italian families, 70 although suggestive evidence for linkage was seen at the same time in our cohort of multiplex families from the US, and was replicated in our cohort of affected sibship pairs. 71 Recent unpublished results suggest that PSORS4 lies within a region harboring SPRR and LEP genes. Hence, PSORS4 is likely to be involved in terminal differentiation of keratinocytes.…”

Characterization of the loricrin (LOR) gene as a positional candidate for the PSORS4 psoriasis susceptibility locus

“…Despite the significant role of several environmental factors, psoriasis displays marked familial clustering and is a typical example of a complex disease (Lyons, 2002). Disease concordance rates are much higher in monozygotic twins compared to dizygotic twins, consistent with genetic factors playing a significant part in disease pathogenesis (Bhalerao & Bowcock, 1998). An association between PSO and the HLA Cw6 antigen has been repeatedly reported (Elder et al 1994), and a susceptibility locus (PSORS1) identified by parametric and nonparametric linkage (NPL) analysis (Nair et al 1997).…”

Molecular classification of psoriasis disease-associated genes through pharmacogenomic expression profiling

“…About one-third of patients report a family member with the disease and family studies estimate the risk to first-degree relatives at between 8-23%. There is a 65-70% concordance in monozygotic twins, compared to 15-20% in dizygotic twins (reviewed in Bhalerao and Bowcock 7 ). Several psoriasis susceptibility loci have been mapped: PSORS1 on 6p21.3, PSORS2 on 17q, PSORS3 on 4q, PSORS4 on 1cen-q21, PSORS5 on 3q21 and PSORS6 on 19p13.…”

“…Several psoriasis susceptibility loci have been mapped: PSORS1 on 6p21.3, PSORS2 on 17q, PSORS3 on 4q, PSORS4 on 1cen-q21, PSORS5 on 3q21 and PSORS6 on 19p13. 7 Despite the identification of disease-associated loci, specific genes that play a causative role in disease progression have yet to be identified. Mutations within coding regions affecting protein function or levels have traditionally been examined for disease-related genes.…”