- Psoriasis is a complex disease that affects approximately 2% of the population. It results in abnormal proliferation of immature keratinocytes and recruitment of T cells to the dermis and epidermis. This results in three major features: induration, scaling, and erythema. A variety of novel proteins have been identified in psoriatic skin that include pro-inflammatory cytokines, adhesion molecules, HLA-DR, keratins, and alteration in the cellular distribution of integrins. The mode of inheritance of psoriasis is complex, although a familial component is now accepted as a result of twin studies, sib pair studies, the identification of large numbers of multiply affected families, and more recently, by evidence for linkage to particular chromosomal regions in some families. The applicants previously provided strong evidence for linkage to the distal end of chromosome 17q. HOMOG estimates indicated that the disease is genetically heterogeneous. A second study recently showed evidence for linkage of psoriasis to chromosome 4 (near D4S1535) in five families from Ireland. In both of these studies, psoriasis susceptibility behaves as an autosomal dominant trait with high penetrance. There is also an autoimmune component to psoriasis, and Cw6 carriers are at 15-fold higher risk of disease. The applicants now propose to localize additional genes conferring susceptibility to psoriasis by performing a genome-wide linkage screen on 250 sib pairs and 27 multiply affected families. Markers will be selected at 3 cM intervals, and genotyping will be performed using an ABI 377. This will require the generation of 1,300,000 genotypes over 3 years (approximately 450,000 per year). Susceptibility loci will be identified by parametric and nonparametric means with GENEHUNTER. Regions where p<0.01 will be analyzed further by collaborators in an additional 250 sib pairs. The applicants will refine potential susceptibility regions with closely linked markers. The results of this study should be the localization of additional psoriasis susceptibility genes to defined regions of the genome. In the last year of funding any highly promising candidate genes in these regions will be screened for alterations in affected individuals from linked families and in sporadic cases. When alterations are found, they will be screened for in 100 unrelated controls to determine the possibility of their contributing to the development of psoriasis.
