Psoriasis is a common, immunologically mediated, inflammatory and hyperproliferative disease of the skin and joints. Available evidence indicates that a major psoriasis gene (PSORS 1) resides in the major histocompatibility complex, and that several additional psoriasis genes reside elsewhere. Identification of the PSORS 1 gene has been hampered by the existence of strong linkage disequilibrium. We have addressed this problem by recombinant ancestral haplotype mapping, followed by DNA sequencing of the critical interval in disease vs. normal chromosomes. Our progress has led us to conclude that HLA-Cw6 and the corneodesmosin allele usually found in cis to it are by far the most viable candidates for PSORS1. Our preliminary data support published associations between psoriasis and the HLA-B46-Cw 1 haplotype, suggesting the hypothesis that PSORS 1 manifests allelic heterogeneity. We and others tested 942 affected sibling pairs for allele sharing across 14 previously-identified candidate regions. Besides strongly confirming linkage to PSORS 1 (p < 1.6 x 10/-12), this study provided suggestive evidence for an interacting locus on chromosome 16q (PSORS8). Also, five independent samples have yielded evidence for linkage to PSORS2 (17q25). Both regions display evidence for disease association. These findings favor the hypothesis that PSORS2 and PSORS8 are ancient and relatively common. Case control association testing provides a powerful method for identifying this type of disease allele. In pursuit of these hypotheses, we propose the following specific aims: 1. To (a) complete ongoing sequence analysis of the expanded PSORS 1 risk region, including one example of the B46-Cw 1 risk haplotype; (b) to test sequence variants unique to the PSORS 1 risk haplotype on additional non-risk haplotypes, and (c) to test for allelic heterogeneity at PSORS 1. 2. To collect 2,000 early-onset psoriasis cases (<= 25 years at onset) and 1,000 controls from the Detroit metropolitan area. 3. To test two positional candidates (PSORS2 and PSORS8) for genetic involvement in psoriasis, using available families and the cases and controls collected in Aim 2. 4. To test two functional candidates (the KIR gene cluster and TNFalpha) for genetic involvement in psoriasis, using available families and/or the cases and controls collected in Aim 2.
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