Genetic factors play an important role in psoriatic arthritis (PsA) and psoriasis vulgaris (PsV). The overall goal of this proposal is to identify the genetic determinant(s) within the MHC that predispose to PsA. Very recently, we identified a 9.7 kb indel located between HLA-B and HLA-C. Our preliminary data support the hypothesis that the MHC component of PsA and PsV arose on an """"""""ancestral risk chromosome"""""""" lacking the 9.7 kb indel segment. Our data are consistent with two models: one in which the HLA-B and HLA-C alleles on this chromosome each confer risk for PsA and PsV (two-determinant model), and one in which a single feature of this chromosome located between HLA-B and C is involved in the genesis of PsA and PsV (one-determinant model). The former model would be consistent with the idea that the ancestral chromosome provided particularly effective protection against a pathogen due to the participation of both HLA-B and HLA-C. The latter model would be more consistent with a regulatory sequence. We have the experimental tools to test these models. However, our PsA phenotype is currently based only on the presence of joint complaints, and not on objective findings of PsA. We have identified a large resource of PsA patients, and a co-investigator with outstanding expertise in the clinical evaluation of PsA. Therefore, to create a genetic resource for PsA, and to provide critical tests for the hypothesis outlined above, we propose the following specific aims: 1. To accurately phenotype joint and skin involvement, to collect blood samples, and to prepare immortalized lymphoblastoid cell lines and DNA from (a) 400 patients with PsA and (b) 400 individuals who have had PsV for at least 5 years without developing PsA. Also, (c) to collect blood samples and to prepare immortalized lymphoblastoid cell lines and DNA from 400 individuals with no history of PsV or PsA. 2. To define the evolutionary history of the ancestral risk chromosome, and to distinguish between the one- and two-determinant risk models, by comparative DNA sequencing across the HLA-B-C interval. 3. To type 40 microsatellites and 40 SNPs across an interval extending from TNFB to STG in the individuals ascertained in Aim 1, to generate and cluster haplotypes in order to identify ancestral chromosomes, to determine the HLA-B and HLA-C alleles carried on each ancestral chromosome, to assess these chromosomes for risk of PsA by case-control association testing, and to sequence any ancestral chromosome segments conferring risk for PsA that have not already been sequenced in Aim 2.
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