MOLECULAR GENETICS OF PSORIASIS AND PSORIATIC ARTHRITIS

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This proposal is directed to advancing understanding of the genetically determined immune recognition event that appears to underlie psoriasis and psoriatic arthritis. HLA genes, especially those of the class I loci, have been identified as major markers of susceptibility and very likely participate in the inappropriate immune response underlying psoriasis and psoriatic arthritis. The precise identity of the HLA genes that confer susceptibility and the mechanism of their genetic action and interaction remains quite obscure. Moreover there is a paradox in that despite strong HLA allelic associations only a weak linkage to the HLA complex has been identified in pedigree studies. The overall aim of this project is to use recently developed methods for the precise identification of HLA alleles and advanced genetic analyses to formalize the basis of the HLA association and thereby identify the nature and number of genes that provide the interrelated molecular basis of susceptibility to the development of psoriasis and psoriatic arthritis. Advantage is taken of a collaboration with clinical investigators who have accumulated 93 unrelated individuals with psoriatic arthritis and their family members. Thirty-four multiplex families have been identified to date. The primary objectives are to (1) use sequence-based typing of the class I and II MHC alleles to perform an association study of 93 ethnically homogenous individuals with psoriatic arthritis using the haplotype relative risk method. Emphasis will be placed on explicitly defining the HLA-A, B, C and DRB1 locus alleles with the goal of identifying the possible presence of shared motifs that correlate better with susceptibility in this analysis. Candidate alleles of other MHC loci that appear promising in preliminary studies will also be studied. (2) Extend the studies to first and second degree relatives of multiplex families with psoriatic arthritis propositi to define the inheritance of MHC haplotypes and their association with affected siblings. (3) Examine the contribution of alleles of both haplotypes to susceptibility using haplotype relative risk and affected sib pair haplotype sharing methods. Identify the combinations of MHC genes responsible for susceptibility through the use of linkage methodology capable of identifying the contribution of two genes.