-Psoriasis is a common, HLA-associated disease of presumed immunopathogenesis. The hypothesis to be tested is that susceptibility to psoriasis is oligogenic, with at least one gene residing in the HLA region. Published results from a cohort of 224 affected sibling pairs have demonstrated three regions of suggestive linkage: HLA (Class I end, Zmax = 3.52), chromosome 16q (Zmax = 2.50), and chromosome 20p (Zmax = 2.62). Linkage to Class I and to 20p has been reported by others. The region in 16q overlaps with a recently identified locus for Crohn's disease. Since psoriasis occurs more commonly in patients with Crohn's disease than in controls (RR = 7. 1, p < 1O-9), it is suggested that susceptibility to both diseases may be controlled by a common locus. Finally, these investigator have confirmed a previously reported susceptibility locus on the distal end of chromosome 17q (Zmax = 2.09), with evidence for this locus increasing to Zmax 3.36 with addition of 41 affected sibling pairs.
Specific aims for the renewal grant are: (1) Increase sample size to 1,000 affected sibling pairs by combining data with those of researchers in the United Kingdom, in which both groups will increase sample size from 300 to 500 pairs, generating two new replication sets, each of which will be subjected to a coarse (15-20 cM) genom scan and analysis for candidate regions (lod > 1); (2) genotype candidate regions from Aim 1 at 5 cM intervals in all available pairs testing for linkage, increasing marker density to 0.5-1 cM in regions of suggestive or significant linkage (lod >2), and narrowing target intervals to approximately cM by multipoint allele sharing and linkage disequilibrium techniques; and (3) identify genes residing in the intervals identified by Aim 2 and in the TNF-HLA-C interval using the human transcript map. Allelic variation of the genes will be tested for segregation using TDT and MBSA, and by identifying alleles shared across haplotypes in regions of strong linkage disequilibrium.
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