Identification and assessment of psoriasis susceptibility loci and investigation of the PSORS1 locus in psoriasis vulgaris
thesisposted on 15.12.2014, 10:38 by Colin David Veal
Psoriasis is a common complex inflammatory disorder of the skin. It affects on average 2% of the UK population, but can vary in other populations. The disease is characterised by hyperproliteration and abnormal differentiation of keratinocytes, and infiltration of immune cells into the skin, including activated CD4+ T-cells in the epidermis and activated CD8+ T-cells in the dermis. This disorder is seen clinically as well-demarcated thickened, erythematous, areas of skin covered by a silvery scale predominantly on extensor surfaces. The disease can have serious implications on the social and mental wellbeing of a patient and recent studies have demonstrated serious social stigmatism attached with the disease. Previous studies have implied complex genetic factors are involved in the pathogenesis of psoriasis along with environment triggers. In attempt to identify novel psoriasis loci and confirm previously reported loci a genome wide scan was performed in a cohort of 158 psoriasis families. Genome wide levels of significance were observed for microsatellite markers on chromosome 6p, spanning the MHC, and a novel locus on chromosome lp. Three further regions provided evidence of linkage on chromosomes 7p, 18p and 19p. All of which had been observed in previous studies of psoriasis or immune related diseases. In parallel to the genome wide scan, a collaboration of a larger collection of families was used to assess fourteen previously reported loci. Only microsatellites within the MHC on chromosome 6 provided highly significant evidence for linkage to psoriasis, confirming that this locus is the major psoriasis susceptibility locus. Support was seen for two other loci on chromosome 16q and 17q. As the PSORS1 locus within the MHC is the major susceptibility locus identified for psoriasis it was subject to in depth investigation. Candidate genes HCR and CDSN were assessed for association with psoriasis and compared to the HLA-Cw6 allele. Significant association was observed at both genes, however their relationship could not be distinguished from the association observed at HLA-Cw6. Further dissection of PSORS1 was attempted through the genotyping of 59 SNPs across the interval. Analysis revealed the entire interval to demonstrate significant association with psoriasis, though a distinct peak of association centromeric of HLA-C was observed. Haplotype analysis revealed a single set of similar haplotypes to be associated with the disease. This also identified a putative recombinant psoriasis associated haplotype raising the possibility of further refinement of the PSORS1 interval.