Psoriasis is an immune-mediated skin disorder that is inherited as a complex trait. Although genome-wide association studies (GWAS) have identified a number of common disease susceptibility alleles, a substantial fraction of psoriasis heritability remains unexplained, suggesting the possibility that rare variants may also be pathogenic. The aim of this project was to further investigate this hypothesis and explore different approaches to the identification of rare susceptibility alleles. A candidate gene approach was initially undertaken, through the re-sequencing of RNF114, a gene that had been associated with psoriasis in various GWAS. This led to the identification of four novel promoter variants (c.-66C>A, C.-64C>A, C.-41C>T and c.-9A>C) which collectively demonstrate significant association with the disease (P < 0.01). The functional characterisation of two representative substitutions showed that they both affected Spl binding as well as RNF114 promoter activity. In the second part of the study, a positional cloning approach was applied to the analysis of a multigenerational psoriasis pedigree, where the disease appeared to segregate as an autosomal dominant trait. Tentative evidence for linkage (LOD > -2) was obtained for two regions on chromosomes 2p21 and 15q25. However, next-generation sequencing of an affected family member failed to identify any pathogenic mutation within the above intervals. In the final part of the study, five unrelated patients affected by a rare and severe variant of psoriasis (generalised pustular psoriasis) were analysed by whole-exome sequencing. This led to the identification of two recessive mutations (p.Ser113Leu and p.Arg48Trp) of the IL36RN gene, which encodes a protein antagonizing the activity of IL-36 cytokines. An ex-vivo analysis of patient cells demonstrated a marked increase in cytokine reduction upon IL-36A stimulation, suggesting that GPP mutations may affect the anti-iflammatory function of IL36RN. While this work suggests that rare variants are likely to contribute to the pathogenesis of psoriasis, it also highlights a number of methodological issues that will need to be considered in the design of future studies.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:628296 |
| Date | January 2013 |
| Creators | Onoufriadis, Alexandros |
| Publisher | King's College London (University of London) |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | https://kclpure.kcl.ac.uk/portal/en/theses/characterisation-of-rare-genetic-variants-conferring-susceptibility-to-psoriasis(78905027-5f07-4927-a535-0ca34f99977d).html |
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