AbstractPustular Psoriasis (PP) is a rare and disabling inflammatory skin disorder that is associated with an increased risk of plaque psoriasis (also known as psoriasis vulgaris or PV). While two PP genes (IL36RN and AP1S3) have been discovered, less than 30% of the patients harbour mutations at these loci. Moreover, the main genetic determinant for PV susceptibility (HLA-Cw6) is not associated with pustular psoriasis. Therefore, the molecular pathogenesis of PP and its clinical association with psoriasis vulgaris remain poorly understood. The aim of the current study was to investigate these issues through the genetic analysis of extended patient resources.
In the first part of the project, the possibility that the IL36RN gene may contribute to PV susceptibility was investigated by sequencing the gene in 363 unrelated individuals and re-analysing genome-wide association data. No enrichment of IL36RN mutations was detected in cases compared to controls, indicating that this important genetic determinant of pustular psoriasis does not confer PV susceptibility.
Next, the CARD14 locus, which had been previously associated with familial PV, was screened in an extended pustular psoriasis cohort (n=205). This revealed a low-frequency p.Asp176His allele that caused constitutive CARD14 activation in functional assays and was significantly enriched in Asian cases compared to controls (P=8.4x10-5; OR=6.4).
In the final part of the project, 17 patients affected by pustular psoriasis were exome-sequenced to identify genes that may be involved in the pathogenesis of the disease and contribute to the increased PV risk. Stepwise filtering of variant profiles uncovered a number of candidate genes that were followed-up in European (n=92) and Asian validation cohorts (n=94). Although extensive genetic heterogeneity was observed, a number of loci deserving further investigation were defined, paving the way for the identification of novel genetic determinants of skin inflammation.
|Date of Award
|Francesca Capon (Supervisor), Richard Trembath (Supervisor) & Jonathan Barker (Supervisor)