A molecular genetic analysis of Crohn’s disease susceptibility loci in psoriasis

Psoriasis is an immune-mediated skin disorder that is inherited as a complex trait. Genome-wide linkage and association studies have identified a major disease susceptibility locus (PSORS1) and several genetic determinants of smaller effect. At least two of these (the IL12B and IL23R genes) have independently been associated with Crohn’’s disease (CD). Thus, the aim of this project was to investigate the genetic overlap between psoriasis and CD, with a view to identifying shared pathogenic pathways.In the first phase of the study, 26 CD variants were genotyped in 1,256 psoriatic patients and 2,938 unaffected individuals. Significant associations (FDR < 0.01) were observed for three markers, mapping to chromosomes 6p22, 21q21 and 21q22. The analysis of an independently ascertained dataset (1,348 cases vs. 1,368 controls) validated the chromosome 6p22 association, with the critical SNP (rs6908425) yielding a combined P value of 4 x 10-6. This marker lies within the CDKAL1 gene, which also harbours type 2 diabetes (T2D) associated alleles.Since the mechanisms mediating the pathogenic effect of CDKAL1 are poorly understood, an investigation into gene function was undertaken in the second part of the study. Real-time PCR analyses of multiple cDNA panels showed that CDKAL1 is abundantly expressed in immune cells, especially in CD4+ and CD19+ lymphocytes. Stable CDKAL1 knock-down cell lines generated by sh-RNA lentiviral transduction were also analysed. This showed that CDKAL1 silencing results in reduced cell proliferation and altered cell cycle progression. Transcription profiling of the knock- down cells identified a number of differentially expressed genes, mostly involved in housekeeping functions and inflammatory responses.Taken together, these findings indicate that CDKAL1 is a pleiotropic gene conferring susceptibility to psoriasis, CD and T2D. The results of functional studies suggest that this pathogenic role may be mediated by an effect on inflammatory responses and cell cycle progression