Differential contribution of CDKAL1 variants to psoriasis, Crohn's disease and type II diabetes

Abstract

Psoriasis is an immune-mediated skin disorder, which is inherited as a complex trait. Genome-wide linkage and association studies have identified a major disease susceptibility locus on chromosome 6p21, as well as a number of genetic determinants of smaller effect. Our group has also documented a significant association between psoriasis and CDKAL1, a gene previously implicated in the pathogenesis of Crohn's disease (CD) and type II diabetes (TIID). With this study, we validate this association, through the analysis of CDKAL1 single nucleotide polymorphism (SNP) rs6908425 in an independently ascertained psoriasis dataset (replication sample: 1323 cases vs 1368 controls, P ¼ 0.00012, odds ratio (OR): 1.28; combined sample: 2579 cases vs 4306 controls, P ¼ 4 Â 10 À6 , OR: 1.26). We also show that the association with psoriasis and CD is completely independent from that with TIID. Finally, we report the results of expression studies demonstrating that CDKAL1 transcripts are virtually absent from skin keratinocytes, but are abundantly expressed in immune cells, especially in CD4 þ and CD19 þ lymphocytes. It is to be noted that our data indicate that CDKAL1 becomes markedly downregulated when immune cells are activated with proliferating signals. Taken together, our results document the presence of allelic heterogeneity at the CDKAL1 locus and suggest that CDKAL1 alleles may confer susceptibility to clinically distinct disorders through differential effects on diseasespecific cell types.

CDK5 Regulatory Subunit-associated Protein 1-Like 1 (CDKAL1) Is a Tail-anchored Protein in the Endoplasmic Reticulum (ER) of Insulinoma Cells

“…We show that human islets and rat insulinoma INS-1 cells express only the transcript for isoform 1, which migrates as a 61-kDa protein by SDS-PAGE. In all tissues investigated, isoform 1 has been the only form detected (34). It would be interesting to determine whether this is also the case in subjects with single nucleotide polymorphisms in CDKAL1, which increase the risk for T2D and could affect its splicing, possibly in a tissue-specific manner.…”

“…By increasing the translation fidelity of mRNAs coding for proteins in transit through the ER, and thus minimizing misfolding and energy consumption involved in ER-associated protein degradation, CDKAL1 may be critical in professional secretory cells. Accordingly, lymphocytes also display high CDKAL1 expression levels (34).…”

Cardiovascular Changes in Psoriasis

“…[18] Common genetic loci of susceptibility PSORS2, PSORS3 and PSORS4 have been demonstrated for psoriasis, metabolic syndrome, type 2 diabetes, familial hyperlipidaemia and cardiovascular disease. [19] Individual genes such as CDKAL1 are associated with psoriasis and type 2 diabetes, [ 20 ] and Apolipoprotein E with psoriasis and hyperlipidaemia. [21,22] Increased serum levels of homocysteine in psoriasis and the associated dyslipidaemia lead to atherothrombosis in these patients.…”

Modify or die? - RNA modification defects in metazoans

“…However, the alleles associated with CD and Psoriasis are not linked to TIID. 46,47 TRDMT1 causes more subtle phenotypes than FTO or CDKAL1. The protein was described as a DNA methylase but is in fact required to form 5-methylcytidine (m 5 C) on tRNA and mRNA.…”