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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=0.00012, odds ratio (OR): 1.28; combined sample: 2579 cases vs 4306 controls, P=4 × 10−6, 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+ and CD19+ 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 disease-specific cell types.

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Acknowledgements

We thank Massimo Mangino for his contribution to the statistical analyses and John Mee for providing access to primary keratinocytes. Funding support for the CASP study was provided by the National Institutes of Health and the genotyping of samples was implemented through the Genetic Association Information Network (GAIN). Samples and associated phenotype data for the CASP study were provided by Goncalo Abecasis. We acknowledge the use of genotype data from the British 1958 Birth Cohort DNA collection, funded by the Medical Research Council (grant G0000934) and The Wellcome Trust (grant 068545/Z/02). This work was also supported by a PhD studentship from The Psoriasis Association (MQ) and grants from the British Skin Foundation (FC) and the Medical Research Council (JNB, RCT). Funding: British Skin Foundation, The Psoriasis Association, Medical Research Council

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Correspondence to R C Trembath.

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Supplementary Information accompanies the paper on Genes and Immunity website (http://www.nature.com/gene)

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Quaranta, M., Burden, A., Griffiths, C. et al. Differential contribution of CDKAL1 variants to psoriasis, Crohn's disease and type II diabetes. Genes Immun 10, 654–658 (2009). https://doi.org/10.1038/gene.2009.51

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Keywords

  • psoriasis
  • Crohn's disease
  • type II diabetes
  • CDKAL1

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