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

被引：51

作者：

Quaranta, M. ^{[1
]}

Burden, A. D. ^{[2
]}

Griffiths, C. E. M. ^{[3
]}

Worthington, J. ^{[4
]}

Barker, J. N. ^{[1
]}

Trembath, R. C. ^{[1
]}

Capon, F. ^{[1
]}

机构：

[1] Kings Coll London, Div Genet & Mol Med, London SE1 9RT, England

[2] Univ Glasgow, Dept Dermatol, Glasgow G12 8QQ, Lanark, Scotland

[3] Univ Manchester, Dept Dermatol, Manchester, Lancs, England

[4] Univ Manchester, Arc Epidemiol Unit, Manchester, Lancs, England

来源：

GENES AND IMMUNITY | 2009年 / 10卷 / 07期

基金：

英国医学研究理事会; 美国国家卫生研究院; 英国惠康基金;

关键词：

psoriasis; Crohn's disease; type II diabetes; CDKAL1; GENOME-WIDE ASSOCIATION; SUSCEPTIBILITY LOCI; RISK LOCI; GENES; DEFINES; IL23R; IDENTIFICATION; PATHOGENESIS; SEQUENCE; LINKAGE;

D O I：

10.1038/gene.2009.51

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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 x 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. Genes and Immunity (2009) 10, 654-658; doi:10.1038/gene.2009.51; published online 9 July 2009

引用

页码：654 / 658

页数：5

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