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Crohn's disease (CD; MIM 266600) is one of the most common forms of inflammatory bowel disease (IBD), and represents a significant burden to health care in developed countries. Our aim was to determine whether a gene in the IBD linkage region on chromosome 19q13, with a role in Paneth cell secretion and T-cell activation, conferred genetic susceptibility to the development of CD.In total, 792 CD cases and 1,244 controls of Australian origin (Caucasian) were genotyped for seven single-nucleotide polymorphisms (SNPs) in the gene encoding the intermediate conductance calcium-activated potassium channel protein (KCNN4) at 19q13.2. CD cases were phenotyped using the Montreal classification. The replication set comprised an additional 326 CD cases and 951 population-based Caucasian controls. Analysis of theKCNN4mRNA transcript was carried out using quantitative reverse transcriptase-PCR.KCNN4SNP rs2306801 was associated with CD (primaryP=0.0008, odds ratio (OR) (95% confidence interval (CI)): 0.76 (0.65–0.89); replicationP=0.01, OR (95% CI): 0.77 (0.61–0.97). Stratification by disease location identified the association between SNP rs2306801 and ileal CD (P=0.01). Non-inflamed ileal mucosa from CD patients carrying any of the common disease-predisposingNOD2variants (R702W, G908R, 1007fs) had significantly reduced levels ofKCNN4mRNA expression (P=0.001). KCNN4 protein expression was detected in Paneth cells, and in T cells in inflamed lamina propria.Our data implicate the role ofKCNN4in ileal CD. The dual roles ofKCNN4in Paneth cell secretion and T-cell activation and also its nature as a potassium channel make it an important and practical therapeutic target.