KCNN4Gene Variant Is Associated With Ileal Crohn's Disease... : Official journal of the American College of Gastroenterology | ACG (original) (raw)

ORIGINAL CONTRIBUTIONS: INFLAMMATORY BOWEL DISEASE

KCNN4 Gene Variant Is Associated With Ileal Crohn's Disease in the Australian and New Zealand Population

Simms, Lisa A BSc (Hons)1,2; Doecke, James D PhD2,3; Roberts, Rebecca L PhD4; Fowler, Elizabeth V PhD5; Zhao, Zhen Zhen PhD2; McGuckin, Michael A PhD6,7; Huang, Ning MAppScl1,2; Hayward, Nicholas K PhD2; Webb, Penelope M PhD2; Whiteman, David C MBBS(Hons), PhD, FAFPHM2; Cavanaugh, Juleen A PhD8; McCallum, Ruth BSc9; Florin, Timothy HJ MSc, MBBS, FRACP6,10,11; Barclay, Murray L MB, ChB, MD, FRACP12,13; Gearry, Richard B MB, ChB, FRACP, PhD12,13; Merriman, Tony R PhD9; Montgomery, Grant W PhD2; Radford-Smith, Graham L MB, BCh, MRCP, FRACP, PhD1,2,14

1Inflammatory Bowel Diseases Laboratory, Royal Brisbane and Women's Research Foundation, Brisbane, Queensland, Australia

2Queensland Institute of Medical Research, Brisbane, Queensland, Australia

3Australian E-Health Research Centre, CSIRO Mathematical and Information Sciences, Brisbane, Queensland, Australia

4Department of Pathology, University of Otago, Christchurch, New Zealand

5Department of Paediatrics and Child Health, The University of Queensland, Royal Children's Hospital, Brisbane, Queensland, Australia

6Inflammatory Bowel Disease Team, Brisbane, Queensland, Australia

7Mater Medical Research Institute, Brisbane, Queensland, Australia

8Medical Genetics Research Unit, Research School of Biological Sciences and Medical School, Australian National University, Canberra, Australian Capital Territory, Australia

9Department of Biochemistry, University of Otago, Dunedin, New Zealand

10Department of Medicine, The University of Queensland, Brisbane, Queensland, Australia

11Mater Health Services, Brisbane, Queensland, Australia

12Department of Gastroenterology, Christchurch Hospital, Christchurch, New Zealand

13Department of Medicine, University of Otago, Christchurch, New Zealand

14Department of Gastroenterology, Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia

Correspondence: Lisa A. Simms, BSc (Hons), Inflammatory Bowel Diseases Laboratory, Queensland Institute of Medical Research, Brisbane 4006, Australia. E-mail. [email protected]

published online 20 April 2010

SUPPLEMENTARY MATERIAL accompanies this paper at https://links.lww.com/AJG/B199, https://links.lww.com/AJG/B200

Received 13 January 2010; accepted 16 March 2010

Abstract

OBJECTIVES:

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.

METHODS:

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 the KCNN4 mRNA transcript was carried out using quantitative reverse transcriptase-PCR.

RESULTS:

KCNN4 SNP rs2306801 was associated with CD (primary P =0.0008, odds ratio (OR) (95% confidence interval (CI)): 0.76 (0.65–0.89); replication P =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-predisposing NOD2 variants (R702W, G908R, 1007fs) had significantly reduced levels of KCNN4 mRNA expression ( P =0.001). KCNN4 protein expression was detected in Paneth cells, and in T cells in inflamed lamina propria.

CONCLUSIONS:

Our data implicate the role of KCNN4 in ileal CD. The dual roles of KCNN4 in Paneth cell secretion and T-cell activation and also its nature as a potassium channel make it an important and practical therapeutic target.