KCNN4 gene variant is associated with ileal Crohn's Disease in the Australian and New Zealand population

Am J Gastroenterol. 2010 Oct;105(10):2209-17. doi: 10.1038/ajg.2010.161. Epub 2010 Apr 20.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Alleles
  • Australia
  • Chi-Square Distribution
  • Colon / pathology
  • Crohn Disease / genetics*
  • Crohn Disease / pathology
  • Female
  • Gene Frequency
  • Genetic Association Studies
  • Genetic Linkage
  • Genetic Predisposition to Disease
  • Genotype
  • Haplotypes
  • Humans
  • Ileum / pathology*
  • Immunohistochemistry
  • Inflammation / genetics
  • Inflammation / pathology
  • Intermediate-Conductance Calcium-Activated Potassium Channels / genetics*
  • Male
  • Middle Aged
  • New Zealand
  • Polymorphism, Single Nucleotide
  • Reverse Transcriptase Polymerase Chain Reaction
  • Statistics, Nonparametric


  • Intermediate-Conductance Calcium-Activated Potassium Channels
  • KCNN4 protein, human