title: KCNN4 gene variant is associated with ileal Crohn's Disease in the Australian and New Zealand population.
abstract: OBJECTIVE
  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.
authors.affiliation: Royal Brisbane and Women's Research Foundation, Brisbane, Queensland, Australia. Lisa.Simms@qimr.edu.au
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Simms
authors.forename: James D
authors.initials: JD
authors.lastname: Doecke
authors.forename: Rebecca L
authors.initials: RL
authors.lastname: Roberts
authors.forename: Elizabeth V
authors.initials: EV
authors.lastname: Fowler
authors.forename: Zhen Zhen
authors.initials: ZZ
authors.lastname: Zhao
authors.forename: Michael A
authors.initials: MA
authors.lastname: McGuckin
authors.forename: Ning
authors.initials: N
authors.lastname: Huang
authors.forename: Nicholas K
authors.initials: NK
authors.lastname: Hayward
authors.forename: Penelope M
authors.initials: PM
authors.lastname: Webb
authors.forename: David C
authors.initials: DC
authors.lastname: Whiteman
authors.forename: Juleen A
authors.initials: JA
authors.lastname: Cavanaugh
authors.forename: Ruth
authors.initials: R
authors.lastname: McCallum
authors.forename: Timothy H J
authors.initials: TH
authors.lastname: Florin
authors.forename: Murray L
authors.initials: ML
authors.lastname: Barclay
authors.forename: Richard B
authors.initials: RB
authors.lastname: Gearry
authors.forename: Tony R
authors.initials: TR
authors.lastname: Merriman
authors.forename: Grant W
authors.initials: GW
authors.lastname: Montgomery
authors.forename: Graham L
authors.initials: GL
authors.lastname: Radford-Smith
mesh_terms: D000328:Adult; D000483:Alleles; D001315:Australia; D016009:Chi-Square Distribution; D003106:Colon / Q000473:pathology; D003424:Crohn Disease / Q000235:genetics* / Q000473:pathology; D005260:Female; D005787:Gene Frequency; D056726:Genetic Association Studies; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D007082:Ileum / Q000473:pathology*; D007150:Immunohistochemistry; D007249:Inflammation / Q000235:genetics / Q000473:pathology; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009520:New Zealand; D020641:Polymorphism, Single Nucleotide; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018709:Statistics, Nonparametric
chemical_list: D051660:Intermediate-Conductance Calcium-Activated Potassium Channels; C496923:KCNN4 protein, human