KCNN4 gene variant is associated with ileal Crohn's Disease in the Australian and New Zealand population.
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.
Simms
Lisa A
LA
Royal Brisbane and Women's Research Foundation, Brisbane, Queensland, Australia. Lisa.Simms@qimr.edu.au
Doecke
James D
JD
Roberts
Rebecca L
RL
Fowler
Elizabeth V
EV
Zhao
Zhen Zhen
ZZ
McGuckin
Michael A
MA
Huang
Ning
N
Hayward
Nicholas K
NK
Webb
Penelope M
PM
Whiteman
David C
DC
Cavanaugh
Juleen A
JA
McCallum
Ruth
R
Florin
Timothy H J
TH
Barclay
Murray L
ML
Gearry
Richard B
RB
Merriman
Tony R
TR
Montgomery
Grant W
GW
Radford-Smith
Graham L
GL
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
D051660:Intermediate-Conductance Calcium-Activated Potassium Channels; C496923:KCNN4 protein, human