Autophagy gene ATG16L1 but not IRGM is associated with Crohn's disease in Canadian children.
BACKGROUND
Recent genome-wide studies have implicated the autophagy genes ATG16L1 and IRGM in the pathogenesis of Crohn's disease (CD). We investigated whether these genes were associated with CD in Canadian children.


METHODS
A case-control study was carried out at 2 pediatric gastroenterology clinics in Canada. Confirmed cases of CD <20 years diagnosed using standard criteria were classified according to the Montreal Classification scheme. Single nucleotide polymorphisms (SNPs) rs2241880 (ATG16L1) and rs10065172 (IRGM) along with CARD15 SNPs, SNP8, SNP12, and SNP13 were genotyped.


RESULTS
A total of 289 CD cases and 290 controls were studied. The mean age (+/-SD) of the cases was 12.1 (+/-3.5) years of age. Most cases were male (55.4%), had disease location L3 +/- L4 (56.7%), and an inflammatory phenotype B1 +/- p (87.2%) at diagnosis. rs2241880 (ATG16L1) was strongly associated with CD (allelic P = 1.24 x 10(-6)). Children with GG genotype had a more than 3-fold elevated risk for disease as compared to the wildtype AA homozygotes (odds ratio [OR], 3.1; 95% confidence interval [CI], 1.93-4.94; P = 1.8 x 10(-6)). Association with SNP rs2241880 was specific for ileal disease (with or without colonic involvement) (case-based allelic P = 0.02; P-value versus controls = 9.5 x 10(-8)). The frequency of IRGM SNP rs10065172 was higher in cases but differences with controls were not statistically significant. No interactions between CARD15 and either ATG16L1 or IRGM were evident.


CONCLUSIONS
We have confirmed associations between CD and ATG16L1 in a pediatric cohort of Canadian children. Associations with IRGM need to be further evaluated in larger studies.
Amre
Devendra K
DK
Department of Pediatrics, University of Montreal, Montreal, Canada. devendra.amre@umontreal.ca
Mack
David R
DR
Morgan
Kenneth
K
Krupoves
Alfreda
A
Costea
Irina
I
Lambrette
Philippe
P
Grimard
Guy
G
Dong
Jinsong
J
Feguery
Houda
H
Bucionis
Vytautas
V
Deslandres
Colette
C
Levy
Emile
E
Seidman
Ernest G
EG
D000293:Adolescent; D001343:Autophagy / Q000235:genetics*; D000071183:Autophagy-Related Proteins; D002170:Canada / Q000453:epidemiology; D002352:Carrier Proteins / Q000235:genetics*; D016022:Case-Control Studies; D002648:Child; D003424:Crohn Disease / Q000453:epidemiology* / Q000235:genetics*; D005260:Female; D019204:GTP-Binding Proteins / Q000235:genetics*; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease / Q000453:epidemiology; D005838:Genotype; D006801:Humans; D008297:Male; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors
C518959:ATG16L1 protein, human; D000071183:Autophagy-Related Proteins; D002352:Carrier Proteins; C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein; D019204:GTP-Binding Proteins; C513539:IRGM protein, human