Replication and meta-analysis of 13,000 cases defines the risk for interleukin-23 receptor and autophagy-related 16-like 1 variants in Crohn's disease.
OBJECTIVE
Variants in the interleukin-23 receptor (IL23R) and the autophagy-related 16-like 1 (ATG16L1) genes have been associated with an increased risk of Crohn's disease (CD). Both genes were identified through genome-wide association scans and subsequent studies have validated these associations. To assess the effect size of these variants, an independent case-control association study and meta-analysis were performed.


METHODS
British Caucasian subjects with inflammatory bowel disease (n=500) and 877 ethnically matched controls were genotyped for the disease-associated variants in IL23R and ATG16L1. In addition, meta-analyses of 12,991 patients and 14,598 controls, and 11,909 patients and 15,798 controls, were conducted on independently published data for the associations between IL23R and ATG16L1 variants and CD, respectively.


RESULTS
In the present cohort, both susceptibility variants showed highly significant associations, including IL23R (rs11209026, P=0.0006; OR 0.37; 95% CI 0.21 to 0.67) and ATG16L1 (rs2241880, P=0.0017; OR 1.36; 95% CI 1.12 to 1.66). The meta-analysis based on the random effects model showed similar combined effects for rs11209026 (n=26, OR 0.41; 95% CI 0.37 to 0.46) and rs2241880 (n=25, OR 1.33; 95% CI 1.28 to 1.39). There was no statistically significant gene-gene interaction between caspase recruitment domain (CARD15) variants and the IL23R or ATG16L1 polymorphisms (P=0.44 and P=0.24, respectively).


CONCLUSIONS
The present cohort and meta-analysis provides strong evidence that, in addition to CARD15, polymorphisms in both IL23R and ATG16L1 alter susceptibility to CD and that these effects are consistent across all populations of European ancestry; however, only ATG16L1 is relevant to inflammatory bowel disease in the Asian population.
Cotterill
Lynn
L
Department of Medical Genetics, Manchester Academic Health, Manchester, United Kingdom.
Payne
Debbie
D
Levinson
Scott
S
McLaughlin
John
J
Wesley
Emma
E
Feeney
Mark
M
Durbin
Hilary
H
Lal
Simon
S
Makin
Alistair
A
Campbell
Simon
S
Roberts
Stephen A
SA
O'Neill
Catherine
C
Edwards
Cathryn
C
Newman
William G
WG
D000071183:Autophagy-Related Proteins; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D003424:Crohn Disease / Q000235:genetics* / Q000378:metabolism; D004247:DNA / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D011110:Polymorphism, Genetic; D018123:Receptors, Interleukin / Q000235:genetics* / Q000378:metabolism; D012307:Risk Factors
C518959:ATG16L1 protein, human; D000071183:Autophagy-Related Proteins; D002352:Carrier Proteins; C515500:IL23R protein, human; D018123:Receptors, Interleukin; D004247:DNA