A nonsynonymous SNP in ATG16L1 predisposes to ileal Crohn's disease and is independent of CARD15 and IBD5.
OBJECTIVE
A genome-wide association scan of nonsynonymous DNA polymorphisms identified association of a threonine-to-alanine substitution (T300A) in the autophagy-related 16-like gene ATG16L1 with Crohn's disease. We investigated this association in independent U.K. cohorts of Crohn's disease and ulcerative colitis.


METHODS
The T300A variant (rs2241880) was genotyped in an independent sample of 727 Crohn's disease and 877 ulcerative colitis cases, and in 579 controls. We then performed an extension analysis combining these data with the U.K. data from the initial study to give a total of 1236 U.K. Crohn's disease cases and 1235 controls to estimate disease risk and test for interaction with the CARD15 and IBD5 risk loci and for association with disease subtypes.


RESULTS
The association of T300A was replicated in the independent sample of 727 Crohn's disease cases (P = .001), and was strongly associated in the extended analysis of 1236 Crohn's cases (P = 2.4 x 10(-6)). The 300A/A genotype conferred a 1.65-fold risk of Crohn's disease, with a 2.2-fold risk of ileal disease. Analysis of the interaction of ATG16L1 with CARD15 and IBD5 indicated that all 3 loci contribute independently to disease risk. Homozygosity for the risk allele at all 3 loci conferred a combined risk of 20.4 (95% confidence interval: 8.71, 47.7) for Crohn's disease. The ATG16L1 risk genotype showed a modest but significant association with ulcerative colitis (P = .026).


CONCLUSIONS
The association of ATG16L1 with Crohn's disease and possibly with ulcerative colitis supports a role for autophagy in the pathogenesis of inflammatory bowel disease.
Prescott
Natalie J
NJ
Department of Medical and Molecular Genetics, King's College London School of Medicine, Guy's Hospital, London, UK.
Fisher
Sheila A
SA
Franke
Andre
A
Hampe
Jochen
J
Onnie
Clive M
CM
Soars
Dianne
D
Bagnall
Richard
R
Mirza
Muddassar M
MM
Sanderson
Jeremy
J
Forbes
Alastair
A
Mansfield
John C
JC
Lewis
Cathryn M
CM
Schreiber
Stefan
S
Mathew
Christopher G
CG
D000293:Adolescent; D000328:Adult; D000368:Aged; D001343:Autophagy / Q000235:genetics / Q000502:physiology; D000071183:Autophagy-Related Proteins; D002352:Carrier Proteins / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D002895:Chromosomes, Human, Pair 5 / Q000235:genetics*; D015331:Cohort Studies; D003093:Colitis, Ulcerative / Q000235:genetics; D003424:Crohn Disease / Q000235:genetics* / Q000503:physiopathology; D004843:Epistasis, Genetic; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006801:Humans; D007079:Ileitis / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D008957:Models, Genetic; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012307:Risk Factors; D006113:United Kingdom
C518959:ATG16L1 protein, human; D000071183:Autophagy-Related Proteins; D002352:Carrier Proteins; C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein