Confirmation of the role of ATG16L1 as a Crohn's disease susceptibility gene.
BACKGROUND
A German genome-wide nonsynonymous single nucleotide polymorphism (nsSNP) association study identified ATG16L1 as a Crohn's disease (CD) susceptibility gene. The association appeared to be confined to the nsSNP rs2,241,880 and was confirmed in 2 German independent case-control collections (combined P = 4.0 x 10(-8), odds ratio [OR] 1.45; 95% confidence interval [CI]: 1.21-1.74), a CD transmission disequilibrium test (TDT) collection, and an independent UK cohort. A weak statistical interaction with CARD15 was demonstrated. No association with ulcerative colitis (UC) was demonstrated. The aims of the study were to replicate the association with CD, examine subphenotype associations and statistical interactions with CARD15, IL23R, and the IBD5 risk haplotype, as well as explore the association with UC.


METHODS
The study included 645 CD and 676 UC rigorously phenotyped patients recruited from a single UK center. Unaffected controls comprised either spouses of patients (141) or individuals recruited from well-person clinics (1,049). The nsSNP rs2,241,880 was genotyped using MassArray (Sequenom).


RESULTS
A strong association with CD was demonstrated (P = 2.33 x 10(-7), OR 1.45 [1.25-1.67]), but no significant association was demonstrated with any subphenotype. We failed to replicate the reported interaction between rs2,241,880 and the CARD15 low-risk haplotypes dd and Dd. No significant statistical interaction with the 3 known CD susceptibility genes was seen. No association with UC susceptibility (P = 0.37, OR 1.06 [0.93-1.22]), or any UC subphenotype was identified.


CONCLUSIONS
We confirmed the findings that ATG16L1 is a CD susceptibility gene and found no evidence of interaction with CARD15, IL23R, or IBD5.
Cummings
J R Fraser
JR
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK. fraserc@well.ox.ac.uk
Cooney
Rachel
R
Pathan
Saad
S
Anderson
Carl A
CA
Barrett
Jeffrey C
JC
Beckly
John
J
Geremia
Alessandra
A
Hancock
Laura
L
Guo
Changcun
C
Ahmad
Tariq
T
Cardon
Lon R
LR
Jewell
Derek P
DP
D000293:Adolescent; D000328:Adult; D000071183:Autophagy-Related Proteins; D002352:Carrier Proteins / Q000235:genetics*; D003093:Colitis, Ulcerative / Q000235:genetics; D003424:Crohn Disease / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D008297:Male; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D018123:Receptors, Interleukin / Q000235:genetics
C518959:ATG16L1 protein, human; D000071183:Autophagy-Related Proteins; D002352:Carrier Proteins; C515500:IL23R protein, human; D053473:Nod2 Signaling Adaptor Protein; D018123:Receptors, Interleukin