title: ATG16L1 T300A shows strong associations with disease subgroups in a large Australian IBD population: further support for significant disease heterogeneity.
abstract: OBJECTIVE
  Crohn's disease (CD) and ulcerative colitis (UC) are the two most common forms of inflammatory bowel disease (IBD), representing a significant health-care burden. A variant in the autophagy gene ATG16L1 (T300A) has been newly identified as a CD susceptibility locus by genome-wide association. Our aim was to assess the contribution of T300A in determining disease susceptibility and phenotype in two independent Australian IBD cohorts and explore the relationship between T300A and known CD risk factors (NOD2[nucleotide-binding oligomerization domain containing 2] status and smoking).
  
  
  METHODS
  In total, 669 CD and 543 UC cases, and 1,244 controls (study 1), 154 CD cases and 420 controls (study 2), and 702 unaffected parents from both groups were genotyped. We conducted case-control and family association analyses, and investigated relationships between T300A and disease subgroups and between NOD2 status and cigarette smoking (CD only).
  
  
  RESULTS
  The strong association between CD and T300A was confirmed (P < 0.001), with a two-fold increase in disease risk associated with the GG genotype (odds ratio [OR] 1.96, 95% confidence interval [CI] 1.49-2.58), while ileal CD risk was almost three-fold (OR 2.73, CI 1.87-4.0). ATG16L1 and NOD2 were found to contribute independently to CD risk. A greater than seven-fold increased CD risk was observed for current smokers with a GG genotype (vs nonsmoking AA genotype; P < 0.001, OR 7.65, CI 4.21-13.91). A significant inverse association was found between T300A and UC (P= 0.002). This was strongest for patients with extensive, severe disease.
  
  
  CONCLUSIONS
  We confirm the strong association between T300A and CD, specifically ileal subphenotype, and also report the first strong association of this variant with UC.
authors.affiliation: Inflammatory Bowel Disease Laboratory, Royal Brisbane and Women's Research Foundation, Brisbane, Australia.
authors.forename: Elizabeth V
authors.initials: EV
authors.lastname: Fowler
authors.forename: James
authors.initials: J
authors.lastname: Doecke
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Simms
authors.forename: Zhen Zhen
authors.initials: ZZ
authors.lastname: Zhao
authors.forename: Penelope M
authors.initials: PM
authors.lastname: Webb
authors.forename: Nicholas K
authors.initials: NK
authors.lastname: Hayward
authors.forename: David C
authors.initials: DC
authors.lastname: Whiteman
authors.forename: Timothy H
authors.initials: TH
authors.lastname: Florin
authors.forename: Grant W
authors.initials: GW
authors.lastname: Montgomery
authors.forename: Juleen A
authors.initials: JA
authors.lastname: Cavanaugh
authors.forename: Graham L
authors.initials: GL
authors.lastname: Radford-Smith
mesh_terms: D000071183:Autophagy-Related Proteins; D002352:Carrier Proteins / Q000235:genetics*; D016001:Confidence Intervals; D004247:DNA / Q000235:genetics*; D005838:Genotype; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000453:epidemiology / Q000235:genetics*; D016017:Odds Ratio; D011110:Polymorphism, Genetic; D011159:Population Surveillance; D015995:Prevalence; D011379:Prognosis; D011446:Prospective Studies; D011793:Queensland / Q000453:epidemiology; D012307:Risk Factors; D012907:Smoking / Q000009:adverse effects / Q000453:epidemiology
chemical_list: C518959:ATG16L1 protein, human; D000071183:Autophagy-Related Proteins; D002352:Carrier Proteins; D004247:DNA