Autophagy gene ATG16L1 influences susceptibility and disease location but not childhood-onset in Crohn's disease in Northern Europe

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http://www3.interscience.wiley.com/cgi-bin/abstract/117868249/ABSTRACT?CRETRY=1 & SRETRY=0

Inflammatory Bowel Diseases

Volume 14, Issue 3 , Pages 338 - 346

Original ArticleAutophagy gene ATG16L1 influences susceptibility and disease location but not childhood-onset in Crohn's disease in Northern Europe

*Correspondence to J. Van Limbergen, Gastrointestinal Unit-Molecular Medicine Centre, Western General Hospital-University of Edinburgh, Crewe Road South, Edinburgh EH4 2XU, UK

The authors declare they have no competing interests.

Funded by: Research Training Fellowship from Action Medical Research Gay-Ramsay-Steel-Maitland or Stafford Trust Hazel M Wood Charitable Trust Wellcome Trust Programme Grant; Grant Number: 072789/Z/03/Z Schering-Plough and the GI/Nutrition Research Fund Child Life and Health University of Edinburgh

Keywords

ATG16L1 • autophagy • Crohn's disease • inflammatory bowel disease • genetics • pediatrics

Abstract

Background: The rs2241880A/G variant of the ATG16L1 gene has been associated with susceptibility to ileal Crohn's disease (CD) in adults. Our aim was to assess whether germline variation of ATG16L1 acts as an independent determinant of susceptibility to childhood-onset CD in the high-incidence ish population.

Methods: In all, 2195 subjects (361 children (inflammatory bowel disease [iBD] diagnosis <17 years), their parents (n = 634), 855 adult IBD patients, and 345 controls were genotyped. Case-control analysis was powered to detect effect sizes with an odds ratio (OR) >1.39 in pediatric CD. Case-control analysis, transmission disequilibrium testing (TDT), analysis of variance (ANOVA) of growth parameter z-scores, Kruskal-Wallis test (age at diagnosis), and multifactorial genotype-phenotype analysis (Montreal classification) were performed. 7.8% of pediatric CD patients and 37.2% of adult CD patients had pure ileal disease.

Results: We confirmed the association of the rs2241880G-allele with adult-onset CD (60.7% versus controls 53.9%, P = 0.01, OR 1.32, 95% confidence interval [CI] 1.07-1.63) in contrast to childhood-onset CD (54.1% versus controls, P = 0.95, OR 1.01, 95% CI 0.80-1.26). TDT analysis was negative. Genotype-phenotype analysis demonstrated an association of pure ileal disease with the rs2241880G-allele (P = 0.02, OR 1.34, 95% CI 1.03-1.74). Using binary logistic regression analysis we confirmed the effect of rs2241880 genotype (GG) on ileal disease versus colonic disease (P = 0.03, OR 2.43, 95% CI 1.05-5.65). ATG16L1 genotype did not influence age at CD diagnosis. ANOVA of z-scores of height, weight, and body mass index (BMI) at CD diagnosis in children showed no association with genotype.

Conclusions: The ATG16L1 variant is associated with susceptibility to adult CD in Scotland, but not early-onset disease. These contrasting effects are primarily driven by differences in disease location between early-onset and adult-onset disease.

(Inflamm Bowel Dis 2007)

Received: 13 October 2007; Accepted: 19 October 2007

Digital Object Identifier (DOI)10.1002/ibd.20340