P250 - Autophagy 16-like 1 on chromosome 2q37.1 is associated with inflammatory bowel disease in children

Abstract

Introduction: Genome-wide association studies have described a variety of susceptibility genes for IBD. Among them, a polymorphism within the autophagy 16-like gene ATG16L1 has been shown to be associated with Crohn’s disease in independent IBD cohorts. In this gene, which encodes a small coiled-coil domain protein that is part of a protein complex essential for autophagy, the rs2241880 variant leads to a threonine-to-alanine substitution at amino acid position 300 (T300A) and confers strong risk for CD in adults. This locus has been evaluated in three pediatric IBD cohorts with conflicting results. Therefore, the aim of this study was to investigate the association of rs2241880 in a German pediatric IBD cohort and to describe the transcriptional activity of ATG16L1 in colonic tissues. Methods: Subjects: 232 German Caucasian children with IBD (152 CD, 80 UC) and 253 ethnically matched healthy adult blood donors. Gene expression analysis: Determination of mRNA expression of ATG16L1 and IL-8 as a proinflammatory control in large bowel biopsies of selected IBD patients and controls using real-time PCR. Genotyping: Investigation of the rs2241880 polymorphism of the ATG16L1 gene on chromosome 2q37.1 using a pre-designed TaqMan® SNP Genotyping Assay (Applied Biosystems, Foster City, CA, USA). To verify potential interactions of the T300A variant with the NOD2/CARD15 gene we also tested for epistasis with NOD2/CARD15. Results: Genotyping for the rs2241880 polymorphism exhibited significant differences in the genotypes between CD patients and controls (p < 0.01), whereas there were no differences between UC patients and controls in genotype or allele frequencies. Subgrouping for phenotypes according to disease localization and behavior showed no significant differences in the frequency of the genotypes. We could not demonstrate an epistatic interaction between the NOD2/CARD15 gene and the A300T variant of the ATG16L1 gene. The gene expression analysis did not reveal a characteristical overexpression or downregulation of ATG16L1 in CD and UC patients compared to unaffected controls. Conclusion:We have confirmed the association between CD and the rs2241880 polymorphism in ATG16L1 in a pediatric cohort of German Caucasian children. However, no association of UC and A300T variant could be found. We could not demonstrate an epistatic interaction between the NOD2/CARD15 gene and the rs2241880 polymorphism. These results mirror the findings in adult patients that even in the absence of NOD2/CARD15 mutations the ATG16L1 variation is a risk factor in pediatric CD thereby supporting a role for autophagy in the pathogenesis of this disease. P251 Clinical parameters available in early Crohn’s disease patients predict a progressive disease course and the subsequent need for immunosuppressive therapy S. Wenger1 *, S. Nikolaus2, S. Howaldt3, B. Bokemeyer4, A. Sturm5, J. Preis6, A. Stallmach1, C. Schmidt1. 1FriedrichSchiller-University, Clinic of Internal Medicine II, Jena, Germany, 2Christian Albrechts-University, Clinic of Internal Medicine, Kiel, Germany, 3Gastroenterologie am Rothenbaum, Hamburg, Germany, 4Gastroenterologische Gemeinschaftspraxis, Minden, Germany, 5Charite, Campus Virchow Clinic, Clinic of Internal Medicine, Berlin, Germany, 6Charite, Campus Benjamin Franklin, Medical Clinic I, Berlin, Germany