L. Henckaerts is a doctoral fellow, I. Cleynen is a postdoctoral fellow, and S. Vermeire is a clinical researcher of the Fund for Scientific Research (FWO), Flanders, Belgium. This work was supported by the ‘Geconcerteerde Onderzoekacties (GOA)’ of the KU Leuven (grant number GOA/11/015). J.M. Mahachie John and K. Van Steen are supported by the Belgian Network BioMAGNet (Bioinformatics and Modeling: from Genomes to Networks), within the Interuniversity Attraction Poles Program (Phase VI/4), initiated by the Belgian State, Science Policy Office and partially supported by the IST Program of the European Community, under the PASCAL2 Network of Excellence (Pattern Analysis, Statistical Modeling and Computational Learning), IST-2007-216886.
Genetic variation in the autophagy gene ULK1 and risk of Crohn's disease†
Article first published online: 28 NOV 2010
Copyright © 2010 Crohn's & Colitis Foundation of America, Inc.
Inflammatory Bowel Diseases
Volume 17, Issue 6, pages 1392–1397, June 2011
How to Cite
Henckaerts, L., Cleynen, I., Brinar, M., John, J. M., Van Steen, K., Rutgeerts, P. and Vermeire, S. (2011), Genetic variation in the autophagy gene ULK1 and risk of Crohn's disease. Inflamm Bowel Dis, 17: 1392–1397. doi: 10.1002/ibd.21486
- Issue published online: 10 MAY 2011
- Article first published online: 28 NOV 2010
- Manuscript Accepted: 16 AUG 2010
- Manuscript Received: 10 AUG 2010
- Crohn's disease;
The autophagy pathway has been linked with Crohn's disease (CD) through association of the ATG16L1 and IRGM genes with susceptibility for CD, and also to the Nod2 pathway, involved in CD. Our aim was to investigate polymorphisms in selected autophagy genes for their association with susceptibility to CD.
We prioritized all known human homologs of yeast autophagy (Atg) genes according to their location in a known inflammatory bowel disease (IBD) locus or in a genomic region detected in a genome-wide association study (GWAS) or GWAS-meta-analysis. A total of 70 haplotype tagging single nucleotide polymorphisms (tSNPs) in 12 genes were genotyped in a cohort of CD patients (n = 947) and controls (n = 548). Transmission disequilibrium testing (TDT) was performed in an independent cohort of 335 parent–child CD-trios.
The frequency of the T-allele of tSNP rs12303764 in ULK1 was significantly higher in CD (64%) versus controls (57%, corrected P-value 0.002). TDT demonstrated overtransmission of this allele to affected offspring (P = 0.02). Model-based multifactor dimensionality reduction (MB-MDR) interaction analysis confirmed a strong main effect for rs12303764. No interaction was found between ULK1 and CARD15, or between ULK1 genotypes and CD phenotypes.
We report a genetic association with a tSNP in ULK1, an interesting candidate gene for IBD, given the role of ULK1 in autophagy initiation, and the interaction between Nod2 and autophagy pathways. To further clarify the role of ULK1 in CD, an in-depth investigation of the variation in the region and possible role for copy number variation in this region should be evaluated. (Inflamm Bowel Dis 2011)