Genetic variation in the autophagy gene ULK1 and risk of Crohn's disease

Authors

  • Liesbet Henckaerts MD, PhD,

    Corresponding author
    1. Department of Gastroenterology, University Hospitals Leuven, Leuven, Belgium
    • Department of Gastroenterology, University Hospitals Leuven, Herestraat 49, 3000 Leuven, Belgium
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    • The first two authors contributed equally to this study.

  • Isabelle Cleynen PhD,

    1. Department of Gastroenterology, University Hospitals Leuven, Leuven, Belgium
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    • 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.

    • The first two authors contributed equally to this study.

  • Marko Brinar MD,

    1. Department of Gastroenterology, University Hospitals Leuven, Leuven, Belgium
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    • 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.

  • Jestinah Mahachie John PhD,

    1. Systems and Modeling Unit, Montefiore Institute, University of Liège, Liège, Belgium
    2. Bioinformatics and Modeling, GIGA-R, University of Liège, Liège, Belgium
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    • 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.

  • Kristel Van Steen PhD,

    1. Systems and Modeling Unit, Montefiore Institute, University of Liège, Liège, Belgium
    2. Bioinformatics and Modeling, GIGA-R, University of Liège, Liège, Belgium
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    • 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.

  • Paul Rutgeerts MD, PhD, FRCP,

    1. Department of Gastroenterology, University Hospitals Leuven, Leuven, Belgium
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    • 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.

  • Séverine Vermeire MD, PhD

    1. Department of Gastroenterology, University Hospitals Leuven, Leuven, Belgium
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    • 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.


Abstract

Background:

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.

Methods:

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.

Results:

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.

Conclusions:

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)

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