title: Genetic variation in the autophagy gene ULK1 and risk of Crohn's disease.
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.
authors.affiliation: Department of Gastroenterology, University Hospitals Leuven, Leuven, Belgium. liesbet.henckaerts@gmail.com
authors.forename: Liesbet
authors.initials: L
authors.lastname: Henckaerts
authors.forename: Isabelle
authors.initials: I
authors.lastname: Cleynen
authors.forename: Marko
authors.initials: M
authors.lastname: Brinar
authors.forename: Jestinah Mahachie
authors.initials: JM
authors.lastname: John
authors.forename: Kristel
authors.initials: K
authors.lastname: Van Steen
authors.forename: Paul
authors.initials: P
authors.lastname: Rutgeerts
authors.forename: Séverine
authors.initials: S
authors.lastname: Vermeire
mesh_terms: D001343:Autophagy / Q000235:genetics*; D000071189:Autophagy-Related Protein-1 Homolog; D016022:Case-Control Studies; D003424:Crohn Disease / Q000235:genetics*; D056726:Genetic Association Studies; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D012307:Risk Factors
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D000071189:Autophagy-Related Protein-1 Homolog; D017346:Protein Serine-Threonine Kinases; C484754:ULK1 protein, human