title: Genetic variants in autophagy-related genes and granuloma formation in a cohort of surgically treated Crohn's disease patients.
abstract: OBJECTIVE
  Granulomas are a characteristic microscopic finding in Crohn's disease. Their clinical significance is controversial and their pathogenesis is unknown, but impaired processing of bacterial components has been suggested. Autophagy is a fundamental process involved in the elimination of intracellular bacteria. Genetic variants in autophagy genes IRGM and ATG16L1 have been associated with susceptibility to Crohn's disease. We therefore investigated whether variants in autophagy genes contribute to granuloma formation.
  
  
  METHODS
  Surgical specimens from 464 clinically well-documented Crohn's patients were reviewed and scored for the presence and distribution of granulomas. All patients were genotyped for the CD-associated SNPs in ATG16L1 and IRGM as well as for 77 haplotype tagging SNPs in 13 additional autophagy genes.
  
  
  RESULTS
  Granulomas were found in 75% of the patients. Their frequency increased with more distal involvement of the GI tract. Granuloma positive patients were significantly younger at the time of diagnosis and surgery, and were more likely to smoke. We identified associations between granulomas and autophagy gene variants ATG4A (rs5973822), FNBP1L (rs17109951) and ATG4D (rs7248026; rs2304165; rs10439163).
  
  
  CONCLUSIONS
  These findings suggest that granuloma formation is a marker of a more aggressive disease course, and that variants in autophagy genes ATG4A, ATG2A, FNBP1L and ATG4D, may contribute to granuloma formation.
authors.affiliation: Department of Gastroenterology, University Hospital Gasthuisberg, Leuven, Belgium. marko.brinar@zg.t-com.hr
authors.forename: Marko
authors.initials: M
authors.lastname: Brinar
authors.forename: Séverine
authors.initials: S
authors.lastname: Vermeire
authors.forename: Isabelle
authors.initials: I
authors.lastname: Cleynen
authors.forename: Bart
authors.initials: B
authors.lastname: Lemmens
authors.forename: Xavier
authors.initials: X
authors.lastname: Sagaert
authors.forename: Liesbet
authors.initials: L
authors.lastname: Henckaerts
authors.forename: Gert
authors.initials: G
authors.lastname: Van Assche
authors.forename: Karel
authors.initials: K
authors.lastname: Geboes
authors.forename: Paul
authors.initials: P
authors.lastname: Rutgeerts
authors.forename: Gert
authors.initials: G
authors.lastname: De Hertogh
mesh_terms: D000293:Adolescent; D000328:Adult; D001343:Autophagy / Q000235:genetics*; D003424:Crohn Disease / Q000235:genetics* / Q000473:pathology; D005260:Female; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006099:Granuloma / Q000235:genetics* / Q000473:pathology; D006801:Humans; D016015:Logistic Models; D008297:Male; D055815:Young Adult
chemical_list: D005819:Genetic Markers