title: Genetic factors conferring an increased susceptibility to develop Crohn's disease also influence disease phenotype: results from the IBDchip European Project.
abstract: OBJECTIVE
  Through genome-wide association scans and meta-analyses thereof, over 70 genetic loci (Crohn's disease (CD) single nucleotide polymorphisms (SNPs)) are significantly associated with CD. We aimed to investigate the influence of CD-SNPs and basic patient characteristics on CD clinical course, and develop statistical models to predict CD clinical course.
  
  
  METHODS
  This retrospective study included 1528 patients with CD with more than 10 years of follow-up from eight European referral hospitals. CD outcomes of interest were ileal (L1), colonic (L2) and ileocolonic disease location (L3); stenosing (B2) or penetrating behaviour (B3); perianal disease; extraintestinal manifestations; and bowel resection. A complicated disease course was defined as stenosing or penetrating behaviour, perianal disease and/or bowel resection. Association between CD-SNPs or patient characteristics and specified outcomes was studied.
  
  
  RESULTS
  Several CD-SNPs and clinical characteristics were statistically associated with outcomes of interest. The NOD2 gene was the most important genetic factor, being an independent predictive factor for ileal location (p=2.02 × 10(-06), OR=1.90), stenosing (p=3.16 × 10(-06), OR=1.82) and penetrating (p=1.26 × 10(-02), OR=1.25) CD behaviours, and need for surgery (p=2.28 × e-05, OR=1.73), and as such was also the strongest factor associated with a complicated disease course (p=6.86 × 10(-06), OR=2.96). Immunomodulator (azathioprine/6-mercaptopurine and methotrexate) use within 3 years after diagnosis led to a reduction in bowel stenoses (p=1.48 × 10(-06), OR=0.35) and surgical rate (p=1.71 × 10(-07), OR=0.34). Association between each outcome and genetic scores, created using significant SNPs in the univariate analysis, revealed large differences in the probability of developing fistulising disease (IL23R, LOC441108, PRDM1, NOD2; p=9.64e-4, HR=1.43), need for surgery (IRGM, TNFSF15, C13ORF31, NOD2; p=7.12 × 10(-03), HR=1.35), and stenosing disease (NOD2, JAK2, ATG16L1; p=3.01 × 10(-02), HR=1.29) among patients with low and high score.
  
  
  CONCLUSIONS
  This large multicentre cohort study has found several genetic and clinical factors influencing the clinical course of CD. NOD2 and early immunomodulator use are the clinically most meaningful predictors for its clinical course.
authors.affiliation: Department of Clinical and Experimental Medicine, KU Leuven, , Leuven, Belgium.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Cleynen
authors.forename: Juan R
authors.initials: JR
authors.lastname: González
authors.forename: Carolina
authors.initials: C
authors.lastname: Figueroa
authors.forename: Andre
authors.initials: A
authors.lastname: Franke
authors.forename: Dermot
authors.initials: D
authors.lastname: McGovern
authors.forename: Martin
authors.initials: M
authors.lastname: Bortlík
authors.forename: Bart J A
authors.initials: BJ
authors.lastname: Crusius
authors.forename: Maurizio
authors.initials: M
authors.lastname: Vecchi
authors.forename: Marta
authors.initials: M
authors.lastname: Artieda
authors.forename: Magdalena
authors.initials: M
authors.lastname: Szczypiorska
authors.forename: Johannes
authors.initials: J
authors.lastname: Bethge
authors.forename: David
authors.initials: D
authors.lastname: Arteta
authors.forename: Edgar
authors.initials: E
authors.lastname: Ayala
authors.forename: Silvio
authors.initials: S
authors.lastname: Danese
authors.forename: Ruud A
authors.initials: RA
authors.lastname: van Hogezand
authors.forename: Julian
authors.initials: J
authors.lastname: Panés
authors.forename: Salvador Amado
authors.initials: SA
authors.lastname: Peña
authors.forename: Milan
authors.initials: M
authors.lastname: Lukas
authors.forename: Derek P
authors.initials: DP
authors.lastname: Jewell
authors.forename: Stefan
authors.initials: S
authors.lastname: Schreiber
authors.forename: Severine
authors.initials: S
authors.lastname: Vermeire
authors.forename: Miquel
authors.initials: M
authors.lastname: Sans
mesh_terms: D000293:Adolescent; D000328:Adult; D003092:Colitis / Q000453:epidemiology / Q000235:genetics; D003424:Crohn Disease / Q000150:complications / Q000453:epidemiology / Q000235:genetics* / Q000628:therapy; D018450:Disease Progression; D005060:Europe / Q000453:epidemiology; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D060005:Genotyping Techniques / Q000379:methods; D006801:Humans; D007079:Ileitis / Q000453:epidemiology / Q000235:genetics; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D007415:Intestinal Obstruction / Q000453:epidemiology / Q000209:etiology / Q000235:genetics / Q000517:prevention & control; D053614:Janus Kinase 2 / Q000235:genetics; D008297:Male; D015233:Models, Statistical; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D012189:Retrospective Studies; D055815:Young Adult
chemical_list: D007166:Immunosuppressive Agents; C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein; C507924:JAK2 protein, human; D053614:Janus Kinase 2