title: A case-only study of gene-environment interaction between genetic susceptibility variants in NOD2 and cigarette smoking in Crohn's disease aetiology.
abstract: BACKGROUND
  Genetic variation in NOD2 and cigarette smoking are well-established risk factors for the development of Crohn's disease (CD). However, little is known about a potential interaction between these risk factors. We investigated gene-environment interactions between CD-associated NOD2 alleles and cigarette smoking in a large sample of patients with CD.
  
  
  METHODS
  Three previously reported CD-associated variants in NOD2 (R702W, G908R, 1007fs) were genotyped in 1636 patients with CD continuously recruited between 1995 and 2010 based on physician referral. Data on history of smoking behaviour was obtained for all participants through a written questionnaire. Using a case-only design, we performed logistic regression analyses to investigate statistical interactions between NOD2 risk alleles and smoking status.
  
  
  RESULTS
  We detected a significant negative interaction between carriership of at least one of the NOD2 risk alleles and history of ever having smoked (OR = 0.71; p = 0.005) as well as smoking at the time of CD diagnosis (OR = 0.68; p = 0.005). Subsequent separate analyses of the three variants revealed a significant negative interaction between the 1007fs variant and history of ever having smoked (OR = 0.64; p = 9 × 10-4) and smoking at the time of CD diagnosis (OR = 0.53; p = 7 × 10-5).
  
  
  CONCLUSIONS
  The observed significant negative gene-environment interaction suggests that the risk increase for CD conferred simultaneously by cigarette smoking and the 1007fs NOD2 polymorphism is smaller than expected and may point to a biological interaction. Our findings warrant further investigation in epidemiological and functional studies to elucidate pathophysiology as well as to aid in the development of recommendations for disease prevention.
authors.affiliation: Institute for Experimental Medicine, Section of Epidemiology, Christian-Albrechts-University of Kiel, Arnold-Heller-Strasse 3, Haus 3, 24105 Kiel, Germany. k.helbig@iem.uni-kiel.de
authors.forename: Katherine L
authors.initials: KL
authors.lastname: Helbig
authors.forename: Michael
authors.initials: M
authors.lastname: Nothnagel
authors.forename: Jochen
authors.initials: J
authors.lastname: Hampe
authors.forename: Tobias
authors.initials: T
authors.lastname: Balschun
authors.forename: Susanna
authors.initials: S
authors.lastname: Nikolaus
authors.forename: Stefan
authors.initials: S
authors.lastname: Schreiber
authors.forename: Andre
authors.initials: A
authors.lastname: Franke
authors.forename: Ute
authors.initials: U
authors.lastname: Nöthlings
mesh_terms: D000328:Adult; D000483:Alleles; D016022:Case-Control Studies; D003424:Crohn Disease / Q000209:etiology / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D059647:Gene-Environment Interaction; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006579:Heterozygote; D006801:Humans; D008297:Male; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics*; D016017:Odds Ratio; D011110:Polymorphism, Genetic; D012307:Risk Factors; D012907:Smoking
chemical_list: C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein