title: Genetic polymorphisms in metabolizing enzymes modifying the association between smoking and inflammatory bowel diseases.
abstract: BACKGROUND
  Cigarette smoking is a well-established environmental risk factor for Crohn's disease (CD) and ulcerative colitis (UC). The exact mechanism of its effect remains unexplained. Genetic polymorphisms in metabolizing enzymes may influence susceptibility to the effect of smoking and shed light on its mechanism of action.
  
  
  METHODS
  We used a prospective cohort of patients with CD, UC, and healthy controls. Smoking status was defined as current, former, or never smoking. Patients were genotyped for polymorphisms in CYP2A6, glutathione transferase enzymes (GSTP1 and GSTM1), NAD(P)H quinone oxidoreductase (NQO), and heme oxygenase 1 using a Sequenom platform. Multivariate logistic regression models with CD or UC as the outcome, stratified by genotype, were developed and interaction P-values calculated.
  
  
  RESULTS
  Our study included 634 patients with CD, 401 with UC, and 337 healthy controls. Ever smokers had an increased risk of CD (odds ratio = 3.88, 95% confidence interval = 2.35-6.39) compared with nonsmokers among patients with AG/AA genotypes at CYP2A6. However, ever smoking was not associated with CD among patients with the AA genotype (Pinteraction = 0.001). Former smoking was associated with an increased risk for UC only in the presence of GG/AG genotypes for GSTP1 but not in those with the AA genotype (Pinteraction = 0.012). Polymorphisms at the NQO and HMOX loci did not demonstrate a statistically significant interaction with smoking and risk of CD or UC.
  
  
  CONCLUSIONS
  Genetic polymorphisms in metabolizing enzymes may influence the association between smoking and CD and UC. Further studies of gene-environment interaction in inflammatory bowel disease are warranted.
authors.affiliation: *Division of Gastroenterology, Massachusetts General Hospital, Boston, Massachusetts; †Harvard Medical School, Boston, Massachusetts; ‡Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, Massachusetts; and §Broad Institute, Cambridge, Massachusetts.
authors.forename: Ashwin N
authors.initials: AN
authors.lastname: Ananthakrishnan
authors.forename: Deanna D
authors.initials: DD
authors.lastname: Nguyen
authors.forename: Jenny
authors.initials: J
authors.lastname: Sauk
authors.forename: Vijay
authors.initials: V
authors.lastname: Yajnik
authors.forename: Ramnik J
authors.initials: RJ
authors.lastname: Xavier
mesh_terms: D000293:Adolescent; D000328:Adult; D015415:Biomarkers / Q000032:analysis*; D016022:Case-Control Studies; D003093:Colitis, Ulcerative / Q000201:enzymology / Q000209:etiology* / Q000473:pathology; D003424:Crohn Disease / Q000201:enzymology / Q000209:etiology* / Q000473:pathology; D065637:Cytochrome P-450 CYP2A6 / Q000235:genetics; D005260:Female; D005500:Follow-Up Studies; D020022:Genetic Predisposition to Disease; D051549:Glutathione S-Transferase pi / Q000235:genetics; D005982:Glutathione Transferase / Q000235:genetics; D051547:Heme Oxygenase-1 / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000235:genetics; D011110:Polymorphism, Genetic / Q000235:genetics*; D011379:Prognosis; D011446:Prospective Studies; D012307:Risk Factors; D012907:Smoking / Q000009:adverse effects*; D055815:Young Adult
chemical_list: D015415:Biomarkers; D065637:Cytochrome P-450 CYP2A6; D051549:Glutathione S-Transferase pi; D005982:Glutathione Transferase; D051547:Heme Oxygenase-1; D016660:NAD(P)H Dehydrogenase (Quinone); C585710:CYP2A6 protein, human; C447479:NQO1 protein, human; C496556:GSTP1 protein, human