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Genetic Polymorphisms in Metabolizing Enzymes Modifying the Association Between Smoking and Inflammatory Bowel Diseases

Ananthakrishnan, Ashwin N. MD, MPH*,†; Nguyen, Deanna D. MD*,†; Sauk, Jenny MD*,†; Yajnik, Vijay MD, PhD*,†; Xavier, Ramnik J. MD, PhD*,†,‡,§

doi: 10.1097/MIB.0000000000000014
Original Basic Science Articles

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.

Article first published online 19 March 2014

*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.

Reprints: Ashwin N. Ananthakrishnan, MD, MPH, Massachusetts General Hospital Crohn's and Colitis Center, 165 Cambridge Street, 9th Floor, Boston, MA 02114 (e-mail: aananthakrishnan@partners.org).

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site (www.ibdjournal.org).

Supported by the National Institutes of Health (NIH) (P30 DK043351) to the Center for Study of Inflammatory Bowel Diseases. A. N. Ananthakrishnan is supported in part by a grant from the NIH (K23 DK097142) and the American College of Gastroenterology. R. J. Xavier is supported by Grants U01 DK062432 and R01 DK064869 from the NIH.

The authors have no conflicts of interest to disclose.

Received January 20, 2014

Accepted January 29, 2014

© Crohn's & Colitis Foundation of America, Inc.
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