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Influence of Crohn's Disease Risk Alleles and Smoking on Disease Location

Chen, Hongyan M.S.5; Lee, Alexander M.D.1; Bowcock, Anne Ph.D.2; Zhu, Wei Ph.D.5; Li, Ellen M.D., Ph.D.1,4; Ciorba, Matthew M.D.1; Hunt, Steven M.D.3

Diseases of the Colon & Rectum: August 2011 - Volume 54 - Issue 8 - pp 1020-1025
doi: 10.1007/DCR.0b013e31821b94b3
Original Contribution

OBJECTIVE: Our objective is to assess the effect of genetic and environmental factors on Crohn's disease location.

DESIGN: We identified 628 patients with Crohn's disease within the Washington University database (April 2005 through February 2010) that had complete information on 31 Crohn's disease-associated genotypes and clinical information on disease location (L1 to L4), smoking, sex, race, and age at diagnosis. For statistical reasons, the 3 major NOD2 alleles (rs2066844, rs2066845, and rs2066847) were grouped together. Logistic regression incorporating all of the genotypes and clinical covariates, including smoking, was performed with stepwise variable selection and by best subset selection.

RESULTS: Stepwise variable selection selected 3 major covariates, composite NOD2 genotype, smoking, and TNFSF15 genotype, which are also the 3 covariates selected by the best subset method. Whereas the NOD2 genotype and smoking are positively associated with ileal (L1 + L3) disease, the TNFSF15 genotype is positively associated with isolated colonic (L2) disease.

LIMITATIONS: The ability to detect disease site associations in this single-center study may be limited by the population size, low allelic frequency, and/or low odds ratio of certain Crohn's disease risk alleles.

CONCLUSION: These results indicate that NOD2 genotype, smoking status, and TNFSF15 genotype should be included as covariates in assessing the effect of genetic and environmental factors on Crohn's disease site location.

1Department of Medicine, Washington University School of Medicine, Saint Louis, Missouri

2Department of Genetics, Washington University School of Medicine, Saint Louis, Missouri

3Department of Surgery, Washington University School of Medicine, Saint Louis, Missouri

4Department of Medicine, Stony Brook University, Stony Brook, New York

5Department of Applied Mathematics and Statistics, Stony Brook University, Stony Brook, New York

Funding/Support: This work was supported in part by National Institutes of Health grants UH2 DK grant (to E.L.) and P30 DK 52574, a Senior Research Award from the Crohn's and Colitis Foundation of America (to E.L.), a grant from the Simons Foundation (to E.L.). We acknowledge use of the Washington University Digestive Diseases Research Core Center Tissue Procurement Facility (P30 DK52574) and the Human Genetics Genotyping Core. Dr. Ciorba is a recipient of a Crohn's and Colitis Foundation Career Development Award and DK089016-01. Dr. Lee participated in the Mentors in Medicine Program and the Clinical Science Training and Research Pathway in the Department of Medicine at Washington University.

Presented in part at the meeting of the American Gastroenterology Association, New Orleans, LA, May 1 to 5, 2010.

Correspondence: Steven Hunt, M.D., Department of Surgery, Campus Box 8109, 660 S. Euclid Avenue, Washington University School of Medicine, Saint Louis, MO 63124. E-mail: HUNTS@wudosis.wustl.edu

© The ASCRS 2011