Genetic variation in UGT genes modify the associations of NSAIDs with risk of colorectal cancer: Colon cancer family registry |
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| Authors: | Dominique Scherer Lisel M. Koepl Elizabeth M. Poole Yesilda Balavarca Liren Xiao John A. Baron Li Hsu Anna E. Coghill Peter T. Campbell Sarah E. Kleinstein Jane C. Figueiredo Johanna W. Lampe Katharina Buck John D. Potter Richard J. Kulmacz Mark A. Jenkins John L. Hopper Aung K. Win Polly A. Newcomb Karen W. Makar |
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| Affiliation: | 1. Department of Preventive Oncology, National Center for Tumor Diseases and German Cancer Research Center, Heidelberg, Germany;2. Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA;3. Channing Laboratory, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA;4. Department of Epidemiology, Harvard School of Public Health, Boston, MA;5. University of North Carolina School of Medicine, Chapel Hill;6. Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, NC;7. University of Southern California, Keck School of Medicine, Los Angeles, CA;8. Centre for Public Health Research, Massey University, Wellington, New Zealand;9. University of Texas Health Science Center at Houston, Houston, TX;10. Centre for MEGA Epidemiology, School of Population & Global Health, The University of Melbourne, Melbourne, VIC, Australia |
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| Abstract: | The use of non‐steroidal anti‐inflammatory drugs (NSAIDs) is associated with reduced risk of colorectal neoplasia. Previous studies have reported that polymorphisms in NSAID‐metabolizing enzymes central to NSAID metabolism including UDP‐glucuronosyltransferases (UGT) and cytochrome P450 (CYP) 2C9 may modify this protective effect. We investigated whether 35 functionally relevant polymorphisms within CYP2C9 and UGT genes were associated with colorectal cancer risk or modified the protective effect of NSAIDs on colorectal cancer susceptibility, using 1,584 colorectal cancer cases and 2,516 unaffected sibling controls from the Colon Cancer Family Registry. A three‐SNP genotype in UGT1A6 (G–A–A; Ala7–Thr181–Arg184) and the Asp85 variant in UGT2B15 increased the risk of colorectal cancer (OR 3.87; 95% CI 1.04–14.45 and OR 1.34; 95% CI 1.10–1.63, respectively). We observed interactions between UGT1A3 Thr78Thr (A>G) and NSAID use (P‐interaction = 0.02), a three‐SNP genotype within UGT2B4 and ibuprofen use (P‐interaction = 0.0018), as well as UGT2B15 Tyr85Asp (T>G) and aspirin use (P‐interaction = 0.01). The interaction with the UGT2B4 and the UGT2B15 polymorphisms were noteworthy at the 25% FDR level. This study highlights the need for further pharmacogenetic studies to identify individuals who might benefit from NSAID use as part of developing effective strategies for prevention of colorectal neoplasia. © 2014 Wiley Periodicals, Inc. |
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