title: Genetic variation in UGT genes modify the associations of NSAIDs with risk of colorectal cancer: colon cancer family registry.
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.
authors.affiliation: Department of Preventive Oncology, National Center for Tumor Diseases and German Cancer Research Center, 69120, Heidelberg, Germany.
authors.forename: Dominique
authors.initials: D
authors.lastname: Scherer
authors.forename: Lisel M
authors.initials: LM
authors.lastname: Koepl
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Poole
authors.forename: Yesilda
authors.initials: Y
authors.lastname: Balavarca
authors.forename: Liren
authors.initials: L
authors.lastname: Xiao
authors.forename: John A
authors.initials: JA
authors.lastname: Baron
authors.forename: Li
authors.initials: L
authors.lastname: Hsu
authors.forename: Anna E
authors.initials: AE
authors.lastname: Coghill
authors.forename: Peter T
authors.initials: PT
authors.lastname: Campbell
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Kleinstein
authors.forename: Jane C
authors.initials: JC
authors.lastname: Figueiredo
authors.forename: Johanna W
authors.initials: JW
authors.lastname: Lampe
authors.forename: Katharina
authors.initials: K
authors.lastname: Buck
authors.forename: John D
authors.initials: JD
authors.lastname: Potter
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Kulmacz
authors.forename: Mark A
authors.initials: MA
authors.lastname: Jenkins
authors.forename: John L
authors.initials: JL
authors.lastname: Hopper
authors.forename: Aung K
authors.initials: AK
authors.lastname: Win
authors.forename: Polly A
authors.initials: PA
authors.lastname: Newcomb
authors.forename: Cornelia M
authors.initials: CM
authors.lastname: Ulrich
authors.forename: Karen W
authors.initials: KW
authors.lastname: Makar
mesh_terms: D000328:Adult; D000368:Aged; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects* / Q000627:therapeutic use; D016022:Case-Control Studies; D015179:Colorectal Neoplasms / Q000209:etiology / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D014453:Glucuronosyltransferase / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012042:Registries; D012306:Risk; D055815:Young Adult
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D014453:Glucuronosyltransferase