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Genetic variation in UGT genes modify the associations of NSAIDs with risk of colorectal cancer: Colon cancer family registry
Author(s) -
Scherer Dominique,
Koepl Lisel M.,
Poole Elizabeth M.,
Balavarca Yesilda,
Xiao Liren,
Baron John A.,
Hsu Li,
Coghill Anna E.,
Campbell Peter T.,
Kleinstein Sarah E.,
Figueiredo Jane C.,
Lampe Johanna W.,
Buck Katharina,
Potter John D.,
Kulmacz Richard J.,
Jenkins Mark A.,
Hopper John L.,
Win Aung K.,
Newcomb Polly A.,
Ulrich Cornelia M.,
Makar Karen W.
Publication year - 2014
Publication title -
genes, chromosomes and cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.754
H-Index - 119
eISSN - 1098-2264
pISSN - 1045-2257
DOI - 10.1002/gcc.22167
Subject(s) - colorectal cancer , medicine , genotype , single nucleotide polymorphism , snp , cyp2c9 , pharmacogenetics , cancer , oncology , aspirin , cyp3a5 , cytochrome p450 , endocrinology , gene , genetics , biology , metabolism
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.