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.

Association between UDP‐glucuronosyltransferase 2B7 tagSNPs and breast cancer risk in Chinese females

“…Moreover, the rs13129471 A>G polymorphism of UGT2B4 was significantly associated with breast cancer after adjusting for ethnicity . Scherer et al observed an association between a UGT2B15 polymorphism and increased risk of colorectal cancer. Vidal et al reported African American men who carry the wild‐type functional UGT2B15 gene have an elevated risk of prostate cancer.…”

PharmGKB summary

“…A subsequent study in a larger population validated this potential interaction between ibuprofen use and the PPARG Pro12Ala variant in modifying rectal cancer risk ( P for interaction =0.03) [107]. Other studies in colorectal cancer patients have reported significant interactions between ibuprofen use and genetic variants of CYP2C9 ( CYP2C9 * 2 and * 3 ) [105], SMAD7 (rs4939827 and rs4464148) [104], and UGT2B4 (rs1131878, rs1966151, and rs13119049) [106], but not PTGS2 (rs68946, rs20432, and rs5275) [99]. Studies in men with advanced prostate cancer have suggested that the protective effect of ibuprofen may be modified by the LTA C +80A ( P for interaction =0.008) [102] and PTGS2 rs2745557 ( P for interaction =0.12) [101] variants, but the numbers of ibuprofen users in these studies were relatively small.…”

The role of metabolism (and the microbiome) in defining the clinical efficacy of dietary flavonoids

“…One UGT1A1 SNP (rs887829) exhibited significant association with warfarin use with T -allele carriers requiring higher doses than for individuals with the CC genotype (6.3 compared with 5.2 mg/d, respectively). In a study of 1600 colorectal cancer patients and 2500 unaffected siblings, the variation in 4 UGT genes ( UGT1A3, UGT1A6, UGT2B4 , and UGT2B15 ) modified risk of colorectal cancer either independently of interactively with nonsteroidal anti-inflammatory use (79). Variants in the promoter of the UGT1A1 gene (UGT1A1*28, rs8175347), which result in 5, 7, or 8 repeats instead of 6 thymine-adenine repeats, were associated with decreased UGT1A1 transcription and higher serum bilirubin with increased numbers of thymine-adenine repeats (75, 82).…”