The effect of UGT1A and UGT2B polymorphisms on colorectal cancer risk: Haplotype associations and gene–environment interactions

Abstract

UDP-glucuronosyltransferases (UGTs) play an important role in the phase II metabolism of exogenous and endogenous compounds. As colorectal cancer (CRC) etiology is thought to involve the biotransformation of dietary factors, UGT polymorphisms may affect CRC risk by altering levels of exposure. Genotyping of over 1800 Caucasian subjects was completed to identify the role of genetic variation in nine UGT1A and five UGT2B genes on CRC risk. Unconditional logistic regression and haplotype analyses were conducted to identify associations with CRC risk and potential gene-environment interactions. UGT1A haplotype analysis found that the T-G haplotype in UGT1A10 exon 1 (block 2: rs17864678, rs10929251) decreased colon cancer risk [proximal (OR = 0.28, 95% CI=0.11–0.69), distal (OR = 0.32, 95% CI=0.12–0.91)] and that the C-T-G haplotype in the 3′ region flanking the UGT1A shared exons (block 11: rs7578153, rs10203853, rs6728940) increased CRC risk in males (OR = 2.56, 95% CI=1.10–5.95). A haplotype in UGT2B15 containing a functional variant (rs4148269, K523T) and an intronic SNP (rs6837575) was found to affect rectal cancer risk overall (OR = 2.57, 95% CI=1.21–5.04) and in females (OR = 3.08, 95% CI=1.08–8.74). An interaction was found between high NSAID use and the A-G-T haplotype (block 10: rs6717546, rs1500482, rs7586006) in the UGT1A shared exons that decreased CRC risk. This suggests that UGT genetic variation alters CRC risk differently by anatomical sub-site and gender and that polymorphisms in the UGT1A shared exons may have a regulatory effect on gene expression that allows for the protective effect of NSAIDs on CRC risk.

A novel UGT1 marker associated with better tolerance against irinotecan-induced severe neutropenia in metastatic colorectal cancer patients

“…25 In line with a protective effect conferred by this allele, a second study found an interaction between a haplotype comprising the intergenic marker rs7586006 tightly linked to rs11563250 and frequent NSAID use that significantly decreased colorectal cancer risk. 26 …”

Repression of intestinal transporters and FXR-FGF15 signaling explains bile acids dysregulation in experimental colitis-associated colon cancer

“…Although the overall rate of BA glucuronidation is low in comparison with tauro- and glyco-conjugation, it represents a major form in the urinal and fecal elimination of BAs since BA glucuronides do not undergo enterohepatic circulation [ 30 ]. Moreover, UDP-glucuronosyltransferases that catalyze BA glucuronidation are susceptible to regulation by various pathophysiological factors [ 31 , 32 ]; therefore, it is important to monitor BA glucuronides in the pathological conditions for the intensive understanding of BA dysregulation patterns. To facilitate the process of simultaneous quantification of 28 BAs including the glucuronidation products, a method based on a UFLC-Triple-TOF/MS system was developed and validated.…”

Systematic review: interactions between aspirin, and other nonsteroidal anti‐inflammatory drugs, and polymorphisms in relation to colorectal cancer

“…studies with retrospective collection of data on NSAID use (case–control studies). In total, eight prospective and 21 case–control studies were identified. Tables and S1 show results on interactions between NSAID use and polymorphisms in relation to CRC from prospective and case–control studies respectively.…”

“…Figure shows the search strategy. A new search (May 2014) identified no new studies in PubMed and one case–control study in Embase which was included in Table …”