TY - JOUR
T1 - The effect of UGT1A and UGT2B polymorphisms on colorectal cancer risk
T2 - Haplotype associations and gene-environment interactions
AU - Angstadt, Andrea Y.
AU - Hartman, Terryl J.
AU - Lesko, Samuel M.
AU - Muscat, Joshua E.
AU - Zhu, Junjia
AU - Gallagher, Carla J.
AU - Lazarus, Philip
PY - 2014/6
Y1 - 2014/6
N2 - 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 cancer risk for the colon [proximal (OR=0.28, 95% CI=0.11-0.69) and for the distal colon (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.
AB - 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 cancer risk for the colon [proximal (OR=0.28, 95% CI=0.11-0.69) and for the distal colon (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.
UR - http://www.scopus.com/inward/record.url?scp=84897522332&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84897522332&partnerID=8YFLogxK
U2 - 10.1002/gcc.22157
DO - 10.1002/gcc.22157
M3 - Article
C2 - 24822274
AN - SCOPUS:84897522332
SN - 1045-2257
VL - 53
SP - 454
EP - 466
JO - Genes Chromosomes and Cancer
JF - Genes Chromosomes and Cancer
IS - 6
ER -