Media type: E-Article Title: The effect of UGT1A and UGT2B polymorphisms on colorectal cancer risk: Haplotype associations and gene–environment interactions Contributor: Angstadt, Andrea Y.; Hartman, Terryl J.; Lesko, Samuel M.; Muscat, Joshua E.; Zhu, Junjia; Gallagher, Carla J.; Lazarus, Philip imprint: Wiley, 2014 Published in: Genes, Chromosomes and Cancer Language: English DOI: 10.1002/gcc.22157 ISSN: 1045-2257; 1098-2264 Origination: Footnote: Description: <jats:p>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 <jats:italic>UGT1A</jats:italic> and five <jats:italic>UGT2B</jats:italic> genes on CRC risk. Unconditional logistic regression and haplotype analyses were conducted to identify associations with CRC risk and potential gene‐environment interactions. <jats:italic>UGT1A</jats:italic> haplotype analysis found that the T‐G haplotype in <jats:italic>UGT1A10</jats:italic> 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 <jats:italic>UGT1A</jats:italic> shared exons (block 11: rs7578153, rs10203853, rs6728940) increased CRC risk in males (OR = 2.56, 95% CI = 1.10–5.95). A haplotype in <jats:italic>UGT2B15</jats:italic> 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 <jats:italic>UGT1A</jats:italic> 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 <jats:italic>UGT1A</jats:italic> shared exons may have a regulatory effect on gene expression that allows for the protective effect of NSAIDs on CRC risk. © 2014 Wiley Periodicals, Inc.</jats:p>