Association between the UGT1A1 tandem repeat promoter polymorphism and prostate cancer risk. Free

B183

Glucuronidation by UDP-glucuronosyltransferases (UGT) is a major pathway of metabolism of many endogenous and exogenous compounds including steroid hormones and antioxidants such as bilirubin. Glucuronidation increases the hydrophilicity of UGT substrates facilitating excretion of these compounds. An important polymorphism in the promoter of UGT1A1 (UGT1A1*28), resulting in 5, 7 or 8, instead of 6 thymine-adenine (TA) repeats that alters gene expression has been identified. We genotyped 448 prostate cancer cases and 515 age-matched cancer free controls for the UGT1A1*28 polymorphism and used unconditional logistic regression to estimate odds ratios and 95% confidence intervals of association between prostate cancer and genotype. There was a significant difference in the distribution of UGT1A1*28 genotype comparing prostate cancer cases with controls (P<0.009). The three most prevalent UGT1A1*28 genotypes (homozygous 6 TA repeats, homozygous 7 TA repeats and heterozygous 6 and 7 TA repeats) had odds ratios close to unity while the other less common genotypes had lower crude odds ratios. The less common genotypes were grouped for comparison with the more common UGT1A1*28 genotype. When all subjects were considered, compared to individuals with the 6/6, 6/7 or 7/7 genotypes, individuals with the less common genotypes were at significantly reduced risk of prostate cancer after adjusting for age, race, smoking and family history of prostate cancer (odds ratio (OR): 0.44, 95% confidence interval (95% CI): 0.24-0.82). Stratified analyses by race revealed that prevalence of the genotype categories were significantly different in African American controls compared with Caucasian controls (P < 0.001). Among African Americans, there was a 40% reduction in risk of prostate cancer among individuals possessing the variant genotypes compared with those with the common genotypes although statistical significance was attenuated in the multivariate model (OR, 0.60; 95% confidence interval, 0.31-1.17) adjusting for age, smoking packyears and family history. Among the Caucasians, there were only five individuals with the variant genotypes and all were control individuals. These results suggest that the UGT1A1*28 polymorphism may modify risk of prostate cancer.