Deletion polymorphism of the UGT2B17 gene is associated with increased risk for prostate cancer and correlated to gene expression in the prostate

Abstract

Metabolism of androgens includes glucuronidation, the major pathway of steroid elimination in several steroid target tissues. Glucuronidation is catalysed by UDP-glucuronosyltransferases (UGTs). UGT2B17 has been shown to be particularly active against androgens and is highly abundant in the prostate. Recently, we discovered that deletion of the UGT2B17 gene is associated with low or undetectable urinary testosterone levels. Here, we determined the phenotypic outcome of the deletion by quantifying the UGT2B17 mRNA expression in normal prostate tissues in individuals with different genotypes. Additionally, the frequency of UGT2B17 deletion polymorphism was studied in a Swedish population-based case-control study including 176 patients diagnosed with prostate cancer and 161 controls. We found that the individuals homozygous for the insertion allele expressed 30 times more UGT2B17 mRNA in prostate tissue than the heterozygotes. Carriers of the deletion allele had a significantly increased risk of prostate cancer (OR ¼ 2.07; 95% CI ¼ 1.32-3.25). In conclusion, these results show the UGT2B17 deletion polymorphism is associated with prostate cancer risk.

Association of Uridine Diphosphate-Glucuronosyltransferase 2B Gene Variants with Serum Glucuronide Levels and Prostate Cancer Risk

“…We showed no association with prostate cancer risk consistent with some previous reports (Gallagher et al, 2007;Olsson et al, 2008;Setlur et al, 2010). However, other studies reported that individuals homozygous for the UGT2B17 deletion were at increased risk for prostate cancer, while a report showed that only carriers of the UGT2B17 deletion had increased risk (Park et al, 2006(Park et al, , 2007Karypidis et al, 2007). These differences across studies could be the result of interindividual variability in the UGT2B gene expression and haplotype structure of the UGT2B genes within each study population (Izukawa et al, 2009;Menard et al, 2009).…”

“…The association of the UGT2B15 D85Y polymorphism with prostate cancer has been examined with conflicting results (MacLeod et al, 2000;Gsur et al, 2002;Hajdinjak and Zagradisnik, 2004;Park et al, 2004;Cunningham et al, 2007). Similarly, numerous studies have explored the association of the UGT2B17 CNV and prostate cancer also with inconsistent conclusions (Park et al, 2006(Park et al, , 2007Gallagher et al, 2007;Karypidis et al, 2007;Olsson et al, 2008;Setlur et al, 2010). Some of the inconsistencies in these findings could be explained by differences in the composition of the study participants.…”

A population-based study of copy number variants and regions of homozygosity in healthy Swedish individuals

“…Besides these phase II metabolizing enzymes, several disease-associated genes were also found to overlap with these CNPs, such as the FCG receptor genes (autoimmune or inflammatory diseases), 30 TP63 31 and WWOX 26 (lung adenocarcinoma, gastric, pancreatic and other cancers), CFHR3 and CFHR1 (age-related macular degeneration), 32 UGT2B17 (prostate cancer and graft-versus-host disease), 33,34 Abbreviations: CNPs, copy number polymorphisms; UCSC, University of California Santa Cruz genes.…”

Effect of Dose and 5α‐Reductase Inhibition on the Circulating Testosterone Metabolite Profile of Men Administered Oral Testosterone

“…In particular, UGT2B17 is the major testosterone‐glucuronidation enzyme. UGT2B17 is of interest as it is highly polymorphic and copy number variations in its genes are associated with multiple potentially testosterone related pathologies (e.g., obesity,17 prostate cancer,18 osteoporosis,19 ankylosing spondylitis,20 and endometrial cancer) 21. UGT2B17 is highly expressed in the intestines and the liver 22, 23.…”