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

Abstract

Aims: Uridine diphosphate-glucuronosyltransferase 2B (UGT2B) enzymes conjugate testosterone metabolites to enable their excretion in humans. The functional significance of the UGT2B genetic variants has never been described in humans. We evaluated UGT2B variants in relation to plasma androstane-3a,17b-diol-glucuronide (AAG) levels and the prostate cancer risk. Results: AAG levels were measured in sera from 150 controls and compared to the polymorphisms of UGT2B17, UGT2B15, and UGT2B7. Genomic DNA from controls (301) and cases (148) was genotyped for the polymorphisms, and odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated using unconditional logistic regression analyses. Having two copies of UGT2B17 was associated with higher AAG levels in controls among Whites ( p = 0.02), but not Blacks ( p = 0.82). Logistic regression models adjusting for age and race revealed that homozygosity for the G allele of the UGT2B15 D85Y polymorphism was directly associated with the prostate cancer risk (OR = 2.70, 95% CI = 1.28, 5.55). Conclusions: While the small sample size limits inference, our findings suggest that an association between the UGT2B17 copy number variant (CNV) and serum AAG levels in Whites, but unexpectedly not in Blacks. This novel observation suggests that genetic determinants of AAG levels in Blacks are unrelated to the UGT2B17 CNV. This study replicates the results that show an association of UGT215 D85Y with an increased prostate cancer risk.

Nuclear Receptor Corepressor 1 Expression and Output Declines with Prostate Cancer Progression

“…PCDH11Y mRNA in normal prostates, primary prostate tumors, and untreated PCa is low but increases significantly in CRPC (29), consistent with a negative correlation between NCOR1 and PCDH11Y observed in LNCaP cells. AR-repressed genes, UGT2B15 and UGT2B17, cause DHT conjugation and excretion (28, 37) and are associated with prostate cancer risk (38, 39). We show that NCOR1 is required for optimal UGT2B15 expression under all conditions, while for UGT2B17 expression of NCOR1 was required only in the presence of androgens.…”

Novel associations of UDP-glucuronosyltransferase 2B gene variants with prostate cancer risk in a multiethnic study

“…Comparison of two studies with different sample sizes revealed contradictory results: no associations between SNP UGT2B15 D85Y and prostate cancer risk were found in a study with a large sample size [9], whereas a study with a smaller sample size found an increased risk of prostate cancer associated with the UGT2B15 D85Y variant in Caucasian subjects [32]. In reference to allele dosage, we previously concluded [33], concordant with previous reports [31,32,39], that homozygous carriers of the dominant UGT2B15 D85Y (G) allele missense polymorphism, (rs1902023), had an almost three-fold higher risk of prostate cancer. Our current results further confirm that associations with UGT2B15 polymorphisms are allele dose-dependent and may also be dependent on race/ethnicity.…”

Androgen Glucuronidation: An Unexpected Target for Androgen Deprivation Therapy, with Prognosis and Diagnostic Implications

“…Experimental inhibition of these enzymes significantly improves the proproliferative properties of DHT in prostate cancer cells (14), suggesting that they are major determinants for the androgen response. Accordingly, positive associations were reported between prostate cancer risk and a low-activity UGT2B15 allele or a complete UGT2B17 gene deletion (15)(16)(17)(18)(19). On the other hand, various studies illustrated the negative control that androgens exert on UGT2B15 and UGT2B17 expression in prostate cancer cells (14,20,21).…”