The Uridine Diphosphate Glucuronosyltransferase 2B15 D85Y and 2B17 Deletion Polymorphisms Predict the Glucuronidation Pattern of Androgens and Fat Mass in Men

Swanson, Charlotte; Mellström, Dan; Lorentzon, Mattias; Vandenput, Liesbeth; Jakobsson, Jenny; Rane, Anders; Karlsson, Magnus K.; Ljunggren, Östen; Smith, Ulf; Eriksson, Ann-Marie; Bélanger, Alain; Labrie, Fernand; Ohlsson, Claes

doi:10.1210/jc.2007-0359

Cited by 58 publications

(51 citation statements)

References 15 publications

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“…We have reported previously from the EMAS cohort associations of the AR exon 1 CAG repeat polymorphism with endocrine and metabolic parameters (23), and of AR exon 1 CAG repeat and other polymorphisms with heel ultrasound parameters (8). Other genes with polymorphisms associated with androgen and/or estrogen levels in men include SHBG (28), CYP17 (29), CYP19A1 (30), 17␤HSD5 (31), and uridine diphosphate glucuronyltransferase 2B7 (UGT2B7) (32), but many potentially important polymorphic influences have apparently not yet been identified.…”

Section: Discussionmentioning

confidence: 99%

Effect of Polymorphisms in Selected Genes Involved in Pituitary-Testicular Function on Reproductive Hormones and Phenotype in Aging Men

Huhtaniemi

Pye

Holliday

et al. 2010

The Journal of Clinical Endocrinology & Metabolism

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, and the European Male Aging Study Group* † Context: Polymorphisms in genes involved in regulation, biosynthesis, metabolism, and actions of testicular sex hormones may influence hormone balance and phenotype of aging men. Objective:We investigated the relationships between polymorphisms in genes related to pituitarytesticular endocrine function and health status. Design and Setting:Using cross-sectional baseline data, we conducted a multinational prospective cohort observational study consisting of a population survey of community-dwelling men.Participants: A total of 2748 men, aged 40 -79 (mean Ϯ SD, 60.2 ϩ 11.2) yr, were randomly recruited from eight European centers. Forty-three polymorphisms were genotyped in the following genes: androgen receptor (AR), estrogen receptor-␣ and -␤ (ESR1 and ESR2), steroid 5␣-reductase type II (SRD5A2), 17␣-hydroxylase/17,20-lyase (CYP17A1), aromatase (CYP19A1), sex hormone-binding globulin (SHBG), LH ␤-subunit (LHB), and LH receptor (LHCGR). Main Outcome Measures:We measured the associations between gene polymorphisms and endocrine, metabolic, and phenotypic parameters related to aging and sex hormone action. Results: Several polymorphisms in SHBG, ESR2, AR, CYP19A1, and LHB were significantly associated with circulating levels of SHBG, LH, total, free, and bioavailable testosterone and estradiol, the LH ϫ testosterone product, and indices of insulin sensitivity. Apart from several previously reported associations between genes affecting estrogen levels and heel ultrasound parameters, no associations existed between polymorphisms and nonhormonal variables (anthropometry, blood lipids, blood pressure, hemoglobin, prostate symptoms, prostate-specific antigen, sexual dysfunction, cognition). Conclusion:In aging men, polymorphisms in genes related to the pituitary-testicular endocrine function significantly influence circulating LH, testosterone, and estradiol levels, but the downstream effects may be too small to influence secondary phenotypic parameters. (J Clin Endocrinol Metab 95:

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Section: Discussionmentioning

confidence: 99%

Effect of Polymorphisms in Selected Genes Involved in Pituitary-Testicular Function on Reproductive Hormones and Phenotype in Aging Men

Huhtaniemi

Pye

Holliday

et al. 2010

The Journal of Clinical Endocrinology & Metabolism

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“…A study investigating the relationship of the UGT2B genes and hormones showed that both the UGT2B15 D85Y polymorphism and the UGT2B17 CNV were associated with serum levels of AAG ( p < 0.001), but not with levels of another steroid glucuronide, 3a-diol-3-glucuronide, in a populationbased cohort of young adult (n = 1068; mean age = 18.9 years) and elderly (n = 1001; mean age = 75.3 years) Swedish men (Swanson et al, 2007). We did not determine 3a-diol-3-glucuronide levels in our study as AAG represents 80% of the combined isoforms of 3a-diol, and thus we felt measuring AAG, which gave a good overall measure of glucorinidation activity.…”

Section: Ugt2b Variants: Aag Levels and Prostate Cancer Riskmentioning

confidence: 98%

“…In addition, a polymorphism in the regulatory region of the UGT2B17 gene has been associated with altered levels of AAG (Hu et al, 2010). While both the UGT2B17 and UGT2B15 polymorphisms are significantly associated with AAG levels in European populations, no observations have been made in individuals of African descent (Hsing, 2001;Swanson et al, 2007;Olsson et al, 2011).…”

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confidence: 99%

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

Grant

Hoyo

Oliver

et al. 2013

Genetic Testing and Molecular Biomarkers

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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.

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“…First described by Murata et al (2003), this deletion, in the homozygous state, leads to substantially reduced levels of urinary testosterone glucuronide (Jakobsson et al, 2006;Juul et al, 2009) and, to a lesser extent, serum androstane-3␣,17␤-diol-17-glucuronide (Swanson et al, 2007). The deletion seems to be a predictor of fat mass and insulin sensitivity in men (Swanson et al, 2007) and is associated with susceptibility for osteoporosis (Yang et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

A Novel Polymorphism in a Forkhead Box A1 (FOXA1) Binding Site of the Human UDP Glucuronosyltransferase 2B17 Gene Modulates Promoter Activity and Is Associated with Altered Levels of Circulating Androstane-3α,17β-diol Glucuronide

Gardner-Stephen²,

Severi³

et al. 2010

Mol Pharmacol

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UDP glucuronosyltransferase 2B17 is present in the prostate, where it catalyzes the addition of glucuronic acid to testosterone and dihydrotestosterone and their metabolites androsterone and androstane-3␣,17␤-diol. Hence, changes in UGT2B17 gene expression may affect the capacity of the prostate to inactivate and eliminate male sex hormones. In this work, we identify a prevalent polymorphism, Ϫ155G/A, in the proximal promoter of the UGT2B17 gene. This polymorphism modulates UGT2B17 promoter activity, because luciferasegene reporter constructs containing the Ϫ155A allele were 13-fold more active than those containing the Ϫ155G allele in prostate cancer LNCaP cells. The Ϫ155G/A polymorphism is contained within a putative binding site for the transcription factor Forkhead Box A1 (FOXA1). Using gene reporter, electromobility shift, and chromatin immunoprecipitation analyses, we show that FOXA1 binds to this site and stimulates the UGT2B17 promoter. Furthermore, down-regulation of FOXA1 in LNCaP cells substantially reduces UGT2B17 mRNA levels. The binding of FOXA1 and subsequent stimulation of the UGT2B17 promoter is greatly reduced in the presence of the Ϫ155G allele compared with the Ϫ155A allele. Consonant with its capacity to be stimulated by FOXA1, the UGT2B17 Ϫ155A allele, compared with the Ϫ155G allele, is associated with higher levels of circulating androstane-3␣,17␤-diol glucuronide. Although the initial phases of prostate cancer are androgen-dependent and UGT2B17 inactivates androgens, there was no association of the UGT2B17 Ϫ155G/A polymorphism with prostate cancer risk. In summary, this work identifies FOXA1 as an important regulator of UGT2B17 expression in prostate cancer LNCaP cells and identifies a polymorphism that alters this regulation.

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The Uridine Diphosphate Glucuronosyltransferase 2B15 D85Y and 2B17 Deletion Polymorphisms Predict the Glucuronidation Pattern of Androgens and Fat Mass in Men

Cited by 58 publications

References 15 publications

Effect of Polymorphisms in Selected Genes Involved in Pituitary-Testicular Function on Reproductive Hormones and Phenotype in Aging Men

Effect of Polymorphisms in Selected Genes Involved in Pituitary-Testicular Function on Reproductive Hormones and Phenotype in Aging Men

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

A Novel Polymorphism in a Forkhead Box A1 (FOXA1) Binding Site of the Human UDP Glucuronosyltransferase 2B17 Gene Modulates Promoter Activity and Is Associated with Altered Levels of Circulating Androstane-3α,17β-diol Glucuronide

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