A Common Deletion in the Uridine Diphosphate Glucuronyltransferase (<i>UGT</i>)<i>2B17</i>Gene Is a Strong Determinant of Androgen Excretion in Healthy Pubertal Boys

Juul, Anders; Sørensen, Kaspar; Aksglæde, Lise; Garn, Inger; Meyts, Ewa Rajpert‐De; Hullstein, Ingunn; Hemmersbach, Peter; Ottesen, Anne Marie

doi:10.1210/jc.2008-1984

Cited by 31 publications

(50 citation statements)

References 28 publications

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“…UGT2B gene expression plays an important role in steroid hormone metabolism. For example, when the UGT2B17 gene is not expressed because it is removed by a common polymorphic deletion, the steroid hormone clearance is dramatically influenced (Jakobsson et al 2006; Juul et al 2009). Although the relationship between UGT2B4 expression and steroid hormone metabolism has not been investigated in detail, it is plausible that alterations in UGT2B4 expression levels have profound consequences on steroid hormone levels in human body.…”

Section: Resultsmentioning

confidence: 99%

A signature of balancing selection in the region upstream to the human UGT2B4 gene and implications for breast cancer risk

et al. 2011

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UDP-glucuronosyltransferase 2 family, polypeptide B4 (UGT2B4) is an important metabolizing enzyme involved in the clearance of many xenobiotics and endogenous substrates, especially steroid hormones and bile acids. The HapMap data show that numerous SNPs upstream of UGT2B4 are in near-perfect linkage disequilibrium with each other and occur at intermediate frequency, indicating that this region might contain a target of natural selection. To investigate this possibility, we chose three regions (4.8 kb in total) for resequencing and observed a striking excess of intermediate-frequency alleles that define two major haplotypes separated by many mutation events and with little differentiation across populations, thus suggesting that the variation pattern upstream UGT2B4 is highly unusual and may be the result of balancing selection. We propose that this pattern is due to the maintenance of a regulatory polymorphism involved in the fine tuning of UGT2B4 expression so that heterozygous genotypes result in optimal enzyme levels. Considering the important role of steroid hormones in breast cancer susceptibility, we hypothesized that variation in this region could predispose to breast cancer. To test this hypothesis, we genotyped tag SNP rs13129471 in 1,261 patients and 825 normal women of African ancestry from three populations. The frequency comparison indicated that rs13129471 was significantly associated with breast cancer after adjusting for ethnicity [P = 0.003; heterozygous odds ratio (OR) 1.02, 95% confidence interval (CI) 0.81–1.28; homozygous OR 1.50, 95% CI 1.15–1.95]. Our results provide new insights into UGT2B4 sequence variation and indicate that a signal of natural selection may lead to the identification of disease susceptibility variants.

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Section: Resultsmentioning

confidence: 99%

A signature of balancing selection in the region upstream to the human UGT2B4 gene and implications for breast cancer risk

et al. 2011

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“…UGT2B17 exhibits substantial expression variation within and between populations [22], consistent with the different population prevalence of a ~117kb deletion polymorphism surrounding the UGT2B17 gene [22]. Individuals with UGT2B17 deletion(s) have higher serum testosterone levels (by 15%) [23], and lower urinary testosterone excretion (by ~90%) [24–26]. In addition, the UGT2B17 deletion is associated with a lower urinary testosterone to epitestosterone ratio, which is routinely used to detect testosterone abuse in doping control programs [27, 28].…”

Section: Introductionmentioning

confidence: 93%

Genetic and phenotypic variation in UGT2B17, a testosterone-metabolizing enzyme, is associated with BMI in males

Zhu¹,

Cox

Ahluwalia

et al. 2015

Pharmacogenetics and Genomics

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Objective A number of candidate gene and genome-wide association studies have identified significant associations between single nucleotide polymorphisms, particularly in FTO and MC4R, and body weight. However, the association between copy number variation and body weight is less understood. Anabolic androgenic steroids, such as testosterone, can regulate body weight. In humans, UDP-glucuronosyltransferase 2B17 (UGT2B17) metabolizes testosterone to a metabolite, which is readily excreted in urine. We investigate the association between genetic and phenotypic variation in UGT2B17 and body weight. Methods UGT2B17 deletion was genotyped and in vivo UGT2B17 enzymatic activity (as measured by the 3-hydroxycotinine glucuronide to free 3-hydroxycotinine ratio) was measured in 400 Alaska Native individuals and 540 African Americans. Results In Alaska Native people, UGT2B17 deletion was strongly associated with lower BMI in males (P<0.001), but not in females, consistent with testosterone being a male dominant steroid. The gender specific association between UGT2B17 deletion and lower BMI was also observed in African Americans (P=0.01 in males). In both populations, UGT2B17 deletion was significantly associated with lower measured in vivo UGT2B17 activity. In males, lower in vivo UGT2B17 activity was associated with lower BMI, as observed in the gender specific genotypic association. Conclusion These data suggest that UGT2B17 deletion leads to reduced UGT2B17 activity, and lower BMI in males. This is consistent with the hypothesis that reduced UGT2B17-mediated testosterone excretion results in higher testosterone levels. Future studies could confirm this hypothesis by directly measuring serum testosterone levels.

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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

Molecular Pharmacology

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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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A Common Deletion in the Uridine Diphosphate Glucuronyltransferase (UGT)2B17Gene Is a Strong Determinant of Androgen Excretion in Healthy Pubertal Boys

Abstract: In pubertal boys, a common homozygous deletion in the UGT2B17 gene strongly affected urinary excretion pattern of androgen metabolites but did not influence circulating androgen levels.

Cited by 31 publications

References 28 publications

A signature of balancing selection in the region upstream to the human UGT2B4 gene and implications for breast cancer risk

A signature of balancing selection in the region upstream to the human UGT2B4 gene and implications for breast cancer risk

Genetic and phenotypic variation in UGT2B17, a testosterone-metabolizing enzyme, is associated with BMI in males

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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