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

Abstract

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.

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

“…Interestingly, relative proportions of AG and EtioG to all metabolites ( Figure 2) were marginally different from their proportion at baseline; however the proportion of TG (baseline vs. treated) to all metabolites differs significantly. Although genotype data were not available to us in this study, high interindividual variability (Supplementary Tables S12 and S13) in TG PK profiles was consistent with polymorphic nature of UGT2B17 17…”

“…PK profiles was consistent with polymorphic nature of UGT2B17. 17 Although AED can also be biosynthesized from dehydroepiandrosterone (DHEA) by 3α-HSD, 39 testosterone to AED via 17β-HSD2 was observed as the major testosterone metabolic pathway, which subsequently metabolized to the major metabolites, AG and EtioG. These data are corroborated by Bhasin et al 40 study, which showed the association of aldo-keto reductase 1C3 (AKR1C3/17β-HSD5) polymorphism (rs12529) with variable testosterone circulating levels in men.…”

“…This is supported with controversial association of UGT2B17 with testosterone‐related pathophysiological conditions, prostate cancer 44. That is, whereas some studies support association of UGT2B17 gene deletion with prostate cancer,18 a recent large study failed to confirm the same,40 perhaps due to high variability in UGT2B17 17, 45. Particularly, we recently demonstrated that UGT2B17 is associated with single nucleotide polymorphism (rs7436962, rs9996186, rs28374627, and rs4860305), age, and gender besides gene deletion 36…”

“…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.…”

New insights into the risk of phthalates: Inhibition of UDP-glucuronosyltransferases

“…UGT1A3 can conjugate the bile acids (Erichsen et al, 2010). UGT2B17 is involved in the metabolism of testosterone (Zhu et al, 2015). Therefore, the inhibition of UGTs’ activity might significantly disrupt the metabolism of xenobiotics and endogenous compounds.…”