title: 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 male individuals (P<0.001), but not in female individuals, consistent with testosterone being a male dominant steroid. The sex-specific association between UGT2B17 deletion and lower BMI was also observed in African Americans (P=0.01 in male individuals). In both populations, UGT2B17 deletion was significantly associated with lower measured in-vivo UGT2B17 activity. In male individuals, lower in-vivo UGT2B17 activity was associated with lower BMI, as observed in the sex-specific genotypic association.
  
  
  CONCLUSIONS
  These data suggest that UGT2B17 deletion leads to reduced UGT2B17 activity, and lower BMI in male individuals. 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.
authors: aDepartment of Pharmacology and Toxicology bDepartment of Psychiatry, Center for Addiction and Mental Health, Campbell Family Mental Health Research Institute, University of Toronto, Toronto, Ontario, Canada cDepartment of Preventive Medicine and Public Health, School of Medicine, University of Kansas, Kansas City, Kansas dDepartment of Medicine and Center for Health Equity, University of Minnesota Medical School eDepartment of Psychiatry, University of Minnesota, Minneapolis, Minnesota fAlaska Native Medical Center, Cardiology Research and Program Development, Anchorage, Alaska gDepartment of Medicine and Bioengineering and Therapeutic Sciences, Division of Clinical Pharmacology and Experimental Therapeutics, University of California, San Francisco, California, USA.
authors: Andy Z X
authors: AZ
authors: Zhu
authors: Lisa S
authors: LS
authors: Cox
authors: Jasjit S
authors: JS
authors: Ahluwalia
authors: Caroline C
authors: CC
authors: Renner
authors: Dorothy K
authors: DK
authors: Hatsukami
authors: Neal L
authors: NL
authors: Benowitz
authors: Rachel F
authors: RF
authors: Tyndale
mesh_terms: D000328:Adult; D001741:Black or African American / Q000235:genetics; D015992:Body Mass Index; D056915:DNA Copy Number Variations / Q000235:genetics*; D005006:Ethnicity / Q000235:genetics; D005260:Female; D017353:Gene Deletion; D056726:Genetic Association Studies; D005838:Genotype; D014453:Glucuronosyltransferase / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007198:Indians, North American / Q000235:genetics; D008297:Male; D008875:Middle Aged; D015778:Minor Histocompatibility Antigens; D009765:Obesity / Q000097:blood / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D013739:Testosterone / Q000235:genetics* / Q000378:metabolism
chemical_list: D015778:Minor Histocompatibility Antigens; D013739:Testosterone; D014453:Glucuronosyltransferase; C500513:UGT2B17 protein, human