title: Genetic variation of genes involved in dihydrotestosterone metabolism and the risk of prostate cancer.
abstract: OBJECTIVE
  Dihydrotestosterone (DHT) is an important factor in prostate cancer (PCA) genesis and disease progression. Given PCA's strong genetic component, we evaluated the possibility that variation in genes involved in DHT metabolism influence PCA risk.
  
  
  METHODS
  We investigated copy number variants (CNV) and single nucleotide polymorphisms (SNP). We explored associations between CNV of uridine diphospho-glucuronosyltransferase (UGT) genes from the 2B subclass, given their prostate specificity and/or involvement in steroid metabolism and PCA risk. We also investigated associations between SNPs in genes (HSD3B1, SRD5A1/2, and AKR1C2) involved in the conversion of testosterone to DHT, and in DHT metabolism and PCA risk. The population consisted of 426 men (205 controls and 221 cases) who underwent prostate-specific antigen screening as part of a PCA early detection program in Tyrol, Austria.
  
  
  RESULTS
  No association between CNV in UGT2B17 and UGT2B28 and PCA risk was identified. Men carrying the AA genotype at SNP rs6428830 (HSD3B1) had an odds ratio (OR) of 2.0 [95% confidence intervals (95% CI), 1.1-4.1] compared with men with GG, and men with AG or GG versus AA in rs1691053 (SRD5A1) had an OR of 1.8 (95% CI, 1.04-3.13). Individuals carrying both risk alleles had an OR of 3.1 (95% CI, 1.4-6.7) when compared with men carrying neither (P = 0.005). Controls with the AA genotype on rs7594951 (SRD5A2) tended toward higher serum DHT levels (P = 0.03).
  
  
  CONCLUSIONS
  This is the first study to implicate the 5alpha-reductase isoform 1 (SRD5A1) and PCA risk, supporting the rationale of blocking enzymatic activity of both isoforms of 5alpha-reductase for PCA chemoprevention.
authors.affiliation: Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Sunita R
authors.initials: SR
authors.lastname: Setlur
authors.forename: Chen X
authors.initials: CX
authors.lastname: Chen
authors.forename: Ruhella R
authors.initials: RR
authors.lastname: Hossain
authors.forename: Jung Sook
authors.initials: JS
authors.lastname: Ha
authors.forename: Vanessa E
authors.initials: VE
authors.lastname: Van Doren
authors.forename: Birgit
authors.initials: B
authors.lastname: Stenzel
authors.forename: Eberhard
authors.initials: E
authors.lastname: Steiner
authors.forename: Derek
authors.initials: D
authors.lastname: Oldridge
authors.forename: Naoki
authors.initials: N
authors.lastname: Kitabayashi
authors.forename: Samprit
authors.initials: S
authors.lastname: Banerjee
authors.forename: Jin Yun
authors.initials: JY
authors.lastname: Chen
authors.forename: Georg
authors.initials: G
authors.lastname: Schäfer
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Horninger
authors.forename: Charles
authors.initials: C
authors.lastname: Lee
authors.forename: Mark A
authors.initials: MA
authors.lastname: Rubin
authors.forename: Helmut
authors.initials: H
authors.lastname: Klocker
authors.forename: Francesca
authors.initials: F
authors.lastname: Demichelis
mesh_terms: D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase / Q000235:genetics; D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D013196:Dihydrotestosterone / Q000378:metabolism*; D018628:Gene Dosage; D020022:Genetic Predisposition to Disease; D005838:Genotype; D014453:Glucuronosyltransferase / Q000235:genetics; D006801:Humans; D006913:Hydroxysteroid Dehydrogenases / Q000235:genetics; D008297:Male; D008875:Middle Aged; D015778:Minor Histocompatibility Antigens; D020641:Polymorphism, Single Nucleotide; D017430:Prostate-Specific Antigen / Q000097:blood; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism; D012307:Risk Factors; D013739:Testosterone / Q000378:metabolism; D045002:3-alpha-Hydroxysteroid Dehydrogenase (B-Specific)
chemical_list: D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase; D014408:Biomarkers, Tumor; D004268:DNA-Binding Proteins; D013196:Dihydrotestosterone; D014453:Glucuronosyltransferase; D006913:Hydroxysteroid Dehydrogenases; D015778:Minor Histocompatibility Antigens; D017430:Prostate-Specific Antigen; D013739:Testosterone; C482323:SPATA7 protein, human; C435496:AKR1C2 protein, human; D045002:3-alpha-Hydroxysteroid Dehydrogenase (B-Specific); C428927:UDP-glucuronosyltransferase, UGT2B28; C500513:UGT2B17 protein, human