Genetic variation of genes involved in dihydrotestosterone metabolism and the risk of prostate cancer.
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.
Setlur
Sunita R
SR
Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
Chen
Chen X
CX
Hossain
Ruhella R
RR
Ha
Jung Sook
JS
Van Doren
Vanessa E
VE
Stenzel
Birgit
B
Steiner
Eberhard
E
Oldridge
Derek
D
Kitabayashi
Naoki
N
Banerjee
Samprit
S
Chen
Jin Yun
JY
Schäfer
Georg
G
Horninger
Wolfgang
W
Lee
Charles
C
Rubin
Mark A
MA
Klocker
Helmut
H
Demichelis
Francesca
F
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)
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