Impact of constitutional genetic variation in androgen/oestrogen-regulating genes on age-related changes in human prostate.
OBJECTIVE
Benign prostatic hyperplasia (BPH) is the most common benign tumour in ageing men. While the etiopathology remains unsolved, a disruption in the endocrine/autocrine-paracrine prostatic homeostasis, involving steroid hormones, contributes to the pathogenesis of BPH. DNA polymorphisms in genes involved in hormone synthesis, signalling and metabolism may, therefore, be responsible for these changes. We have evaluated the correlation between specific genotypes in androgen- and oestrogen-regulating genes (AR, SRD5A2, CYP17 and CYP19), and age-related prostatic changes.


METHODS
We have tested genetic susceptibility to morphological and pathological criteria in 195 French Caucasians, using allelic variants for candidate genes involved in androgen/oestrogen prostatic activity: androgen receptor (CAG repeats), 5alpha-reductase type 2 (TA repeats, V89L and A49T mutations), A2 variant of the 17alpha-hydroxylase (CYP17) and the simple tandem repeat polymorphism (STRP) aromatase (CYP19) polymorphisms.


RESULTS
The A2 variant of 17alpha-hydroxylase (CYP17) and allele 191 of STRP aromatase (CYP19) showed an opposite effect on age-related prostate hyperplasia: CYP17 being associated with increased risk of prostate enlargement and CYP19 with reduced risk. The 5alpha-reductase type II variants studied did not show links with prostate hyperplasia. The androgen receptor gene CAG repeat length showed a low correlation with the increase of prostate weight, suggesting some effect on age-related prostate growth.


CONCLUSIONS
These results suggested that common variants of the CYP17 gene are associated with prostate enlargement and therefore may increase the risk of development of BPH in this population, while infrequent variants of the aromatase gene (CYP19) could be of a protective nature.
Azzouzi
Abdel-Rahmene
AR
CeRePP-EA3104, Universite Paris VII, Genopole, 4 rue Pierre Fontaine, Evry F-91000, France.
Cochand-Priollet
Beatrix
B
Mangin
Philippe
P
Fournier
Georges
G
Berthon
Philippe
P
Latil
Alain
A
Cussenot
Olivier
O
D000728:Androgens / Q000378:metabolism; D001141:Aromatase / Q000235:genetics*; D042944:Cholestenone 5 alpha-Reductase; D004967:Estrogens / Q000378:metabolism; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D008297:Male; D010088:Oxidoreductases / Q000235:genetics*; D010641:Phenotype; D011467:Prostate / Q000378:metabolism; D011470:Prostatic Hyperplasia / Q000235:genetics* / Q000378:metabolism; D011944:Receptors, Androgen / Q000235:genetics*; D013254:Steroid 17-alpha-Hydroxylase / Q000235:genetics*; D018911:Trinucleotide Repeats
D000728:Androgens; D004967:Estrogens; D011944:Receptors, Androgen; D010088:Oxidoreductases; D001141:Aromatase; D013254:Steroid 17-alpha-Hydroxylase; D042944:Cholestenone 5 alpha-Reductase