The Association between Polymorphisms in the CYP17 and 5a- Reductase (SRD5A2) Genes and Serum Androgen Concentrations in Men

Prospective studies suggest that prostate cancer risk may be increased in association with high serum concentrations of free testosterone and androstanediol glucuronide (A-diol-g). Polymorphisms have been identified in the 17-hydroxylase cytochrome P450 gene (CYP17) and the steroid 5a-reductase type II gene (SRD5A2), two genes that are involved in the biosynthesis and metabolism of androgens in men. The CYP17 MspA1 I polymorphism has been associated with increased prostate cancer risk, and the SRD5A2 V89L polymorphism has been associated with low A-diol-g in Asian men, a serum marker of 5a-reductase activity. The purpose of this study was to investigate the association between these two polymorphisms and serum sex hormone concentrations in 621 British men. In particular, we wanted to test the hypotheses that the A2 allele in the CYP17 gene is associated with increased serum testosterone concentrations, and the L allele in the SRD5A2 gene is associated with reduced A-diol-g concentrations. Mean hormone concentrations were evaluated in each genotype and adjusted for age and other relevant factors. We found no evidence that the CYP17 MspA1 I polymorphism was associated with higher testosterone levels. The L/L genotype of the SRD5A2 V89L polymorphism was associated with a 10% lower A-diol-g concentration, but this was not significant at the 5% level. However, the L/L genotype of the V89L polymorphism was associated with significantly lower concentrations of testosterone and free testosterone (by 12% and 16%, respectively) and an 8% higher sex hormone-binding globulin concentration. These results suggest that the CYP17 MspA1 I polymorphism is not associated with testosterone concentrations and that the SRD5A2 V89L polymorphism is not a strong determinant of A-diol-g concentration in Caucasian men. Introduction Testosterone and its metabolite DHT are crucial for the growth and development of the prostate gland (1). Prospective studies suggest that prostate cancer risk may be increased in association with high serum concentrations of bioavailable testosterone (2) and A-diol-g, a serum marker of 5a-reductase activity and intraprostatic DHT (3). Little is known about the determinants of circulating concentrations of sex hormones and their related proteins in men other than age, body mass index (4, 5), and ethnicity (6, 7). Genetic polymorphisms that encode for key enzymes involved in androgen biosynthesis and metabolism have been of much epidemiological interest in their relation to hormone-dependent cancer risk (8–11). However, their role in determining endogenous hormone concentrations has been little studied. The cytochrome P450c17a (CYP17) gene, located on chromosome 10q24.3, codes for the cytochrome P450c17a enzyme, which catalyzes 17a-hydroxylase and 17,20-lyase activity at key points in steroid hormone biosynthesis in both sexes. A T to C transition has been described in the 59 untranslated region that creates an additional Sp-1 type (CCACC) motif and a MspA1 I restriction enzyme site (12). Although the effect of this base change on gene expression is unknown, the variant C allele (designated A2) might result in increased transcriptional activity and, hence, increased biosynthesis of testosterone (12). The A2 allele has been associated with male pattern baldness in men and polycystic ovarian syndrome in women (12), conditions that are associated with high androgen concentrations. The A2 allele has been associated with an increased prostate cancer risk in Caucasian men (9, 10), although not all of the studies have found this (11). The A2 allele has also been associated with elevated levels of estradiol, an important conversion product of the P450c17a enzyme in women (13, 14), although the evidence that this polymorphism affects breast cancer risk is also conflicting (8, 14–16). The 5a-reductase type II (SRD5A2) gene, located on chromosome 2p23, encodes the enzyme that catalyzes the irreversible conversion of testosterone to DHT within prostatic cells. Received 4/5/00; revised 12/8/00; accepted 12/15/00. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. 1 Supported by the Imperial Cancer Research Fund and by the Europe Against Cancer Program of the Commission of the European Communities. 2 To whom requests for reprints should be addressed, at Imperial Cancer Research Fund Cancer Epidemiology Unit, Gibson Building, Radcliffe Infirmary, Woodstock Road, Oxford, OX2 6HE, United Kingdom. Phone: 01865-311933; Fax: 01865-301545; E-mail: [email protected]. 3 Present address: Imperial Cancer Research Fund Cancer Epidemiology Unit, Gibson Building, Radcliffe Infirmary, Woodstock Road, Oxford, OX2 6HE, United Kingdom. 4 Present Address: Imperial Cancer Research Fund Genetic Epidemiology Laboratory, Cancer Genetics Building, St. James’s University Hospital, Leeds, LS9 7TF, United Kingdom. 5 The abbreviations used are: DHT, dihydrotestosterone; A-diol-g, androstanediol glucuronide; EPIC, European Prospective Investigation into Cancer and Nutrition; SHBG, sex hormone-binding globulin; LH, luteinizing hormone; FT, free testosterone; ANCOVA, analysis of covariance. 185 Vol. 10, 185–189, March 2001 Cancer Epidemiology, Biomarkers & Prevention on October 28, 2017. © 2001 American Association for Cancer Research. cebp.aacrjournals.org Downloaded from The SRD5A2 V89L polymorphism is caused by a G to C transversion that results in the substitution of valine for leucine at codon 89 (denoted the L allele). The distribution of the polymorphism appears to parallel prostate cancer risk between different ethnic groups, with Caucasian and African-American men having a low prevalence of the L allele (24% and 22%, respectively), compared with a prevalence of 46% among Asian men (17). The L/L genotype was associated with a significantly lower mean serum A-diol-g concentration within the Asian men, suggesting that the L allele may reduce 5a-reductase activity (17). However, this polymorphism has not been found to be significantly associated with prostate cancer risk among Caucasian men (9, 18). This study aimed to investigate the association between these two genetic polymorphisms and serum concentrations of sex hormones and their related proteins in a large group of Caucasian men. In particular, we sought to test the hypotheses that the CYP17 A2 allele is associated with elevated serum testosterone concentrations and that the SRD5A2 L allele is associated with decreased A-diol-g concentrations. Materials and Methods