Elsevier

The Lancet

Volume 354, Issue 9183, 18 September 1999, Pages 975-978
The Lancet

Articles
Association of mis-sense substitution in SRD5A2 gene with prostate cancer in African-American and Hispanic men in Los Angeles, USA

https://doi.org/10.1016/S0140-6736(98)11282-5Get rights and content

Summary

Background

Prostate cancer is a very common disease in more-developed countries; but its cause is largely unknown. It is an androgen-dependent cancer, and androgens have been proposed as having a substantial role in predisposition to the disease. Thus, variations in androgen metabolism genes may affect risk of this disease.

Methods

We screened 216 African-American and 172 Hispanic men with prostate cancer, and 261 African-American and 200 Hispanic healthy men (controls), from a large prospective cohort study (the Hawaii-Los Angeles Multiethnic Cohort Study) for a mis-sense substitution in the human prostatic (or type II) steroid 5α-reductase (SRD5A2) gene, the product of which controls metabolic activation of testosterone to dihydrotestosterone. This mis-sense substitution results in an alanine residue at codon 49 being replaced with threonine (A49T). We also reconstructed this mutation in the SRD5A2 cDNA, and overexpressed the enzyme in mammalian tissue culture cells.

Findings

The A49T aminoacid substitution in the SRD5A2 gene increased the risk of clinically significant disease 7–2-fold in African-American men (95% CI=2·17–27·91; p=0·001) and 3·6-fold in Hispanic men (1·09–12·27; p=0·04). The mutant enzyme had a higher in-vitro Vmax than the normal enzyme (9·9 vs 1·9 nmol min−1 mg−1).

Interpretation

The A49T variant of the SRD5A2 gene maybe a significant contributor to the incidence of prostate cancer in African-American and Hispanic men in Los Angeles. We estimate that the population attributable risk due to this aminoacid substitution for clinically significant disease is about 8% in both populations. Increased conversion of testosterone to dihydrotestosterone catalysed by this variant steroid 5α-reductase enzyme may be the cause of the increased risk.

Introduction

Prostate cancer is a very common disease in more-developed countries: more than 39200 men died of the disease in the USA in 1998,1 and 50122 died in the European Union in 1990.2 Prostate cancer is androgen dependent,3, 4 and we have previously proposed that variations in androgen metabolism may affect a man's risk of this disease.4, 6 We have provided evidence that increased intraprostatic androgen metabolism, particularly through the enzyme steroid 5α-reductase, may have an important role in predisposition to prostate cancer. This enzyme catalyses the conversion of testosterone to dihydrotestosterone-the most potent androgen in the prostate. Thus, genetic variants encoded by the steroid 5α-reductase gene (SRD5A2) may have an effect on predisposition to prostate cancer. We report our epidemiological and biochemical findings on the relation between prostate cancer and a constitutional (germline) mis-sense substitution in SRD5A2, which results in the replacement of an alanine residue at codon 49 with threonine (A49T).7 This substitution is associated with a significantly increased risk of prostate cancer (particularly of an advanced nature), probably through increased metabolic activation of testosterone to dihydrotestosterone.

Section snippets

Epidemiology

This case-control study was part of the prospective Hawaii-Los Angeles Multiethnic Cohort Study of Diet and Cancer, which has been described in detail elsewhere.8 About 200000 African-American, Japanese-American, Hispanic, and white individuals between the ages of 45 and 75 years are being followed up for incident cancer diagnoses, primarily through linkage with the population-based Surveillance, Epidemiology and End Results cancer registries for Hawaii and Los Angeles County, USA. Data on

Results

The mean age of the controls was 63·6 years, compared with 68·9 years for the cases. The cases and controls did not differ with respect to education level. The racial/ethnic distribution of the study population is presented in table 1.

The A49T mis-sense substitution was uncommon in healthy African-American and Hispanic men in Los Angeles: we found an allele frequency of 1·0% (five of 522) in African-American controls and 2·3% (nine of 400) in Hispanic controls (table 2).

In African-American men

Discussion

We have investigated the relation between three polymorphisms in the SRD5A2 gene and risk of prostate cancer in the cohort described. The first, a (TA)n dinucleotide repeat in the 3′ untranslated region,16 was originally described by Davis and Russell.17 We found differences in the distribution of (TA)n alleles in different racial/ethnic control groups,16 and preliminary case-control study results suggested a weak association between long repeats and risk of prostate cancer. However, we have

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