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

Citation
Nm. Makridakis et al., Association of mis-sense substitution in SRD5A2 gene with prostate cancer in African-American and Hispanic men in Los Angeles, USA, LANCET, 354(9183), 1999, pp. 975-978
Citations number
24
Categorie Soggetti
General & Internal Medicine","Medical Research General Topics
Journal title
LANCET
ISSN journal
01406736 → ACNP
Volume
354
Issue
9183
Year of publication
1999
Pages
975 - 978
Database
ISI
SICI code
0140-6736(19990918)354:9183<975:AOMSIS>2.0.ZU;2-C
Abstract
Background Prostate cancer is a very common disease in more-developed count ries, but its cause is largely unknown. It is an androgen-dependent cancer, and androgens have been proposed as having a substantial role in predispos ition to the disease. Thus, variations in androgen metabolism genes may aff ect 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 C ohort Study) for a mis-sense substitution in the human prostatic (or type I I) steroid 5 alpha-reductase (SRD5A2) gene, the product of which controls m etabolic 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, a nd overexpressed the enzyme in mammalian tissue culture cells, Findings The A49T aminoacid substitution in the SRD5A2 gene increased the r isk 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 V-max than the normal enzyme (9.9 vs 1.9 nmol min(-1) mg(-1)). Interpretation The A49T variant of the SRD5A2 gene may be a significant con tributor to the incidence of prostate cancer in African-American and Hispan ic men in Los Angeles. We estimate that the population attributable risk du e to this aminoacid substitution for clinically significant disease is abou t 8% in both populations. Increased conversion of testosterone to dihydrote stosterone catalysed by this variant steroid 5 alpha-reductase enzyme may b e the cause of the increased risk.