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Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland 20852-7234 [A. W. H., A. P. C.]; Fred Hutchinson Cancer Research Center, Seattle, Washington 98109 [C. C., D. A. D.]; Shanghai Cancer Institute, Shanghai, China 200032 [Y-T. G., J. D., J. C.]; Institute for Genetic Medicine, Department of Biochemistry and Molecular Biology, Keck School of Medicine, University of Southern California, Los Angeles, California 90089 [H. T. N., J. K. V. R.]; Armed Forces Institute of Pathology, Washington, D.C. 20306 [I. A. S., F. K. M.]; and Department of Obstetrics and Gynecology and Preventive Medicine, School of Medicine, University of Southern California, California 90033 [F. Z. S.]
It has been suggested that the activity of the steroid 5
-reductase type II enzyme (encoded by the SRD5A2 gene) may be associated with prostate cancer risk and that population differences in this enzyme’s activity may account for part of the substantial racial/ethnic disparity in prostate cancer risk. To provide etiological clues, we evaluated the relationships of four polymorphic markers in the SRD5A2 gene, specifically, A49T (a substitution of threonine for alanine at codon 49), V89L (a substitution of leucine for valine at codon 89), R227Q (a substitution of glutamine for arginine at codon 227), and a (TA)n dinucleotide repeat, with prostate cancer risk in a population-based case-control study in China, a population with the lowest reported prostate cancer incidence rate in the world. Genotypes of these four markers were determined from genomic DNA of 191 incident cases of prostate cancer and 304 healthy controls using PCR-based assays, and serum androgen levels were measured in relation to these genotypes. All study subjects had the wild-type AA genotype of the A49T marker, and 99% had the RR genotype of the R227Q marker. For the V89L marker, prevalences of the LL, VV, and VL genotypes among controls were 35%, 21%, and 45%, respectively. Compared with men with the VV genotype, those with the LL genotype had a statistically nonsignificant 12% reduced risk (odds ratio = 0.88, 95% confidence interval, 0.53–1.47). In addition, men with the LL genotype had significantly higher serum levels of testosterone and significantly lower serum levels of 5-androstane-3,17ß-diol glucuronide than men with other genotypes. Men heterozygous for the (TA)0 allele of the (TA)n marker had a modest, statistically nonsignificant risk reduction (odds ratio = 0.67; 95% confidence interval, 0.39–1.12) compared with men homozygous for the (TA)0 allele, along with significantly higher serum dihydrotestosterone levels. The observed V89L genotype prevalences and the association between V89L genotypes and serum androgen levels support the hypothesis that genotypes associated with lower levels of 5-reductase activity are more common in low-risk populations. Although we found no statistically significant associations of these SRD5A2 polymorphisms with prostate cancer risk, a small effect of these markers cannot be ruled out because of the rarity of certain marker genotypes. Larger studies are needed to further clarify the role of these markers and to elucidate whether genetic diversity of the SRD5A2 gene, alone or in combination with other susceptibility genes, can help explain the large racial/ethnic differences in prostate cancer risk.
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