Polymorphic markers in the SRD5A2 gene and prostate cancer risk: a population-based case-control study.

It has been suggested that the activity of the steroid 5alpha-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 5alpha-androstane-3alpha,17beta-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 5alpha-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.

Modulation of human glutathione S-transferases by botanically defined vegetable diets.

Glutathione S-transferases (GSTs) conjugate activated xenobiotics with glutathione; thus, GST induction may improve detoxification and excretion of potentially harmful compounds. Using a randomized cross-over design, we tested the hypothesis that, in humans, serum GST-alpha concentration (GST-alpha) and GST activity increase with vegetable consumption and that this effect is GSTM1 genotype dependent. Twenty-one men (10 GSTM1-null and 11 GSTM1+) and 22 women (15 GSTM1-null and 7 GSTM1+), nonsmokers, 20-40 years of age and not on medications, ate four 6-day controlled diets: basal (vegetable-free), and basal supplemented with three botanically defined groups of vegetables (i.e., brassica, allium, and apiaceous). Fasting blood samples, collected on the last 2 days of each feeding period, were analyzed for GST-alpha, serum GST activity [against 1-chloro-2,4-dinitrobenzene (CDNB) and 7-chloro-4-nitrobenzo-2-oxa-1,3-diazole (NBD-Cl)] and peripheral-lymphocyte GST-mu activity (against trans-stilbene oxide). The brassica, but not allium or apiaceous, vegetable diets (relative to the basal diet) increased GST-alpha by 26% (P = 0.005) and GST (NBD-Cl) activity by 7% (P = 0.02) in the GSTM1-null individuals, particularly the women. Apiaceous vegetable supplementation decreased GST-alpha in the GSTM1+ men (P = 0.03). Among the GSTM1+ women, both brassica and the allium diets increased GST-mu activity by 18% (P = 0.02) and 26% (P = 0.001), respectively. The vegetable diets had no effect on GST (CDNB) activity, irrespective of GSTM1 genotype or sex. These results demonstrate that GSTM1 genotype has a significant effect on GST responses to diet and that brassica vegetables are most effective at inducing GST-alpha, whereas both brassica and allium vegetables induce GST-mu. GST responses were more pronounced in women than men, but it is not clear from this study whether this is a dose-per-body-weight or a sex-specific effect.

Low levels of intraspecific variation in the mitochondrial DNA of chum salmon (Oncorhynchus keta).

A total of 798 individuals from 42 different populations of chum salmon (Oncorhynchus keta) were examined for mtDNA variation. Populations were sampled across the geographic range of the species, from mainland Japan around the Pacific Rim to the state of Washington in the United States. The entire D-loop region (approximately 1 kb) was sequenced for 16 individuals from representative populations. Subregions (approximately 200 nucleotides each) of the D-loop reported to be rapidly evolving in salmon were sequenced for another 29 individuals. Only 4 nucleotide variants were detected, and they occurred in only 4 individuals. Four coding regions of the mtDNA genome were also examined using restriction fragment analysis of products amplified via the polymerase chain reaction. Only one, the region coding for NADH dehydrogenase subunits 5 and 6, showed any variation at this level. The restriction enzyme AseI revealed a polymorphism where the frequency of haplotypes was correlated geographically. We surveyed all individuals for this polymorphism and documented a cline in frequency of the haplotypes around the Pacific Rim. There was a significant frequency difference between Japan and 3 other major geographic regions (Russia, Alaska/Yukon, and British Columbia/Washington) for the presence of the 2 haplotypes. This marker may prove useful in the identification of continent-of-origin for individual chum salmon caught in the open ocean.