Prostate Cancer Risk In Caucasians Research Articles

Association of estrogen receptor α PvuII and XbaI polymorphisms with prostate cancer susceptibility and risk stratification: a meta-analysis from case-control studies.

BackgroundStudies on the association between two single nucleotide polymorphisms (SNPs) in estrogen receptor α (ERα), PvuII (rs2234693 T>C) and XbaI (rs9340799 A>G), and the prostate cancer risk are inconsistent. Therefore, we performed a meta-analysis to derive a more accurate estimation of this relationship.MethodsA literature search of PubMed, Embase, Web of Science databases until October 1, 2016, was conducted. Crude odds ratios (ORs) with 95% confidence intervals (CIs) were calculated to assess the strength of this association.ResultsEighteen case-control studies, with a total of 3,317 prostate cancer patients and 8,324 controls, were included. Results showed that both PvuII and XbaI polymorphisms were significantly associated with a higher prostate cancer risk in overall populations. To derive a more accurate estimation, subgroup analysis stratified by ethnicity revealed that this relation-ship existed only in Caucasians, but not in Asians. Furthermore, PvuII polymorphism was significantly associated with high Gleason grade (Gleason score ≥7) cancers.ConclusionThe current meta-analysis demonstrates that ERα PvuII and XbaI polymorphisms are associated with a higher prostate cancer risk in Caucasians, but not in Asians, and PvuII polymorphism is significantly associated with high Gleason grade tumors, indicating the probability of inherited susceptibility to prostate cancer arising from different genomic ERα SNPs, which may help us understand the pathogenesis of prostate cancer in Caucasians.

GSTT1 polymorphism and the risk of developing prostate cancer.

A possible association between glutathione S-transferase theta 1 gene (GSTT1) polymorphism and the risk of developing prostate cancer is currently hotly debated, but evidence from various epidemiologic studies remains unclear. This investigation was performed to assess whether an association between GSTT1 polymorphism and prostate cancer risk exists by using meta-analysis to combine comparable studies, thereby increasing sample size and statistical significance, as well as to identify patterns in various studies. The association reports were identified from the PubMed database and the Cochrane Library on March 1, 2013, and data from eligible studies (from 1999-2012) were synthesized. Thirty-eight reports were included in this meta-analysis on the association of the null genotype of GSTT1 with prostate cancer risk. No solid association between the GSTT1 null genotype and prostate cancer risk could be established for the overall population (odds ratio = 1.11, 95% confidence interval: 0.97, 1.27; P = 0.13). However, the GSTT1 null genotype was distinctly associated with prostate cancer risk in Caucasians (odds ratio = 1.24, 95% confidence interval: 1.03, 1.48, P = 0.02). In conclusion, the GSTT1 null genotype is associated with prostate cancer risk in Caucasians, but not in the overall population.

The influence of ESR1 rs9340799 and ESR2 rs1256049 polymorphisms on prostate cancer risk.

Estrogen receptor 1 (ESR1) and estrogen receptor 2 (ESR2) may play a role in the development of prostate cancer. Many studies focused on ESR1 rs9340799 and ESR2 rs1256049 polymorphisms to explore associations with prostate cancer risk. These studies showed inconsistent and conflicting results. The aim of this meta-analysis was to investigate the pooled association of ESR1 rs9340799 and ESR2 rs1256049 polymorphisms with prostate cancer risk. A systematic literature search was conducted to identify related studies (up to February 2014) in several online databases including PubMed, Google Scholar, CNKI and Wanfang online libraries. A total of 16 eligible articles were enrolled in this updated meta-analysis. The result suggested that ESR1 rs9340799 polymorphism was significantly associated with prostate cancer in overall populations (GG+GA vs. AA: P = 0.002; G vs. A: P = 0.004), Caucasians (GG+GA vs. AA: P = 0.008; G vs. A: P = 0.016) and Africans (GG+GA vs. AA: P = 0.005; G vs. A: P = 0.006), but not in Asians (GG+GA vs. AA: P = 0.462; G vs. A: P = 0.665). The result also showed that there was a significant association between ESR2 rs1256049 polymorphism and prostate cancer in Caucasians (AA+AG vs. GG: P = 0.016; A vs. G: P = 0.005), but no association in overall populations (AA+AG vs. GG: P = 0.826; A vs. G: P = 0.478), Asians (AA+AG vs. GG: P = 0.177; A vs. G: P = 0.703) and Africans (AA+AG vs. GG: P = 0.847; A vs. G: P = 0.707). The cumulative meta-analysis and sensitivity analysis showed the results were robust. In conclusion, this meta-analysis indicated that ESR1 rs9340799 polymorphism was associated with prostate cancer risk in overall populations, Caucasians and Africans, while ESR2 rs1256049 polymorphism was associated with prostate cancer risk in Caucasians. However, the biological mechanisms need to be further investigated.

GSTT1 Null Genotype Is Associated with an Increased Risk of Prostate Cancer in Caucasians: A Meta-Analysis

Background: Many studies have investigated the association between glutathione S-transferase T1 (GSTT1) null genotype and the risk of prostate cancer (PCa), but the impact of GSTT1 null genotype on PCa risk in Caucasians is still unclear owing to the inconsistency of such studies. The present study aimed to quantify the strength of association between GSTT1 null genotype and the risk of PCa in Caucasians. Methods: We searched the PubMed, Embase and Web of Science databases for studies assessing the association between GSTT1 null genotype and the risk of PCa in Caucasians. We estimated the summary odds ratio (OR) with the corresponding 95% confidence interval (95% CI) to assess the association. Results: 16 case-control studies with 11,648 subjects were included in this meta-analysis. Meta-analysis of a total of 16 studies showed GSTT1 null genotype was significantly associated with an increased risk of PCa in Caucasians (random-effects OR 1.30, 95% CI 1.10-1.53, p = 0.002). After adjustment for heterogeneity, GSTT1 null genotype was still associated with an increased risk of PCa in Caucasians (fixed-effects OR 1.33, 95% CI 1.17-1.52, p < 0.001). The cumulative meta-analyses of all 16 studies showed a trend of more obvious association as information accumulated by year. Conclusions: Meta-analysis of available data suggests the GSTT1 null genotype is significantly associated with an increased risk of PCa in Caucasians.

Abstract B51: Genetic polymorphisms of the UDP-glucuronosyltransferase 2B15 and 2B17 genes are associated with prostate cancer in African American men.

Abstract The rate of incidence and mortality from prostate cancer among African American men compared to Caucasian men is more than two-fold higher. Genes related to steroid metabolism have been investigated for their association with prostate cancer etiology. The UDP-glucuronosyltransferase 2B17 (UGT2B17) and UGT2B15 enzymes exhibit specificity for androgen metabolites such as testosterone, dihydrotestosterone (DHT), androsterone (ADT), and androstane-3α,17β-diol (3α-diol) in prostate tissue and cell lines. Copy number variants and SNPs of UGT2B17 and UGT2B15 have been evaluated for prostate cancer risk in Caucasians in several studies but the results have been inconclusive and the studies have included few African Americans subjects. Data from a previous hospital-based case-control study at the Durham Veterans Affairs Medical Center (DVAMC) found that a missense polymorphism UGT2B15D85Y was significantly associated with prostate cancer risk. We hypothesized that functional UGT2B15 and UGT2B17 polymorphisms would show associations for prostate cancer risk. For this study, we selected from the UGT2B15 gene, a panel of eight SNPs; five promoter SNPs, UGT2B15-506, UGT2B15-818, UGT2B15-1139, UGT2B15-1397, and UGT2B15-1844 that are in high LD with UGT2B15D85Y; then SNPs UGT2B15T523K, UGT2B153'UTR that are highly linked; and a UGT2B15 distal promoter SNP. From the UGT2B17 gene, UGT2B17V181I was selected. In addition, two cis-acting SNPs were also included that were linked to UGT2B17 expression alone or to the expression of both UGT2B17 and UGT2B15. Genomic DNA samples, from African Americans (142 cases, 138 controls) and Caucasian men (87 cases, 197 controls) accrued at the DVAMC, were genotyped using Sequenom MassArray technology and assays designed by Sequenom online assay tools. To determine the association of the SNPs with prostate cancer cases compared to controls, logistic regression models were used to estimate odd ratios (ORs) under dominant and log-additive models for the minor allele using the homozygous major allele as the reference group. After adjusting for age, race, and BMI, three (UGT2B15-1139, UGT2B15-1397, and UGT2B15-1844) of the five promoter SNPs in high LD with UGT2B15D85Y and the UGT2B15 distal promoter SNP were found to be inversely associated with risk for prostate cancer under the log-additive model. Similar results were obtained for UGT2B15T523K and UGT2B153'UTR. In contrast, the minor allele for the cis-acting SNP that is linked to UGT2B17 and UGT2B15 expression was found to be associated with increased risk for prostate cancer. After stratifying for race, only associations of the minor alleles of SNPs UGT2B15T523K (OR = 0.52, 95% CI = 0.30, 0.90) and UGT2B153'UTR (OR = 0.56, 95% CI = 0.36, 0.87) remained significant in African Americans under the log-additive model. Variants of the UGT2B15 gene, UGT2B15T523K and UGT2B153'UTR, were shown for the first time to be associated with prostate cancer risk among African Americans and not Caucasians. Log additive models revealed a dose-dependent association. Moreover, these data suggest that wild type alleles confer increased risk to prostate cancer among African American men. Future studies with larger sample sizes are needed to validate these findings. Citation Format: Cocoa Tucker, Adriana C. Vidal, Joellen M. Schildkraut, Ricardo M. Richardson, Stephen J. Freedland, Cathrine Hoyo, Delores J. Grant. Genetic polymorphisms of the UDP-glucuronosyltransferase 2B15 and 2B17 genes are associated with prostate cancer in African American men. [abstract]. In: Proceedings of the Fifth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2012 Oct 27-30; San Diego, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2012;21(10 Suppl):Abstract nr B51.

NAD(P)H:Quinone Oxidoreductase 1 (NQO1) P187S Polymorphism and Prostate Cancer Risk in Caucasians

NAD(P)H:quinone oxidoreductase 1 (NQO1) catalyses the reduction of quinoid compounds to hydroquinones, preventing the generation of free radicals and reactive oxygen. A “C” to “T” transversion at position 609 of NQO1, leading to a nonsynonymous amino acid change (Pro187Ser, P187S), results in an altered enzyme activity. No NQO1 protein activity was detected in NQO1 609TT genotype, and low to intermediate activity was detected in NQO1 609CT genotype compared with 609CC genotype. Thus, this polymorphism may result in altered cancer predisposition. For prostate cancer, only sparse data are available. We therefore analyzed the distribution of the NQO1 P187S SNP (single nucleotide polymorphism) in prostate cancer patients and a healthy control group. Allelic variants were determined using RFLP analysis. Overall, 232 patients without any malignancy and 119 consecutive prostate cancer patients were investigated. The genotype distribution in our cohorts followed the Hardy–Weinberg equilibrium in cases and controls. The distribution of the NQO1 codon 187 SNP did not differ significantly between prostate cancer patients and the control group (p = 0.242). There was also no association between the allelic variants and stage or Gleason score of the tumors. The NQO1 P187S SNP was not significantly associated with an increased prostate cancer risk in our cohorts. The SNP has also no influence on histopathological characteristics of the tumors. A combined analysis of all available data from published European studies also showed no significant differences in the genotype distribution between controls and prostate cancer patients. Our data suggest a minor role of the NQO1 nucleotide 609 polymorphism in prostate carcinogenesis.

Polymorphisms in XPD and hOGG1 and Prostate Cancer Risk: A Meta-Analysis

Objective: To examine the association between XPD and hOGG1 polymorphisms and prostate cancer (PCa) susceptibility. Methods: A comprehensive search was conducted to identify all case-control studies on the relationship between XPD and hOGG1 polymorphisms and PCa risk. Odds ratios (ORs) were used to investigate the strength of the associations. Results: A total of 15 case-control studies including 5,765 cases and 6,270 controls were eligible for the meta-analyses. For XPD Asp312Asn, no evidence indicated that individuals carrying 312Asn had an increased risk of PCa. In subgroup analyses, Asp312Asn polymorphism was associated with PCa risk in Asian populations [OR = 2.09 and 95% CI = 1.39–3.14 for Asn/Asn vs. Asp/Asp; OR = 1.49 and 95% CI = 1.12–1.98 for (Asn/Asn+Asn/Asp) vs. Asp/Asp]. For XPD Lys751Gln, the individuals with 751Gln did not have increased PCa risk compared with those with 751Arg, and no association was found in the subgroup analyses. For hOGG1 Ser326Cys, no significant association between the polymorphism and PCa risk was observed in the overall analysis. However, Ser326Cys was significantly associated with PCa risk under homologous contrast in Caucasians and Asians. Conclusions: XPD Asp312Asn polymorphism is associated with PCa risk in Asians and hOGG1 Ser326Cys polymorphism is associated with PCa risk in Caucasians and Asians.

Murine double minute 2 promoter SNP309 polymorphism and prostate cancer risk: A meta‐analysis

The murine double minute 2 gene encodes a negative regulator of the tumor protein p53. A single nucleotide polymorphism in murine double minute 2 promoter, SNP309 T>G, has been reported to alter murine double minute 2 protein expression and to accelerate tumor formation in humans. We carried out a meta-analysis to explore the association between this polymorphism and prostate cancer risk. All eligible studies were searched in PubMed. Crude odds ratios, with 95% confidence intervals, were assessed for the association using fixed- and random-effects models. Overall, five case-control studies (872 cases, 1005 controls) were included in the meta-analysis. A significant association between murine double minute 2 SNP309 and prostate cancer risk was observed for homozygote genetic model GG versus TT (odds ratio 0.72, 95% confidence interval 0.55-0.95, P < 0.05, P = 0.130 for heterogeneity), and for dominant model TG + GG versus TT (odds ratio 0.79, 95% confidence interval 0.65-0.96, P < 0.05, P = 0.119 for heterogeneity). The stratified analysis based on ethnicity showed a significant effect of the polymorphism on prostate cancer risk in Caucasians for GG versus TT. Findings of the present meta-analysis suggest that the murine double minute 2 309 G allele might be associated with a reduced risk of prostate cancer. The effect of murine double minute 2 309 G allele on tumorigenesis might be influenced by sex and hormonal status.

Association between variants on 8q24 and prostate cancer: A review and meta-analysis.

28 Background: Racial disparities in the incidence prostate cancer exist but remain unexplained. Recent studies implicate single nucleotide polymorphisms (SNPs) within the 8q24 region as a risk factor for prostate cancer (PCa) and the frequency of variant alleles at these SNPs appear to differ by race. To determine the association between 8q24 polymorphisms and PCa among men of different races, we performed meta-analyses, stratified by race. Methods: Twenty-nine studies of seven SNPs and one microsatellite marker located within the 8q24 region were included in the meta-analyses. Allelic odds ratio (OR) values and confidence intervals were calculated using the Mantel-Haenszel test. This test assumes homogeneity so we first used the Breslow-Day test to determine whether or not the assumption of homogeneity was valid in each population. Results: PCa risk was associated with the following SNPs in all included races: rs6983267, rs1447295, rs6983561, rs7837688, rs16901979, and DG8S737(-8). PCa risk in Caucasians was conferred by rs6983267 (OR = 1.22 (1.17-1.27)), rs1447295 (OR = 1.43 (1.45-1.49)), rs6983561 (OR = 1.45 (1.30-1.61), rs7837688 (OR = 1.55 (1.39-1.73)), rs16902979 (OR = 1.39 (1.29-1.49)), and DG8S737(-8) (OR = 1.32 (1.12-1.56)). In African American men, a significant association was found for rs1447295 (OR = 1.1 (1.02-1.18)), rs6983561 (OR = 1.43 (1.29-1.59)), rs16901979 (OR = 1.39 (1.29-1.49)), and DG8S737(-8) (OR =1.34 (1.19-1.50)). Alleles associated with PCa risk in Asians were rs6983267 (OR = 1.15 (1.04-1.26)), rs1447295 (OR = 1.39 (1.25-1.54)), rs6983561 (OR = 1.68 (1.51-1.88)), and rs16901979 (OR = 1.65 (1.48-1.85)). The risk allele at rs1447295 was also associated with PCa risk among Hispanic men. Conclusions: 8q24 contains SNPs that are associated with PCa risk, but the strength of this association depended on race. Racial disparities in the incidence of PCa may in part be accounted for by 8q24 variants.

Genetic Polymorphisms in Inflammation Pathway Genes and Prostate Cancer Risk

Chronic inflammation is an important mechanism for the development and progression of prostate cancer (PC). To better understand the potential relationship between genes in the inflammation pathway and PC risk, we evaluated variants in 16 candidate genes. A total of 143 tagging and amino acid altering single nucleotide polymorphisms (SNPs) were genotyped in Caucasian and African American men participating in one of two population-based, case-control studies (n = 1,458 cases and 1,351 controls). The relative risk of PC was estimated using logistic and polytomous regression models. Ten SNPs in seven genes (CXCL12, IL4, IL6, IL6ST, PTGS2, STAT3, and TNF) were nominally associated (P < 0.05) with risk of PC in Caucasians. The most significant effect on risk was seen with rs11574783 in the interleukin 6 signal transducer (IL6ST) gene (OR = 0.08, 95% CI: 0.01-0.63). Cumulatively, four SNPs in genes interleukin 4 (IL4), IL6ST, PTGS2, and signal transducer and activator of transcription 3 (STAT3) conferred a three-fold elevation in PC risk among men carrying the maximum number of high-risk alleles (OR = 2.97, 95% CI: 1.41-6.25, P(trend) = 0.0003). Risk estimates for seven SNPs varied significantly according to disease aggressiveness (P(homogeneity) < 0.05), with SNPs in AKT1, PIK3R1, and STAT3 independently associated with more aggressive PC; OR = 5.1 (95% CI: 2.29-11.40, P(trend) = 3.8 × 10(-5)) for carriers of all high-risk genotypes. These results suggest that variants in genes within the inflammation pathway may play a role in the development of PC, however, further studies are needed to replicate our findings. These results underline the potential importance of the inflammation pathway in PC development and progression.

Metformin use and prostate cancer in Caucasian men: results from a population-based case–control study

PurposeMetformin is a commonly used medication for type II diabetes mellitus. Epidemiologic studies have suggested a decreased relative risk of cancer with metformin use, and preclinical studies of prostate cancer (PCa) have shown antitumor activity with metformin. In this study, we explore the relationship between metformin use and PCa risk in a population-based case–control study.MethodsCases were men aged 35–74 years diagnosed with PCa between 2002 and 2005 in King County, Washington. Controls were frequency matched by age and identified by random digit dialing. Use of metformin was determined from in-person questionnaires regarding medical and prescription history. The relationship of metformin use with PCa risk was evaluated using logistic regression.ResultsA total of 1,001 cases of PCa and 942 controls were available for analysis. In Caucasian men, metformin use was more common in controls than in cases (4.7 vs. 2.8%, p = 0.04), resulting in a 44% risk reduction for PCa (adjusted OR = 0.56; 95% CI 0.32–1.00). No association was seen in African-American men.ConclusionMetformin use was associated with a borderline significant decrease in the relative risk of PCa in Caucasians. Further study into this relationship is needed to confirm the association and determine the underlying pathways involved.

Molecular evolution of the prostate cancer susceptibility locus RNASEL: Evidence for positive selection

Recent research implicates viral infection as a factor that may contribute to the risk of prostate cancer. Allelic variation at the RNASEL locus is associated with the risk of infection by a newly discovered retrovirus called XMRV, and with hereditary risk of prostate cancer. This evidence suggests that the RNASEL locus has undergone antagonistic coevolution with the retrovirus over evolutionary time. If this is the case, then both the RNASEL locus and the retrovirus should show evidence of positive selection. Here we use molecular-evolutionary methods to investigate the prediction that the RNASEL locus will exhibit evidence of positive selection. We find evidence that positive selection has acted on this locus over evolutionary time. We further find, using a Bayesian estimation procedure, that Asp541Glu, which was found to be associated with prostate cancer risk in Caucasians in a recent meta-analysis, shows an elevated probability of positive selection. Previous studies provide evidence for rapid evolution of the infection-mediating gag gene in the XMRV retrovirus. Taken together, these results suggest that antagonistic coevolution may have occurred between a specific host locus involved in immune defense ( RNASEL) and a viral pathogen. In turn, genetic variation associated with this apparent coevolution may influence susceptibility to prostate cancer.

Functional Variant of Manganese Superoxide Dismutase (SOD2 V16A) Polymorphism Is Associated with Prostate Cancer Risk in the Prostate, Lung, Colorectal, and Ovarian Cancer Study

Superoxide dismutase (SOD) plays a key role in the detoxification of superoxide free radicals. We evaluated the association of prostate cancer with genetic polymorphisms in SOD1 (CuZn-SOD; IVS3-251A>G), SOD2 [MnSOD; Ex2+24T>C (V16A)], and SOD3 (EC-SOD; IVS1+186C>T, Ex3-631C>G, Ex3-516C>T, and Ex3-489C>T), the three main isoforms of SOD. Prostate cancer cases (n = 1,320) from the screening arm of the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial were frequency matched to nondiseased controls (n = 1,842) by age, race, time since initial screening, and year of blood draw. Conditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (95% CI); stratified analysis by the level of antioxidative vitamins was also conducted. The higher activity Ala variant at SOD2 Ex2+24T>C (V16A), which has been hypothesized to suppress prostate carcinogenesis, was associated with elevation of prostate cancer risk in Caucasians (Val/Ala versus Val/Val: OR, 1.17; 95% CI, 0.97-1.42; Ala/Ala versus Val/Val: OR, 1.28; 95% CI, 1.03-1.60; P(trend) = 0.03). Stratification by quartiles of dietary and supplemental vitamin E intake (IU/d) showed risks of prostate cancer tended to be increased among SOD2 Ala allele carriers, except at the highest quartile of vitamin E intake (>222; P(interaction) = 0.06, Q1-Q3 versus Q4). The association between Ala allele and prostate cancer risk among those with lower intake of vitamin E (</=222) was stronger for smokers (OR, 1.44; 95% CI, 1.10-1.90). No significant association with prostate cancer was observed for polymorphic variants in SOD3 or SOD1. These results suggest that the Ala variant of SOD2 is associated with moderately increased risk of prostate cancer, particularly among men with lower intakes of dietary and supplemental vitamin E.

The UGT2B17 gene deletion polymorphism and risk of prostate cancer : A case–control study in Caucasians

Background: UDP-glucuronosyltransferase (UGT) 2B17 is a phase II metabolizing enzyme that mediates the glucuronidation of C 19 steroids. A deletion polymorphism in the UGT2B17 gene is associated with a substantial reduction in glucuronidation activity in vitro. Methods: We examined the association between the UGT2B17 deletion polymorphism and the risk of incident prostate cancer in a population-based study from central Arkansas that included 411 Caucasian cases and 397 Caucasian controls. We developed a novel high-throughput procedure that uses real-time PCR and allelic discrimination for genotyping analysis. Results: The prevalence of the UGT2B17 deletion [(0/0)] was 12% in the controls, which was consistent with previous population estimates and with Hardy Weinberg equilibrium. There was no association between the UGT2B17 deletion polymorphism and prostate cancer risk in unconditional logistic regression analysis. Compared to the wild-type group (+/+), the adjusted odds ratio (OR) was 0.89 (95% CI = 0.55–1.45) for the homozygous deletion (0/0), and the OR was 0.99 (95% CI = 0.73–1.35) for the heterozygote group (+/0). Conclusion: These findings show that the UGT2B17 deletion polymorphism is not associated with prostate cancer risk in Caucasians.

RNASEL Gene Polymorphisms and the Risk of Prostate Cancer: a Meta-analysis

Studies revealing conflicting results on the role of RNASEL polymorphisms Glu265X, Arg462Gln, and Asp541Glu on prostate cancer risk led us to perform a meta-analysis to investigate the association of these polymorphisms and prostate cancer risk. Relevant studies were selected by searching PubMed from January 1996 to August 2005 using keywords "RNASEL gene AND prostate cancer." For each study, odds ratio (OR) with 95% confidence interval (95% CI) was calculated to estimate the gene effect. Pooled estimates of the OR were computed using the random effects model. Ten studies were included in the meta-analysis. The overall results suggested no major influence of these variants on prostate cancer risk. However, analysis of the Asp541Glu polymorphism by ethnic populations showed that Asp/Glu (familial cases versus control: OR, 1.38; 95% CI, 1.04-1.82; sporadic cases versus control: OR, 1.26; 95% CI, 1.07-1.48; prostate cancer versus control: OR, 1.29; 95% CI, 1.12-1.48) and Asp/Glu + Glu/Glu (familial cases versus control: OR, 1.37; 95% CI, 1.10-1.70; sporadic cases versus control: OR, 1.24; 95% CI, 1.07-1.44; prostate cancer versus control: OR, 1.27; 95% CI, 1.13-1.44) increased prostate cancer risk in Caucasians, thus suggesting a dominant model for the Glu variant. Compared with the genotype Asp/Asp, the Glu variant at the Asp541Glu polymorphism increases prostate cancer risk by <2-fold in Caucasians, regardless of family history of the disease. This suggests that genuine genetic effects of this polymorphism may account for only a part of prostate cancer in the Caucasian population.