Polymorphisms in the 5alpha reductase type 2 gene and urologic measures of BPH

BACKGROUND: The objective of the study was to examine associations between SRD5A2 polymorphisms and measures of benign prostatic hyperplasia (BPH). METHODS: Participants were 510 Caucasian men (median age 60 years), randomly selected from the Olmsted County, MN community to participate in a longitudinal study of BPH. From 1990 through 2000, biennial measurements of lower urinary tract symptom severity (assessed from the American Urological Association Symptom Index, AUASI), peak urinary flow rates (Qmax), and prostate volume were made. Genotyping of SRD5A2 V89L, A49T, and TA repeat polymorphisms were performed. RESULTS: Compared with the VV genotype, the LL genotype was associated with an enlarged prostate (Hazard ratio (HR)=1.62, 95% confidence interval (CI)=1.06, 2.43) but not with AUASI, Qmax, or PSA. The A49T and TA repeat polymorphisms were not associated with BPH. When the LL/VL, AT/TT, and TA0/TA0 genotypes were considered high risk, the number of high risk genotypes increased with increasing prostate volume (32.3, 30.7, 34.1, and 38.7, respectively, P for trend=0.04). CONCLUSIONS: These findings do not demonstrate consistent associations between SRD5A2 genotypes and BPH. However, they suggest that the associations of V89L polymorphisms and prostate volume should be investigated further.     

Associations between polymorphisms in the steroid 5-alpha reductase type II (SRD5A2) gene and benign prostatic hyperplasia and prostate cancer

The prostate gland is an androgen-dependent, and polymorphisms in androgen synthesis gene steroid 5-alpha reductase type II (SRD5A2) may be associated with benign prostatic hyperplasia (BPH) and prostate cancer. We evaluated the association between 3 polymorphisms in the SRD5A2 gene (2 single nucleotide polymorphism: alanine-49 to threonine [A49T] and valine-89 to leucine [V89L], and a (TA)n dinucleotide repeat in the 3' untranslated region), and BPH and prostate cancer within a multiethnic population. Men between 60 and 86 years of age were recruited from annual prostate cancer screening programs and from a large urology clinic. Unconditional logistic regression was used to compute odds ratios (OR) and 95% confidence intervals (95% CI). We genotyped 606 men (412 Hispanic, 98 Caucasian, 73 African-American, and 23 Asian), of whom 100 had prostate cancer, 393 had BPH (280 symptomatic and 113 asymptomatic), and 113 had normal prostates. Overall, the V89L variant was associated with prostate cancer; the OR for men with the leucine-leucine (LL) genotype compared to men with the valine-valine (VV) genotype was 4.47 (95% CI, 1.24-16.18). This association was stronger in Hispanics (OR=7.26; 95% CI: 1.49-35.47). Although V89L was nonsignificantly associated with BPH in overall population, BPH risk increased significantly with the number of L alleles in Hispanics (P for trend=0.03). Prostate cancer and BPH were not associated with the alanine-49 to threonine single nucleotide polymorphism and the (TA)n repeat. These results suggest that the SRD5A2 gene may play an important role in both BPH and prostate cancer.     

睾酮5-α还原酶Ⅱ基因V89L多态性与前列腺癌预后关系的研究

目的:探讨睾酮5-α还原酶Ⅱ(SRD5A2)基因V89L多态性与影响前列腺癌预后因素的关系。方法:对V89L多态性位点用Rsa-1限制性内切酶进行酶切鉴定,观察112例前列腺癌患者和89例BPH患者的V89L(VV、VL、LL)多态性分布情况的差异及其多态性与前列腺癌患者年龄、前列腺特异性抗原(PSA)、游离PSA/总PSA值(tPSA/fPSA,F/T)、Gleason评分、临床分期的关系。结果:前列腺癌组112例与BPH组89例的V89L基因频度风险无显著性差异(χ2=3.606,df=2,P=0.165)。前列腺癌组VV和VL+LL基因型与fPSA、tPSA、F/T、T分期、Gleason评分差异无显著性(P>0.05)。VV和VL+LL各评价预后指标差异无显著性(P>0.05)。分段评价PSA水平、Gleason评分、临床分期、年龄,均与两种基因型无相关性(P>0.05)。结论:V89L多态性与预后无明显关系,但是可能与前列腺癌的风险存在间接的关系。     

类固醇5a-还原酶Ⅱ基因89位点多态性与亚洲男性前列腺癌易感性的Meta分析

目的 探讨类固醇5a-还原酶Ⅱ (SRD5a2)基因89位点多态性与亚洲男性前列腺癌易感性的关系。方法 检索PubMed、中国知网、万方、维普数据库,获取SRD5a2基因89位点多态性与亚洲男性前列腺癌易感性的病例-对照研究。以前列腺癌组与对照组人群基因型分布的OR值为效应指标,采用固定或随机效应模型进行合并分析,并进...     

SRD5A2 and HSD3B2 polymorphisms are associated with prostate cancer risk and aggressiveness

BACKGROUND: Dihydrotestosterone (DHT) is believed to play an important role in prostate carcinogenesis. Five alpha reductase type II (SRD5A2) and 3 beta-hydroxysteroid dehydrogenase type II (HSD3B2) are responsible for the biosynthesis and degradation of DHT in the prostate. Two polymorphisms, a valine (V) for leucine (L) substitution at the 89 codon of the SRD5A2 gene and a (TG)n,(TA)n,(CA)n repeat polymorphism within the third intron of the HSD3B2 gene were evaluated with regard to prostate cancer risk. METHODS: Blood samples were collected for 637 prostate cancer cases and 244 age and race frequency matched controls. In analysis, the SRD5A2 VL and LL genotypes were combined into one group and the HSD3B2 repeat polymorphism was dichotomized into short (<283) and long (> or =283) alleles. RESULTS: The SRD5A2 V89L polymorphism was not independently associated with prostate cancer risk. Carriage of at least one HSD3B2 intron 3 intron 3 short allele was associated with a significant increased risk for prostate cancer among all subjects (OR = 2.07, 95% CI = 1.08-3.95, P = 0.03) and Caucasians (OR = 2.80, CI = 2.80-7.43, P = 0.04), but not in African Americans (OR = 1.50, CI = 0.62-3.60, P = 0.37). Stratified analyses revealed that most of the prostate cancer risk associated with the intron 3 HSD3B2 short allele was confined to the SRD5A2 89L variant subgroup and indicated that in combination these polymorphisms may be associated with increased risk of aggressive (Gleason >7) disease (Gleason >7). CONCLUSIONS: In Caucasians, the HSD3B2 (TG)n,(TA)n,(CA)n intron 3 length polymorphism is associated with both prostate cancer risk and aggressiveness and the SRD5A2 V89L polymorphism may modify the risk conferred by this polymorphism.     

Polymorphisms in the androgen receptor and type II 5 alpha-reductase genes and prostate cancer prognosis

BACKGROUND: Cytosine-adenine-guanine repeat length of the androgen receptor gene and the A49T and V89L polymorphisms of the 5 alpha-reductase (SRD5A2) gene have been associated with prostate cancer. METHODS: We investigated the relationship of the three genetic polymorphisms to tumor grade among 211 men who had undergone radical prostatectomy. Subjects had prostate cancer <3 cm(3) with a percentage of cancer represented by Gleason grade 4 or 5 (% Gleason grade 4/5) of either > or = 20% or < or = 5%. We also examined the association between those genetic markers and prostate specific antigen (PSA) failure among 112 subjects with > or = 20% Gleason grade 4/5. RESULTS: In cross-sectional analysis, none of the polymorphisms was a significant predictor of % Gleason grade 4/5. In longitudinal analysis, the LL genotype at the V89L site was associated with statistically significant four- to sixfold increase in PSA failure risk after adjustment for clinicopathologic variables. CONCLUSIONS: We observed poorer prognosis among men with the LL genotype at codon 89 of the SRD5A2 gene. Lack of consistency between studies must be resolved before clinical utility of this marker is established.     

Evaluation of SRD5A2 sequence variants in susceptibility to hereditary and sporadic prostate cancer

BACKGROUND: The 5 alpha-reductase type II (SRD5A2) catalyzes the conversion of testosterone into the more potent androgen, dihydrotestosterone (DHT), and is thus believed to be the key enzyme for the control of intracellular DHT level in the prostate. Several single nucleotide polymorphisms (SNPs) in the SRD5A2 gene have been found to alter enzymatic activities and were associated with prostate cancer risk or clinical features in several case-control studies. However, the role of SRD5A2 sequence variants in the susceptibility to hereditary prostate cancer (HPC) has not been evaluated to date. METHODS: Three SNPs in the SRD5A2 gene (A49T, V89L, and C682G) and two microsatellite markers near SRD5A2 were genotyped in 159 HPC families to assess their linkage to prostate cancer. In addition, the three SNPs were also genotyped in 245 sporadic cases and 222 unaffected controls to assess their association with hereditary and sporadic prostate cancer. RESULTS: Weak evidence for linkage in the SRD5A2 chromosomal region was observed in the 159 HPC families (HLOD = 0.87, P = 0.04). Stronger evidence for linkage was observed in Caucasian families (HLOD = 1.10, P = 0.02). When stratified by the SNP A49T, no significant evidence for linkage was observed in families with or without the "T" allele. Similarly, family-based association tests failed to observe significant over-transmission of any risk alleles of SNPs A49T, V89L, and C682G to affected offspring. Finally, no significant differences in the distributions of SNPs A49T, V89L, and C682G were found among the HPC probands, sporadic cases, and controls. CONCLUSIONS: Polymorphisms of SRD5A2 are unlikely to significantly increase susceptibility to hereditary or sporadic prostate cancer in the study populations.     

Association of prostate cancer risk and aggressiveness to androgen pathway genes: SRD5A2, CYP17, and the AR

BACKGROUND: The prostate is an androgen-regulated organ and polymorphisms in genes involved in testosterone synthesis, in particular, SRD5A2 (A49T and V89L variants), CYP17 (MspAI variant), and the AR (CAG, GGC repeats), represent candidate risk factors for prostate cancer incidence and aggressiveness. METHODS: We evaluated the relationship between these five polymorphisms and prostate cancer risk in a family-based case-control study (N = 920). Cases were diagnosed at major medical institutions in Cleveland Ohio, and Detroit Michigan, and their unaffected brothers were used as controls. Associations were investigated with regard to prostate cancer risk, and clinical characteristics at diagnosis (i.e., tumor stage/grade, age, family history). RESULTS: The SRD5A2 V89L variant was associated with an increased risk of prostate cancer (OR = 1.56, P = 0.02). This association was driven primarily by men diagnosed at an earlier age (OR = 2.35, P = 0.001), or with more aggressive disease (OR = 1.63, P = 0.06). None of the other variants exhibited noteworthy associations with disease. CONCLUSIONS: These findings suggest that the SRD5A2 V89L variant may influence risk of developing prostate cancer, especially among men with a younger age of diagnosis or more aggressive disease.     

Association between hormonal genetic polymorphisms and early-onset prostate cancer

We investigated the association between seven polymorphisms in four candidate genes involved in vitamin D and androgen metabolism with early-onset prostate cancer (CaP) risk. The polymorphisms were genotyped in 288 UK males who were diagnosed with CaP at the age of 55 y or younger and up to 700 population-based controls. An additional 50 cases (not selected for age) and 76 controls were also genotyped. Short (< or =22 repeats) AR (CAG)(n) repeats were associated with a significantly reduced risk of early onset CaP (OR 0.68, 95% CI 0.50-0.91) compared with men with long (> 22) repeats. Men homozygous for the leucine variant of SRD5A2 p.89V > L were also found to be at a significantly increased risk of CaP compared with men who were homozygous for the valine allele (OR 1.84, 95% CI 1.15-2.98). No associations were found with the AR (GGC)(n), CYP17 Msp A1 I, VDR Taq I, SRD5A2 (TA)(n) and p.49A >T polymorphisms and CaP risk. These findings suggest that common polymorphisms in the AR and SRD5A2 genes may be associated with early-onset CaP in British men.     

Significance of vitamin D receptor gene polymorphism for risk and disease severity of prostate cancer and benign prostatic hyperplasia in Japanese

OBJECTIVE: Recent studies have demonstrated an association between vitamin D receptor (VDR) genotype and prostate cancer. Currently, there is a scarcity of data regarding the association of VDR genotype with benign prostatic hyperplasia (BPH). The purpose of this study was to investigate the TaqI VDR polymorphism in Japanese prostate cancer patients, Japanese BPH patients and Japanese controls in order to determine if an association exists between VDR genotype and the risk of developing prostate cancer and BPH as well as disease severity. METHODS: 110 prostate cancer patients, 83 BPH patients and 90 male age-matched controls were genotyped for a previously described TaqI restriction fragment length polymorphism at codon 352 in exon 9 of the VDR gene. Products were digested into T allele or t allele according to the absence or presence of a TaqI restriction site with individuals being classified as TT, Tt or tt. RESULTS: The frequency of the genotype tt was higher in the control group (6.7%) compared to patients with prostate cancer (1.8%) and BPH (3.6%) but this was not statistically significant. However, the frequency of the genotype TT was significantly higher among prostate cancer patients with locally advanced or metastatic disease (T3/ T4/N1/M1) compared to controls (p = 0.001). In addition, the genotype TT was significantly higher among prostate cancer patients with a high Gleason grade of tumor (grade 5) compared to controls (p = 0.0001). In addition, the genotype TT was statistically higher in BPH patients with high prostate volume (volume >50 cm(3)) compared to controls (p = 0.001). CONCLUSION: These data demonstrate that VDR genotype plays an important role in determining the risk of more advanced and aggressive prostate cancer as well as prostatic enlargement in Japanese men.     

Association of polymorphisms within androgen receptor, 5alpha-reductase,and PSA genes with prostate volume,clinical parameters,and endocrine status in elderly men

BACKGROUND: The aim of this study was to assess the impact of polymorphisms of three genes within the androgen pathway on prostate volume, clinical parameters, and endocrine status. METHODS: Elderly men with lower urinary tract symptoms underwent clinical and endocrine work-up. In parallel, polymorphisms within the 5alpha-reductase gene (SRD5A2 V89L and A49T), the androgen receptor gene (AR; number of CAG repeats), and the prostate specific antigen (PSA) gene (A --> G substitution at position-158) were determined by polymerase chain reaction and restriction-length polymorphism analysis by using DNA from peripheral blood. RESULTS: A total of 190 men (66.5 +/- 9.2 yr) were analyzed. The number of CAG repeats within the AR and the PSA polymorphism revealed no associations to clinical and endocrine parameters. Individuals carrying the mutated SRD5A2 A49T allele (5.3% of the total population) had larger prostates (54.1 vs. 39.3 ml), higher PSA levels (12.2 vs. 4.3 ng/ml), and a 35% reduction in prostatic stroma/epithelial cell ratio. Men with the mutated SRD5A2 V89L gene had lower testosterone levels. CONCLUSIONS: In contrast to prostate cancer, polymorphisms within AR and PSA genes do not seem to be of importance for benign prostatic hyperplasia. Polymorphisms within the 5alpha-reductase gene are interesting biomarkers for the development of benign prostatic hyperplasia and benign prostatic enlargement.     

Serum sex steroid hormone levels and polymorphisms of CYP17 and SRD5A2: implication for prostate cancer risk

Polymorphism of the steroid hormone-related genes might affect life-long androgen exposure, thus altering a risk of prostate cancer incidence. To evaluate the effect of the polymorphisms of CYP17 and SRD5A2 on serum steroid hormone levels, the 164 male Japanese cohort were tested for serum hormone levels and the genotype of the polymorphisms of CYP17 (T-C base substitution in the promoter region) and SRD5A2 (V89L). The linear trends across the CYP17 genotypes in serum-free testosterone and androstenedione levels were found, suggesting the importance of the polymorphism of CYP17 in determining the circulating androgen levels.     

Low-activity V89L variant in SRD5A2 is associated with aggressive prostate cancer risk: an explanation for the adverse effects observed in chemoprevention trials using 5-alpha-reductase inhibitors

OBJECTIVE: The 5-alpha-reductase type 2 (5A2) enzyme catalyses the irreversible conversion of testosterone to dihydrotestosterone, the most active androgen in the prostate. This key enzyme in prostate gland physiopathology has recently been targeted by using inhibitors for chemoprevention of prostate cancer. However, some controversies have arisen by the observation of greater than expected high-grade tumours in men diagnosed with prostate cancer in the finasteride chemoprevention trial. To help understand the impact of prolonged exposure to low 5A2 activity on prostate cancer risk, we analysed the rather common genetic V89L polymorphism, which has previously been well characterised functionally for determining low enzymatic activities. METHODS: The study was performed on 1605 white Caucasian French men categorised in 803 patients with prostate adenocarcinoma and 802 matched healthy male controls. The different alleles and genotypes were analysed according to case-control status and the aggressiveness pattern of the tumours. RESULTS: The V89L amino acid substitution leading to the homozygous genotype LL increased the risk of clinically significant disease (odds ratio [OR]=1.89, 95% confidence interval (%95 CI), 1.07-2.74; p=0.0017) and was also associated with the most aggressive patterns of the disease (OR=2.56, 95%CI, 1.41-4.63; p=0.002). CONCLUSIONS: Our data confirm in a large and homogeneous Caucasian French population that the low-activity V89L variant is associated with an increased risk of aggressive prostate cancer. These results corroborate that long-term exposure to 5A2 inhibitors (chemoprevention) must be evaluated in terms of risk of prostate cancer adverse effects.     

Genetic polymorphisms in the androgen receptor and type II 5 alpha-reductase genes in prostate enlargement

PURPOSE: We examined the association of androgen receptor gene cytosine-adenine-guanine (CAG) repeat length and the 2 single nucleotide polymorphisms A49T and V89L in the type II 5 alpha-reductase gene with prostate enlargement measured as the weight of the surgically removed prostate. MATERIALS AND METHODS: A total of 68 men with a prostate weighing 80 gm. or greater were compared with 197 controls with a prostate weighing less than 80 gm. These men had undergone radical prostatectomy between 1992 and 1996. DNA was extracted from archival prostate tissue uninvolved with cancer and genotyped for 3 polymorphic markers. The effects of genetic variants and clinicopathological variables on prostate enlargement risk were estimated by logistic regression. RESULTS: The age adjusted odds ratio estimate of prostate enlargement risk in men with 23 or greater versus 20 or fewer CAG repeats was 0.41 (95% confidence interval 0.19 to 0.89). This risk reduction was consistently found when an alternative prostate enlargement definition and subject restriction were used. No consistent association with prostate enlargement risk was observed for A49T or V89L polymorphisms. CONCLUSIONS: Our finding further supports the hypothesis that the shorter CAG repeat length of the androgen receptor gene is related to prostate enlargement.     

Cystic fibrosis transmembrane conductance regulator (CFTR) gene 5T allele may protect against prostate cancer: a case-control study in Chinese Han population.

BACKGROUND: Cystic fibrosis transmembrane conductance regulator (CFTR) is expressed in a wide variety of epithelial cells including the prostate subglandular epithelia. Previous studies have suggested that CFTR mutations and polymorphisms may be associated with several cancers. Mutations and polymorphisms in the CFTR gene are responsible for cystic fibrosis (CF), and the incidence of prostate cancer in CF patients seemed to be lower than expected. METHODS: A hospital-based case-control study was conducted including 230 prostate cancer patients and 230 age-matched controls. We used nested PCR to analysis the IVS8-poly(T) tract and PCR-RFLP method to analysis the M470V polymorphism in CFTR gene. RESULTS: We observed an association of the low expression allele, IVS8-5T with prostate cancer protection (P=0.002; OR=0.281, 95%CI 0.120-0.658). Logistic regression analysis confirmed the 5T/7T genotype was in protective association with prostate cancer risk (P=0.003; OR=0.232, 95%CI 0.090-0.599). Linkage disequilibrium between IVS8-poly(T) and M470V existed among prostate cancer patients (D'=0.701). The low expression haplotype, "5T-V470" was found to be associated with protection against prostate cancer risk (P=0.010; OR=0.324, 95%CI 0.132-0.796). CONCLUSIONS: Our results indicate that the low expression CFTR polymorphisms may contribute to a reduced risk of prostate cancer in Chinese Han population.     

Factor XIII V34L polymorphism modulates the risk of chronic venous leg ulcer progression and extension

Low Factor XIII (FXIII) activity has been reported in the blood of patients with chronic venous leg ulcer (CVU). In vivo studies have described increased wound healing in CVU patients treated with FXIII concentrate, and in vitro studies have shown increased regenerative capacity in FXIII-treated fibroblasts. In addition, a common G-to-T polymorphism in the FXIIIA-subunit gene (V34L) significantly increases the activity and modifies the cross-linking properties of the FXIII molecule and this variant has been investigated as a protective factor against thrombosis, a recognized risk factor for CVU establishment. Therefore, the role of FXIII levels, FXIII V34L, FVR506Q, and FIIG20210A, common gene polymorphisms in the pathogenesis of CVU was investigated. Ninety-one patients with CVU and 195 healthy controls (91 of them sex- and age-matched) were PCR-genotyped for the FXIIIV34L, FVR506Q, and FIIG20210A substitutions and FXIIIA-subunit levels were determined by immuno-electrophoresis. The extent of the venous ulcer surface in patients was measured by computer software. The allele frequency and the genotype distribution of the FXIII polymorphism did not show significant differences between the whole group of cases and controls as well as prothrombin variants did. On the contrary, the FVR506Q variant (FV Leiden) allele was more frequent in patients, yielding a significant OR value of 5.93 (95 percent CI, 1.83-19.17; p= 0.003). Considering only CVU cases secondary to a post-thrombotic syndrome (n= 24), FV Leiden yielded a greater OR value of 16.08 (95 percent CI, 4.33-59.6; p < 0.0001). When the CVU cases were stratified by the three possible FXIII genotypes, a significant trend toward a lower mean value of the ulcerated area was clearly evident as the number of the polymorphic alleles (L34) increased in the genotype of patients (VV = 11.9 cm(2,)+/- 23.6; VL = 6.1 cm(2,)+/- 6.9; LL = 4.1 cm(2,)+/- 2.8; p= 0.01). On the other hand, FXIIIA antigen levels were similar between CVU cases and matched controls, but 11 percent of cases had FXIII deficiency (FXIIIA 相似文献   

SRD5A2 gene polymorphisms affect the risk of breast cancer

Androgens in breast cancer have been studied alone and in correlation with estrogens as estrogen to testosterone ratio. 5-α-reductase is one of the important enzymes participating in androgen metabolism, which affects androgen activity by affecting conversion of testosterone to dihydrotestosterone. We hypothesized that polymorphisms in the SRD5A2 gene (encoding 5-α-reductase) may affect breast cancer risk by affecting total androgen activity. Complete coding region of the SRD5A2 gene was sequenced in a group of 628 patients and 244 control samples from three southern states (Tamil Nadu, Andhra Pradesh, and Karnataka) of India. We observed three common polymorphisms in this gene; namely, A49T, V89L, and (TA)_n repeats. A49T locus was monomorphic in the study population, but V89L showed a strong correlation with breast cancer (P = 0.03, OR = 1.40, CI = 1.02–1.91). (TA)₀/(TA)₉ and (TA)₉/(TA)₉ genotypes were at a lower risk of breast cancer (P = 0.01, OR = 0.64, CI = 0.46–0.90). We conclude that SRD5A2 genotypes significantly affect breast cancer risk in the South Indian populations.