Vitamin D receptor gene polymorphism and prostate cancer risk

BACKGROUND: 1,25-dihydroxyvitamin D, the active form of vitamin D, exerts antiproliferative effect on prostatic cells, mediated through the vitamin D receptor. In a case-control study, we examined whether the vitamin D receptor (VDR) gene polymorphism in exon 9 could affect prostate cancer susceptibility. METHODS: One hundred ninety newly diagnosed prostate cancer patients and 190 age-matched men with benign prostatic hyperplasia (BPH), in whom the presence of prostate cancer was excluded clinically or histologically, were recruited for this study. The VDR TaqI polymorphism was investigated by polymerase chain reaction (PCR) following restriction fragment length polymorphism using DNA from lymphocytes. Depending on the presence or absence of the TaqI restriction site at the third position of codon 352, patients were classified as TT, Tt, or tt. RESULTS: The frequency of the tt genotype was not significantly different between prostate cancer patients (18%) and controls (12%; P = 0.07). The odds ratio (OR), calculated relative to individuals with the TT genotype was 1.76 (95% confidence limit (CL) = 0.90-3.45). After stratification for Gleason score and prostate specific antigen levels in a case-case comparison (n = 190), no significant associations with the VDR genotypes were detectable either. CONCLUSIONS: In this case-control study of Austrian Caucasians, no statistically significant association of the VDR TaqI polymorphism and prostate cancer risk was found.     

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.     

Polymorphic repeats in the androgen receptor gene in high-risk sibships

BACKGROUND: Genetic susceptibility may explain some familial clusters of prostate cancer. The polymorphic androgen receptor (AR) gene, which mediates androgen activity in the prostate, is a candidate gene that may influence predisposition to the disease. METHODS: We analyzed the polymorphic (CAG)n and (GGN)n repeats within the AR gene in men from 51 high-risk prostate cancer sibships, which included at least one affected and one unaffected man (n = 210). We compared repeat lengths of men with prostate cancer (n = 140) to their brothers (n = 70) without disease, stratified by median age at diagnosis of affected men within each sibship. Conditional logistic regression was used to compute odds ratios (OR) and 95% confidence intervals to evaluate associations between prostate cancer and repeat length. RESULTS: The OR for prostate cancer associated with short (CAG)n repeats (< 22) compared to longer repeats (> or =22) was 1.13 (95% CI 0.5-2.4) overall, but was higher in sibships with a median age of <66 years at diagnosis (OR = 1.72, 95% CI 0.5-6.0). The (GGN)n array also was not associated with prostate cancer in general. However, in older men (> or = 66 years), there was a modest elevation in risk (OR = 1.56, 95% CI 0.6-4.1) among those with short repeats (GGN of < or =16). Men with both a short (CAG)n (< 22) and a short (GGN)n (< or =16) array were not at higher risk (OR = 1.06) compared to men with two long repeats [(CAG)n > or =22 and (GGN)n >16)]. CONCLUSIONS: These results suggest that the (CAG)n and (GGN)n repeats in the AR gene do not play a major role in familial prostate cancer.     

Androgen receptor gene CAG repeat polymorphism and breast cancer risk in Iranian women: a case-control study

We investigated the association between polymorphic expansion of trinucleotide CAG repeats in androgen receptor (AR) gene and breast cancer risk among Iranian women in a matched case-control study. There was a strong overall association between per CAG repeat increments in average repeat length and the risk of the malignancy [OR=3.56; 95% CI, 2.80-5.29]. Women carrying one or two alleles with [CAG]n repeat ≥22 units were at increased risk of breast cancer [OR=2.03; 95% CI, 1.56-2.6]. The risk was significantly increased in homozygous longer repeats, versus homozygous alleles <22. We observed reduced risk of developing the tumor in positive familial breast cancer subjects carrying repeats ≥22 and 23. Homozygosity for the longer [CAG]n repeats may be linked to the increased breast cancer risk. In contrast to previous reports, longer AR [CAG]n repeat alleles may decline the risk among women with a familial breast cancer.     

Vitamin D receptor gene polymorphism in familial prostate cancer in a Japanese population

AIM: Vitamin D acts as an antiproliferative agent against prostate cells. Epidemiological study has shown that a low level of serum vitamin D concentration is a risk factor for prostate cancer. Vitamin D acts via vitamin D receptor (VDR), and an association of genetic polymorphisms of the VDR gene has been reported. In the current study, we examined the association of VDR gene polymorphisms with familial prostate cancer in a Japanese population. METHODS: We performed a case-control study consisting of 81 familial prostate cancer cases and 105 normal control subjects. Three genetic polymorphisms (BsmI, ApaI and TaqI) in the VDR gene were examined by the restriction fragment restriction length polymorphism method. RESULTS: Overall, there was no significant association of the VDR gene polymorphisms with familial prostate cancer risk in the cases and control subjects. However, a weak association between BsmI or TaqI genotypes and cancer risk was observed in subjects under 70 years of age. Stratification of cases by clinical stage or pathological grade did not show significant association between the VDR gene polymorphisms and prostate cancer risk. CONCLUSION: In the present study, we could not confirm any significant association between VDR gene polymorphisms with familial prostate cancer risk in a Japanese population. Further large-scale case-control studies are warranted to confirm the importance of VDR gene polymorphisms in familial prostate cancer.     

Vitamin D receptor gene BsmI and TaqI polymorphisms and fracture risk: a meta-analysis

INTRODUCTION: Fracture is the major clinical outcome of osteoporosis. The vitamin D receptor (VDR) gene is thought to be a candidate gene for osteoporosis. Many genetic studies have suggested an association of VDR polymorphisms and osteoporosis, but evidence remains conflicting. MATERIALS AND METHODS: We searched published studies from 1996 to September 2005 through PubMed and evaluated the genetic effect of the BsmI and TaqI polymorphism of VDR on fracture risk in a meta-analysis. Thirteen studies with a total of 20 eligible comparisons (1632 fracture cases and 5203 controls) were analyzed with fixed and random effects models. RESULT: No evidence of relationship between the VDR BsmI or TaqI polymorphism and fracture risk was observed with any genetic model. The odds ratio (95% confidence interval) of b-allele versus B-allele was 0.98 (0.86-1.12) with random effects calculations. There was significant between-study heterogeneity. Small studies did not differ significantly from larger ones. CONCLUSION: No relationship of the VDR BsmI or TaqI polymorphism and fracture risk was found in the meta-analysis of published data.     

雄激素受体基因ＣＡＧ多态性与前列腺癌的关系

目的：进一步探讨雄激素受体（ＡＲ)基因ＣＡＧ多态性与前列腺癌的关系,方法：采用分子生物学方法对３５８例前列腺癌患者ＡＲ基因ＣＡＧ进行测试,分析ＣＡＧ长度与临床各种指标的关系,结果：经统计学分析显示ＡＲ基因ＣＡＧ与年龄之间呈高相关性（Ｐ＝０．００７,r＝０．１１４）,但与ＰＳＡ、肿瘤分级及分期无显著相关性,结论：ＡＲ基因ＣＡＧ的长度与患者年龄成正比,即前列腺癌患者年龄越轻,其ＣＡＧ长度越短。     

Polymorphisms in the vitamin D receptor gene and the risk of calcium nephrolithiasis in children

OBJECTIVE: Polymorphism in the Vitamin D Receptor (VDR) gene has recently been reported to be associated with calcium metabolism disorders. This study was conducted to investigate the association of VDR gene polymorphism with the risk of calcium nephrolithiasis. METHODS: We investigated the VDR ApaI, BsmI and TaqI polymorphisms, in relation to serum calcium, phosphate, intact parathyroid hormone and 1.25(OH)(2)D(3) in 64 hypercalciuric stone-forming children and 90 healthy children. DNA was isolated from peripheral blood, and genotyping was performed with PCR-based methods. RESULTS: The frequency of ApaI AA genotype was significantly higher in the children with calcium nephrolithiasis than the controls (chi(2)=9.5; p=0.008). The distribution of BsmI and TaqI genotypes in stone-forming patients was similar to those in the control group. There was a significant association between TaqI TT genotype and the strength of the family history. The patients with TT genotype were observed to have a 8 times more risk than patients with Tt/tt genotype for recurrent stone episodes (OR 8, 95%CI 1.61-39.6). CONCLUSION: VDR genotype determination may provide a tool to identify individuals who are at a risk for calcium nephrolithiasis.     

Significance of the CAG repeat polymorphism of the androgen receptor gene in prostate cancer progression

PURPOSE: The CAG repeat polymorphism of the androgen receptor gene has been associated with an increased prostate cancer risk, and the repeat length correlated with cancer stage and grade at presentation. Men with an allele length of 18 CAG repeats, controlling for grade, stage and serum PSA level at diagnosis using Cox proportional hazard modeling. RESULTS: Overall, the CAG repeat allele was not predictive of recurrence; tumor grade, stage and PSA level at diagnosis were the only predictors of recurrence in a multivariate analysis. However, for patients at low risk for recurrence (Gleason score 2 to 6, stage pT2, and PSA 18 CAG repeats. In contrast, for patients at high risk of recurrence (Gleason score >/= 7, stage pT3/4, or PSA >10 ng./ml.), the relative risk associated with the 18 CAG repeat allele. CONCLUSIONS: The length of the CAG repeat polymorphism of the androgen receptor gene may be important for prostate cancer recurrence among patients who are otherwise at low risk for recurrence after radical prostatectomy. These findings have potential implications for patient selection for adjuvant treatment, and for the development of novel treatments.     

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.     

Androgen receptor CAG repeat length polymorphism in benign prostatic hyperplasia (BPH): correlation with adenoma growth.

BACKGROUND: The androgen receptor (AR) gene has a polymorphic CAG microsatellite encoding variable-length glutamine repeats in the AR protein. The purpose of this study was to evaluate the association between the growth of benign prostatic hyperplasia (BPH) and the AR gene CAG repeat length. METHODS: We determined CAG repeat lengths in 176 BPH patients who underwent simple prostatectomy and in 41 control subjects without benign prostatic enlargement (non-BPE group). RESULTS: A statistically significant (P < 0.02) trend for large adenoma size with short CAG repeat length was found among the adenoma quartiles. CAG repeat length in the fourth quartile (large adenoma, 21.5 +/- 2.7) was significantly shorter than in the first quartile (small adenoma, 23.3 +/- 2.1, P < 0.02). It tended to be shorter than in the non-BPE group (23.1 +/- 2.4), but CAG repeat lengths in the entire BPH (22.4 +/- 2.5) and non-BPE groups did not significantly differ. The relative risk of large BPH (the fourth quartile) was 2.75 (95% confidence interval, 1.05-7.24; P < 0.05) on comparing CAG repeats of < or = 22-> or = 23. CONCLUSIONS: Shorter CAG alleles may be a genetic factor that promotes the growth of BPH.     

A systematic review of vitamin D receptor gene polymorphisms and prostate cancer risk

PURPOSE: Polymorphisms in the vitamin D receptor gene have been hypothesized to alter the risk of prostate cancer. However, studies investigating the associations between specific vitamin D receptor polymorphisms and prostate cancer risk have yielded inconsistent results. MATERIALS AND METHODS: We performed a meta-analysis of 26 studies evaluating the association between vitamin D receptor TaqI, poly(A), BsmI, ApaI, and/or FokI polymorphisms, and prostate cancer risk. RESULTS: The studies were heterogeneous in terms of study design, selection of cases and controls, and racial composition. Random effects models were used to estimate the pooled OR and 95% CI of each vitamin D receptor polymorphism under codominant, additive, dominant and recessive genetic models. Overall we did not find evidence to support an association between any of the vitamin D receptor polymorphisms and the risk of prostate cancer. For TaqI, which is the most studied vitamin D receptor polymorphism with 18 studies (total of 2,727 cases and 3,685 controls), the pooled OR was 1.00 (95% CI 0.85 to 1.18) for the Tt vs TT genotypes, 0.94 (95% CI 0.78 to 1.13) for the tt vs TT genotypes and 0.89 (95% CI 0.71 to 1.10) for the recessive model (tt vs Tt plus TT). ORs for the poly(A) microsatellite, BsmI, ApaI and FokI polymorphisms were similar. CONCLUSIONS: The results of this meta-analysis suggest that the vitamin D receptor TaqI, poly(A), BsmI, ApaI and FokI polymorphisms are not related to prostate cancer risk.     

Androgen receptor gene haplotype is associated with male infertility

The purpose of the current study was to evaluate the importance of androgen receptor ( AR ) gene haplotypes and polymorphic CAG/GGN microsatellites in the aetiology of male infertility. We genotyped six haplotype-tagging single nucleotide polymorphisms and CAG/GGN microsatellites of the AR gene in 112 infertile and 212 control Estonian men. A total of 13 AR haplotypes (HAP1–13) were identified, among which HAP4 was found to confer increased risk for male infertility (OR = 5.15, 95% CI = 1.75–15.15, p  = 0.003). However, infertile patients and controls had similar lengths and distributions of both AR CAG (mean ± SD number of repeats 21.1 ± 2.5 vs . 21.2 ± 2.3, respectively) and GGN (mean ± SD number of repeats 22.5 ± 1.5 vs . 22.4 ± 1.9, respectively) repeats. In addition, HAP2 was associated with more CAG repeats ( r  = 1.17, p  = 0.033) and HAP3 with fewer CAG repeats ( r  = −2.93, p  < 0.001) than the major haplotype HAP1. HAP3 and HAP4 were associated with more GGN repeats ( r  = 1.35, p  = 0.001 and r  = 1.36, p  = 0.002, respectively) than HAP1. In conclusion, our results implicated the AR -HAP4 gene haplotype in increased risk for male infertility, while no association was found between AR CAG/GGN microsatellites and impaired spermatogenesis.     

Associations of serum testosterone with microvessel density,androgen receptor density and androgen receptor gene polymorphism in prostate cancer

PURPOSE: We investigate potential associations of serum testosterone with microvessel density, androgen receptor expression and AR gene polymorphism in men with untreated prostate cancer. MATERIAL AND METHODS: Serum luteinizing hormone, follicle-stimulating hormone, estradiol and testosterone were determined in men with newly diagnosed prostate cancer. The number of tumor vessels per 0.46 mm. and androgen receptor density (as the percent positive nuclei) were quantified immunohistochemically on prostate cancer areas of prostate biopsy specimens. Polymorphisms within the AR gene (number of CAG repeats) were determined by polymerase chain reaction and restriction fragment length polymorphism analysis using DNA from peripheral blood. RESULTS: The 39 men entered into this study were grouped into 16 with low (3 ng./ml. or less, group 1) and 23 with normal (greater than 3 ng./ml., group 2) serum testosterone. Mean prostate specific antigen +/- SD was significantly lower in group 1 than in group 2 (18.8 +/- 11.1 versus 27.2 +/- 12.2 ng./ml., p = 0.03). Mean Gleason score (7.4 +/- 1.3 versus 6.0 +/- 1.2, p = 0.01), androgen receptor density (96.6% +/- 2.8% versus 84.8% +/- 7.2%, p = 0.03) and tumor vessel density (63.0 +/- 30.8/0.46 versus 39.0 +/- 22.9/0.46 mm.2, p = 0.007) were significantly higher in group 1 than in group 2. The number of CAG repeats within the AR gene did not correlation with serum androgen. CONCLUSIONS: Low serum testosterone in men with newly diagnosed prostate cancer is associated with higher tumor microvessel and androgen receptor density as well as with higher Gleason score, suggesting enhanced malignant potential.     

Interaction between the vitamin D receptor gene and collagen type Ialpha1 gene in susceptibility for fracture.

Osteoporosis is a common disease with a strong genetic component. Polymorphisms in the vitamin D receptor (VDR) gene have been implicated in osteoporosis but explain only a small part of the genetic effect on bone mineral density (BMD) while their effect on fractures is still uncertain. Recently, a G to T polymorphism in an Sp1 site in the collagen type Ialpha1 (COLIA1) gene was found to be associated with reduced BMD and with increased fracture risk. To analyze the combined influence of polymorphisms in the VDR gene and the COLIA1 gene in determining the susceptibility to osteoporotic fracture, we studied 1004 postmenopausal women. The "baT" VDR haplotype, constructed from three adjacent restriction fragment length polymorphisms, was found to be overrepresented among fracture cases (p = 0.009). This corresponded to an odds ratio (OR) of 1.8 (95% CI, 1.0-3.3) for heterozygous carriers and 2.6 (95% CI, 1.4-5.0) for homozygous carriers of the risk haplotype. The effect was similar for vertebral and nonvertebral fractures and, most importantly, independent of BMD. We observed significant interaction (p = 0.03) between VDR and COLIA1 genotype effects. Fracture risk was not VDR genotype-dependent in the COLIA1 "reference" group (genotype GG) while in the COLIA1 "risk" group (genotypes GT and TT) the risk of fracture was 2.1 (95% CI, 1.0-4.4) for heterozygous and 4.4 (95% CI, 2.0-9.4) for homozygous carriers of the VDR risk haplotype. We conclude that both the VDR and the COLIA1 polymorphisms are genetic markers for osteoporotic fracture in women, independent of BMD. Our data indicate that interlocus interaction is likely to be an important component of osteoporotic fracture risk.     

Androgen receptor CAG polymorphism and the risk of benign prostatic hyperplasia in a Brazilian population

Benign prostatic hyperplasia (BPH) is a very frequent age-related proliferative abnormality in men. Polymorphic CAG repeat in the androgen receptor (AR) can alter transactivation of androgen-responsive genes and potentially influence BPH risk. We investigated the association between CAG repeat length and risk of BPH in a case-control study of a Brazilian population. We evaluated 214 patients; 126 with BPH and 88 healthy controls. DNA was extracted from peripheral leucocytes and the AR gene was analyzed using fragment analysis. Hazard ratio (HR) and 95% confidence interval were estimated using logistic regression models. Mean CAG length was not different between patients with BPH and controls. The CAG repeat length was examined as a categorical variable (CAG ≤ 21 vs. CAG > 21 and CAG ≤ 22 vs. CAG > 22) and did not differ between the control vs. the BPH group. We found no evidence for an association between AR CAG repeat length in BPH risk in a population-based sample of Brazilians.     

Polymorphic forms of prostate specific antigen and their interaction with androgen receptor trinucleotide repeats in prostate cancer

BACKGROUND: Recent data has suggested that polymorphisms in the prostate specific antigen (PSA) may increase prostate cancer (PC) risk. The PSA gene contains a G/A substitution in the androgen response element (ARE) 1 region. The androgen receptor (AR) gene has polymorphic regions containing variable length glutamine and glycine repeats and these are believed to be associated with PC risk. The effect on PC risks from PSA polymorphisms alone and synergistically with the AR gene was examined in this report. METHODS: One hundred PC patients and an age matched cohort of 79 benign prostate hyperplasia and 67 population controls were entered in this study. DNA was extracted from blood and PSA/ARE promoter region amplified by PCR. PCR products were cut with Nhe 1 restriction enzyme to distinguish G/A alleles. AR/CAG and GGC repeat length was detected by automated fluorescence from PCR products. RESULTS: We found a significantly higher PSA/GG distribution in PC (30%) than either benign prostatic hyperplasia (BPH) (18%) or population controls (16%) (P = 0.025). Furthermore the GG distribution within cases was even greater in younger men (< 65 years; 42%; P = 0.012). Additionally, when PSA genotype was cross classified with CAG repeat, significantly more cases than both BPH and population controls were observed to have a short (< 22) CAG/GG genotype (P = 0.006). CONCLUSIONS: Our results indicate that the PSA/ARE GG genotype confers an increased risk of PC especially among younger men. Moreover, we confirm previous results that a short glutamine repeat in conjunction with GG genotype significantly increases the risk of malignant disease.     

Androgen receptor polymorphisms and risk of biochemical failure among prostatectomy patients

BACKGROUND: Little is known about the role of inherited genotypes in prostate cancer (PC) progression. This prospective study evaluated the predictive value of androgen receptor (AR) polymorphisms (CAG and GGC repeats) among prostatectomy patients. METHODS: We studied 354 patients registered at M. D. Anderson Cancer Center from 1991 to 2001. Kaplan-Meier and Cox proportional hazard analyses were used. RESULTS: During an average follow-up of 56 months, 66 (19%) post-prostatectomy patients experienced biochemical failure (BF). Patients with higher CAG repeats (CAG > or = 24) had significantly longer BF-free survival (BFFS) than those with fewer repeats (CAG < or = 23) (P = 0.04). Higher CAG repeats were significantly associated with lower BF risk among Whites and African Americans. Among Whites, longer CAG repeats (relative risk (RR) = 0.45, P = 0.03) and Gleason score > or = 8 (RR = 19.33, P = 0.005) remained significant BFFS predictors in multivariate analysis. GGC repeats were not associated with BF. CONCLUSIONS: Our data showed that an inherited polymorphism (CAG repeats) in the AR is related to differences in genetic susceptibility to BF, supporting the hypothesis that increased AR activity may play a role in PC progression.