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.     

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.     

Polymorphisms in the androgen receptor and the prostate-specific antigen genes and prostate cancer risk

BACKGROUND: Prostate cancer (PCa) is an androgen-dependent disease. Polymorphic CAG and GGC microsatellites in the androgen receptor (AR) can alter transactivation of androgen-responsive genes in in vitro studies. Potentially, this may influence PCa risk. METHODS: Germline DNA samples and survey data were collected from 591 newly diagnosed PCa cases and 538 population-based controls of similar age (40-64 years), from King County, WA. Odds ratios (ORs) and 95% confidence limits were estimated using logistic regression models. RESULTS: No association was detected between PCa and having <22 versus > or =22 CAG repeats (OR = 1.1; 95% CI 0.9, 1.4) or < or =16 GGC versus >16 GGC repeats (OR = 1.0; 95% CI 0.9, 1.4). These findings were unchanged after controlling for body mass index or family history of PCa. No clear relation was detected between APS -158 G/A genotype and risk of PCa or serum prostate-specific antigen (PSA) levels. These findings did not differ by stage or grade of PCa. CONCLUSIONS: We found no evidence that risk of PCa is associated with the AR CAG, GGC, or PSA-158 AREI genetic polymorphisms in middle-aged Caucasian men.     

Androgen receptor gene polymorphisms and the fat-bone axis in young men and women

Androgen receptor (AR) CAG(n) (polyglutamine) and GGN(n) (polyglycine) repeat polymorphisms determine part of the androgenic effect and may influence adiposity. The association of fat mass, and its regional distribution, with the AR CAG(n) and GGN(n) polymorphisms was studied in 319 and 78 physically active nonsmoker men and women (mean ± SD: 28.3 ± 7.6 and 24.8 ± 6.2 years old, respectively). The length of CAG and GGN repeats was determined by polymerase chain reaction and fragment analysis, and confirmed by DNA sequencing of selected samples. Men were grouped as CAG short (CAG(S)) if harboring repeat lengths ≤ 21, the rest as CAG long (CAG(L)). The corresponding cutoff CAG number for women was 22. GGN was considered short (GGN(S)) if GGN ≤ 23, the rest as GGN long (GGN(L)). No association between AR polymorphisms and adiposity or the hormonal variables was observed in men. Neither was there a difference in the studied variables between men harboring CAG(L) + GGN(L),CAG(S) + GGN(S),CAG(S) + GGN(L), and CAG(L) + GGN(S) combinations. However, in women, GGN(n) was linearly related to the percentage of body fat (r = 0.30, P < .05), the percentage of fat in the trunk (r = 0.28, P < .05), serum leptin concentration (r = 0.40, P < .05), and serum osteocalcin concentration (r = 0.32, P < .05). In men, free testosterone was inversely associated with adiposity and serum leptin concentration, and positively with osteocalcin, even after accounting for differences in CAG(n), GGN(n), or both. In summary, this study shows that the AR repeat polymorphism has little influence on absolute and relative fat mass or its regional distribution in physically active men. In young women, GGN length is positively associated with adiposity, leptin, and osteocalcin.     

Polymorphisms in the vitamin D receptor gene and the androgen receptor gene and the risk of benign prostatic hyperplasia

OBJECTIVE: Little is known about risk factors for the development of benign prostatic hyperplasia (BPH). Recently, associations were observed between prostate cancer (CaP) risk and polymorphisms in the vitamin D receptor (VDR) gene and the androgen receptor (AR) gene. Since both receptors are relevant for prostate growth, the VDR and AR are also expected to be involved in the development of BPH. The objective of this study is to establish the relationship between the risk of BPH and a polymorphism in the number of CAG repeats in the AR gene and a TaqI restriction enzyme polymorphism in the VDR gene. METHODS: For this study, 98 patients who had been treated for BPH-related complaints and 61 convenience controls (predominantly bladder cancer patients) were recruited from the outpatient clinic. DNA was isolated from peripheral blood, and genotyping was performed with PCR-based methods. Means as well as odds ratios (ORs) with 95% confidence intervals (CI) were calculated using SPSS software. RESULTS: The mean number of CAG repeats in the AR gene in patients and controls was found to be similar: 21.8 (SD = 2.8) and 21.9 (SD = 2.9), respectively. In the subgroup of patients with a prostate volume of at least 50 cm(3), the mean number of repeats was 21.5 (SD = 2.6). The OR for BPH for individuals with homozygous presence of the VDR TaqI restriction fragment length polymorphism (RFLP) (tt) versus individuals with homozygous absence (TT) or heterozygotes (Tt) was found to be 1.0 (95% CI 0.4-2.4). For individuals with a prostate volume of at least 50 cm(3), the OR was 1.2 (95% CI 0.5-3. 2). CONCLUSION: Unlike earlier observations in prostate cancer, we did not find an association between the CAG repeat polymorphism in the AR gene and the TaqI RFLP polymorphism in the VDR gene and the risk of BPH.     

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.     

Androgen insensitivity syndrome: do trinucleotide repeats in androgen receptor gene have any role?

AIM: To investigate the role of CAG and GGN repeats as genetic background affecting androgen insensitivity syndrome (AIS) phenotype. METHODS: We analyzed lengths of androgen receptor (AR)-CAG and GGN repeats in 69 AIS cases, along with 136 unrelated normal male individuals. The lengths of repeats were analyzed using polymerase chain reaction (PCR) amplification followed by allelic genotyping to determine allele length. RESULTS: Our study revealed significantly shorter mean lengths of CAG repeats in patients (mean 18.25 repeats, range 14-26 repeats) in comparison to the controls (mean 22.57 repeats, range 12-39 repeats) (two-tailed P < 0.0001). GGN repeats, however, did not differ significantly between patients (mean 21.48 repeats) and controls (mean 21.21 repeats) (two-tailed P = 0.474). Among patients' groups, the mean number of CAG repeats in partial androgen insensitivity cases (mean 15.83 repeats) was significantly less than in complete androgen insensitivity cases (mean 19.46 repeats) (two-tailed P < 0.0001). CONCLUSION: The findings suggest that shorter lengths of repeats in the AR gene might act as low penetrance genetic background in varying manifestation of androgen insensitivity.     

前列腺癌与雄激素受体基因(CAG)n重复多态性的关系

目的　探讨前列腺癌 (PC)与雄激素受体 (AR)基因 (CAG)n重复多态性的关系。　方法　应用DNA双链循环测序方法对 34例PC组织与癌旁正常组织、2例PC患者外周血白细胞内的AR基因 (CAG)n重复数进行测定。　结果　同一PC患者的癌组织与癌旁正常组织 (CAG)n重复数相同 ;36例患者癌组织AR基因 (CAG)n呈重复多态性 ,平均 2 0 .0 6 ,显著低于正常组织 ,差别有显著性意义 (P <0 .0 5 ) ;不同分化程度的癌组织 (CAG)n重复数差别无显著性意义 (P >0 .0 5 )。　结论　AR基因 (CAG)n重复数改变的体细胞突变在PC癌细胞中罕见 ,该重复数的减少可能与PC发病相关     

雄激素受体基因CAG多态性对男性激素避孕有效性影响的研究

目的:分析应用肌注十一酸睾酮酯(TU)进行激素避孕的男性志愿者中起反应者与不起反应者雄激素受体(AR)基因(CAG)n微卫星多态性,并探讨该多态性对激素避孕效果的影响。方法:29例TU不起反应者和34例起反应者分别作为试验组和对照组,应用PCR和DNA测序技术对两组外周血标本进行CAG重复数测定,分析该微卫星多态性对激素避孕效果的影响。结果:试验组和对照组CAG重复数的均数分别为23.62和22.97,均数比较差异无显著性(P>0.05)。短组CAG(n≤22)在试验组和对照组的分布分别为51.7%、50.0%;长组CAG(n>22)在试验组和对照组分布分别为48.3%、50.0%,长短组分布相同。CAG重复数与精子密度之间未见相关性。在FSH浓度>0.2IU/L组中,CAG重复数>22的受试者达到无精子症的机会是其他受试者的1.5倍。结论:受试者AR基因(CAG)n重复数呈多态性,但不反应组与反应组之间不具有显著性差异,AR基因CAG重复数或其他因素与男性激素避孕效果之间的关系有待进一步探讨。     

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.     

Evidence for association of sex hormone-binding globulin and androgen receptor genes with semen quality

The roles of androgen receptor AR(CAG)n gene polymorphisms and sex hormone-binding globulin SHBG(TAAAA)n gene polymorphisms on semen quality were studied. One hundred fourteen men were included in the study: 85 with normal sperm count and 29 oligospermic. The genotype analysis, on DNA extracted from spermatozoa, revealed five SHBG(TAAAA)n alleles with 6–10 repeats and 18 AR(CAG)n alleles with 12–32 repeats. The SHBG allelic distribution showed that in men with normal sperm count and motility, those with short SHBG alleles had higher sperm concentration than men with long SHBG alleles ( P  = 0.039). As concerns AR(CAG)n polymorphisms, men with short AR alleles had lower sperm motility compared to those with long AR alleles ( P  < 0.001) in both total study population and normal sperm count men. The synergistic effect analysis of the two polymorphisms revealed an association between sperm motility ( P  = 0.036), because of the effect of AR(CAG)n polymorphism on sperm motility. In conclusion, long AR alleles were found to be associated with higher sperm motility, while short SHBG alleles were associated with higher sperm concentration, supporting the significance of these genes in spermatogenesis and semen quality.     

No association of androgen receptor GGN repeat length polymorphism with infertility in Indian men

Androgens, acting through the androgen receptor (AR), play a role in secondary sexual differentiation from the prenatal stage to adulthood, including spermatogenesis. The AR gene has 2 polymorphic trinucleotide repeats (CAG and GGN) in exon 1. The CAG repeat length polymorphism has been well studied in a variety of medical conditions, including male infertility. Many of these studies have shown an association of the expanded CAG repeats with male infertility, although this is not true for all populations. The GGN repeat, in contrast, has been less thoroughly studied. Thus far, only 4 reports worldwide have analyzed the GGN repeat, alone or in combination with the CAG repeat, in male infertility cases. No such study has been undertaken on infertile Indian men. Therefore, we have analyzed AR-GGN repeats in a total of 595 Indian males, including 277 azoospemric, 97 oligozoospermic, and 21 oligoteratozoospermic cases, along with 200 normozoospermic controls. The analysis revealed no difference in the mean number or the range of the repeat between cases (mean = 21.51 repeats, range 15-26 repeats) and controls (mean 21.58 repeats, range 15-26 repeats). Furthermore, no difference was observed when azoospermic (mean = 21.53 repeats, range 15-26 repeats), oligozoospermic (mean = 21.46 repeats, range 15-26 repeats), and oligoteratozoospermic cases (mean = 21.48, range 19-26 repeats) were compared individually with the controls.     

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.     

The polymorphic androgen receptor gene CAG repeat,pituitary-testicular function and andropausal symptoms in ageing men

The activity of androgen receptor (AR) is modulated by a polymorphic CAG trinucleotide repeat in the AR gene. In the present study, we investigated hormonal changes among ageing men, and whether the number of AR CAG triplets is related to the appearance of these changes, as well as symptoms and diseases associated with ageing. A total of 213 41-70-year-old men donated blood for hormone analyses (LH, testosterone, oestradiol and SHBG) and answered questions concerning diseases and symptoms associated with ageing and/or androgen deficiency. Of these men, 172 donated blood for the measurement of the CAG repeat length of AR. The CAG repeat region of the AR gene was amplified by polymerase chain reaction (PCR) and the products were sized on polyacrylamide gels. The repeat number was analysed as a dichotomized variable divided according to cut-off limits of the lowest (< or =20 repeats) and the highest quartile (> or =23 repeats), and as a continuous variable. The proportion of men with serum LH in the uppermost quartile (>6.0 IU/L) with normal serum testosterone (>9.8 nmol/L, above the lowest 10%) increased significantly with age (p = 0.01). There were fewer men with this hormonal condition among those with CAG repeat number in the uppermost quartile (> or =23 repeats) (p = 0.03). These men also reported less decreased potency (p < 0.05). The repeat number was positively correlated with depression, as expressed by the wish to be dead (r = 0.45; p < 0.0001), depressed mood (r = 0.23; p = 0.003), anxiety (r = 0.15; p < 0.05), deterioration of general well-being (r = 0.22; p = 0.004), as well as decreased beard growth (r = 0.49; p < 0.0001). A hormonal condition where serum testosterone is normal but LH increased is a frequent finding in male ageing. Only certain types of age-related changes in ageing men were associated with the length of the AR gene CAG repeat, suggesting that this parameter may play a role in setting different thresholds for the array of androgen actions in the male.