The CAG repeat polymorphism of androgen receptor gene and prostate cancer: a meta-analysis

The association between the polymorphic CAG repeat in androgen receptor gene (AR) and prostate cancer susceptibility has been studied extensively. However, the results are contradictory. The purpose of our meta-analysis was to investigate whether CAG repeat related to prostate cancer risk and had genetic heterogeneity across different geographic regions and study designs. Random-effects model was performed irrespective of between-study heterogeneity. Data and study quality were assessed in duplicate. Publication bias was assessed by the fail-safe number and Egger’s test. There were 16 (patients/controls: 2972/3792), 19 (3835/4908) and 12 (3372/2631) study groups for comparisons of ≥20, 22 and 23 repeats of CAG sequence, respectively. Compared with CAG repeat <20, 22 or 23, carriers of ≥20, 22 or 23 repeats had 21% (95% CI: 0.61–1.02; P = 0.076), 5% (95% CI: 0.81–1.11; P = 0.508) and 5% (95% CI: 0.76–1.20; P = 0.681) decreased risk of prostate cancer. After classifying studies by geographic areas, carriers of ≥20 repeats had 11% decreased risk in populations from USA, 53% from Europe, and 20% from Asia (P > 0.05), whereas comparison of ≥23 repeats with others generated a significant prediction in European populations (OR = 1.17; P = 0.039). Stratification by study designs revealed no material changes in risk estimation. Meta-regression analysis found no significant sources of between-study heterogeneity for age, study design and geographic region for all comparisons. There was no identified publication bias. Taken together, our results demonstrated that AR CAG repeat polymorphism with ≥20 repeats might confer a protective effect among the prostate cancer patients with 45 years older but not all the prostate cancer patients.     

Gender diagnosticity and androgen receptor gene CAG repeat sequence.

The gender diagnosticity (GD) approach of Lippa (1995) was used to evaluate the relationship of within-sex differences in psychological masculinity-femininity to a genetic characteristic, the length of a repeated CAG sequence in the X-linked androgen receptor (AR) gene. Previously assessed adult samples in Australia and Sweden were used for this purpose. A weak relationship (correlations in the range .11 to .14) was obtained in both countries. Additional data from adolescent twins from Australia (12-, 14-, 16-year-olds) did not confirm such a relationship at those ages, especially for males. The fact that this sample consisted of twins permitted two kinds of within-pair comparisons: (1) Did the dizygotic twin who had the longer AR sequence have the higher GD score? (2) Was one twin's GD score more highly correlated with the other twin's AR score in MZ than in DZ pairs? The answer in both cases was negative. Clarification of these relationships will require large samples and measurements at additional ages.     

CAG repeat polymorphism in the androgen receptor (AR) gene of SBMA patients and a control group

Spinobulbar muscular atrophy (SBMA) is an X-linked form of motor neuron disease characterized by progressive atrophy of the muscles, dysphagia, dysarthria and mild androgen insensitivity. SBMA is caused by CAG repeat expansion in the androgen receptor gene. CAG repeat polymorphism was analysed in a Polish control group (n = 150) and patients suspected of SBMA (n = 60). Normal and abnormal ranges of CAG repeats were established in the control group and in 21 patients whose clinical diagnosis of SBMA was molecularly confirmed. The ranges are similar to those reported for other populations.     

雄激素受体基因（CAG）重复序列长度多态性与前列腺疾病

雄激素受体基因中的CAG重复序列长度的多态性，与前列腺疾病的发病率密切相关，有可能成为有效的危险判定因子。本文试图对这方面的进展作一简要介绍。     

CAG polymorphism of the androgen receptor gene in azoospermic and oligozoospermic men from Ukraine

An analysis of the number of CAG repeats in exon 1 of the gene was conducted in a group of 228 infertile males with azoospermia (n = 68) and oligozoospermia (n = 160), and in a control group (124 proven fathers) by means of polymerase chain reaction with subsequent fragment analysis on an ALF-Express automated fluorescent analyzer. Allele frequency with the number of CAG repeats ≤ 18 was found to be significantly higher (P < 0.01) in the group of patients with azoospermia (17.7%) as compared to the control group (2.4%), and in the group of patients with oligozoospermia (12.5%) as compared to the control group (2.4%). Allele frequency with the number of CAG repeats ≥ 28 was shown to be significantly higher (P < 0.01) in patients with oligozoospermia (12.5%) as compared to the control group (2.4%). Our data suggest an association between the number of CAG repeats and impaired spermatogenesis in azoospermic and oligozoospermic males.     

Androgen receptor gene methylation and exon one CAG repeat length in ovarian cancer: differences from breast cancer

More than one neoplastic founder clone can exist in benign epithelial tumours. Although theories of clonal selection make pluriclonality appear unlikely in carcinomas, published data do not exclude this possibility. This study looked for evidence of multiclonal X inactivation in ovarian carcinoma using AR methylation as a marker. Fifteen unifocal ovarian carcinomas and 14 multifocal carcinomas all in Scottish patients were studied. One representative formalin-fixed paraffin-embedded tumour block was chosen for each of the former and two for the latter. From each of these 43 tumour blocks three samples each of approximately 10(4) carcinoma cells were obtained by microdissection (129 in all). DNA released by proteinase K digestion was subjected to PCR amplification of the androgen receptor gene AR exon I CAG repeat polymorphism with and without prior digestion with methylation-sensitive restriction enzymes HpaII and HhaI. Complex amplification patterns were consistent with mosaic X inactivation in some ovarian carcinomas but acquired anomalies of AR methylation cannot be excluded. Parallel analysis of other X-linked polymorphic loci would strengthen the inference of clonality status from DNA methylation data in tumour X studies. Strikingly, the number of CAG repeats in the 29 ovarian tumour patients (median 16, range 11 - 20) was substantially fewer than in 34 previously studied breast cancer patients from the same scottish population (median 21, range 14 - 26; P < 0.0001), and women homozygous for the AR CAG repeat were over-represented in the ovarian cancer patients but not in the breast cancer series. These findings reinforce recent suggestions that AR may have a role in ovarian carcinogenesis.     

CAG repeat polymorphism in androgen receptor gene is not directly associated with polycystic ovary syndrome but influences serum testosterone levels

Hyperandrogenemia has been the most consistent feature of polycystic ovary syndrome (PCOS). Androgens exert their effects through androgen receptors (ARs). The expansion of the codon CAG trinucleotide repeat polymorphism in exon 1 of the AR gene represents a type of genetic alteration associated with changes in the AR gene function. The purpose of this study was to establish a possible association of the AR gene CAG repeat length polymorphism with PCOS, and its influence on clinical and biochemical androgen traits. Two hundred and fourteen Croatian women with PCOS and 209 healthy control women of reproductive age were enrolled. Phenotypic hyperandrogenism, BMI and waist to hip ratio were recorded. Hormonal profiles, fasting insulin and glucose levels were measured on cycle days 3-5. Genotyping of the CAG repeat polymorphism in the AR gene was performed. We found no significant difference in the mean CAG repeat number between the PCOS patients and controls (22.1±3.4 vs. 21.9±3.2, P=0.286). There was a positive correlation between the CAG repeat length and total testosterone (TT) in the PCOS group (R=0.225, P=0.015). A multiple linear regression model using mean CAG repeat length, BMI, age and HOMA-IR as predictors explained 8.5% (adjusted R2) of the variability in serum TT levels. In this model the CAG repeat polymorphism was found to be a significant predictor of serum TT levels in PCOS patients (P=0.015). The logistic regression analysis revealed that the CAG repeat length is not a significant predictor of hirsutism and acne status (P=0.921 and P=0.437, respectively). The model was adjusted for serum TT, free testosterone, androstendione and DHEAS levels as independent variables, which were also not found to be significant predictors of hirsutism (P=0.687, P=0.194, P=0.675 and P=0.938, respectively) or acne status (P=0.594, P=0.095, P=0.290 and P=0.151, respectively). In conclusion, the AR CAG repeat polymorphism is not a major determinant of PCOS in the Croatian population, but it is a predictor of serum TT level variability in women with PCOS.     

The androgen receptor CAG repeat length polymorphism associates with prostate volume in Finnish men with benign prostatic hyperplasia

The development of benign prostatic hyperplasia requires the presence of testicular androgens during prostate development, puberty, and ageing. We thus examined the association of three polymorphisms, namely, CYP3A5 6986A>G, CYP19A1 1531C>T, and androgen receptor (AR) gene CAG repeat length, which have previously been linked to the androgen pathway and with clinical characteristics of benign prostatic hyperplasia. Tissue samples from 262 consecutive prostate operations were used for genotyping. Prostate volumes and prostate-specific antigen values were collected from patient records. Linear regression analysis was performed to study the polymorphisms in an age-adjusted model. We did not find any association between the CYP3A5 6986A>G polymorphism and clinical characteristics of benign prostatic hyperplasia. Further, the previously published CYP19A1 1531C>T polymorphism association with an enlarged prostate could not be confirmed with this material. However, we detected an association between short AR gene CAG repeat length and a small prostate volume, which confirms a previous finding in the Finnish population. The data presented suggest a negligible role for the CYP3A5 6986A>G polymorphism in benign prostate enlargement in the Finnish population. However, the results presented do provide further evidence for potentially different genetic mechanisms behind benign prostatic hyperplasia in Finnish and other Caucasian populations. This is based on the conflicting results for AR gene CAG repeat length associations with benign prostatic hyperplasia found in published works.     

Role of androgen receptor CAG repeat polymorphism and X-inactivation in the manifestation of recurrent spontaneous abortions in Indian women

The aim of the present study was to investigate the role of CAG repeat polymorphism and X-chromosome Inactivation (XCI) pattern in Recurrent Spontaneous Abortions among Indian women which has not been hitherto explored. 117 RSA cases and 224 Controls were included in the study. Cases were recruited from two different hospitals - Lakshmi Fertility Clinic, Nellore and Fernandez Maternity Hospital, Hyderabad. Controls were roughly matched for age, ethnicity and socioeconomic status. The CAG repeats of the Androgen Receptor gene were genotyped using a PCR-based assay and were analysed using the GeneMapper software to determine the CAG repeat length. XCI analysis was also carried out to assess the inactivation percentages. RSA cases had a significantly greater frequency of allele sizes in the polymorphic range above 19 repeats (p = 0.006), which is the median value of the controls, and in the biallelic mean range above 21 repeats (p = 0.002). We found no evidence of abnormal incidence of skewed X-inactivation. We conclude that longer CAG repeat lengths are associated with increased odds for RSA with statistical power estimated to be ∼90%.     

Automated fragment analysis method for determining androgen receptor CAG repeat length

Several studies have associated polymorphisms in the androgen receptor gene with the risk of developing hormone-dependent cancers. A highly polymorphic (CAG)n repeat in exon 1 encodes a polyglutamine tract of varying length. The determination of the number of CAG repeats in the androgen receptor has typically been performed on denaturing polyacrylamide gels with autoradiographic orfluorescent detection of differently sized alleles. Samples run on a capillary electrophoresis-based ABI Prism 310 Genetic Analyzer gave anomalous results when internal standards supplied by the manufacturer were used Here we report a modified procedure for androgen receptor allele size determination that can be used on an automated capillary electrophoresis-based DNA sequencer equipped with the appropriate software. The assay is very precise, comparable to DNA sequencing, and is compatible with the latest generation of automated DNA sequencers.     

Androgen receptor CAG polymorphism and prostate cancer risk

Recent studies have suggested that polymorphisms of the androgen receptor gene ( AR) may influence the risk of prostate cancer (PC) development and progression. Here, we analyzed the length of the CAG repeat of the AR gene in 1363 individuals, including patients with PC, benign prostate hyperplasia (BPH), and population controls. There was a tendency for short CAG repeats to be associated with PC. The Odds Ratio (OR) for PC was 1.47 ( P=0.05) when individuals with short CAG repeats (18). CAG repeat length was not significantly associated with family history, disease stage, grade, age at diagnosis, prostate-specific antigen (PSA) level at diagnosis, or prognosis of the patients. Unexpectedly, short CAG repeats were significantly less common in patients with BPH compared with controls (OR=0.47, P=0.03). Our results suggest that the CAG polymorphism of the AR gene is unlikely to have a major role in the development or progression of PC in the Finnish population. The association of CAG repeats with the risk of BPH warrants further study.     

Variation in CAG repeat length of the androgen receptor gene predicts variables associated with intrasexual competitiveness in human males

An expanding body of research suggests that circulating androgens regulate the allocation of energy between mating and survival effort in human males, with higher androgen levels promoting greater investment in mating effort. Because variations in the number of CAG codon repeats in the human androgen receptor (AR) gene appear to modulate the phenotypic effects of androgens - with shorter repeat lengths associated with greater androgenic effects per unit androgen - polymorphisms in this gene may predict trait-like individual differences in the degree to which men are calibrated toward greater mating effort. Consistent with this, men in the present study with shorter CAG repeat lengths exhibited greater upper body strength and scored higher on self-report measures of dominance and prestige, all of which are argued to be indices of mating effort. Repeat length failed to predict sociosexual orientation (i.e. pursuit of short-term mating relationships), however, suggesting that the traits correlated with this polymorphism may be primarily associated with intrasexual competitiveness in the service of long-term mating effort. None of these measures of mating effort was related to baseline testosterone concentrations (either as main effects or as interactions with CAG repeat length), implying that long-term androgen exposure associated with AR gene polymorphisms may account for more variance in some androgen-dependent traits than does current testosterone concentration. These findings provide further evidence for the importance of the CAG repeat polymorphism in the AR gene in explaining a broad range of individual differences in human males.     

Association of the CAG repeat polymorphisms in androgen receptor gene with polycystic ovary syndrome: A systemic review and meta-analysis

Background

Many studies have reported the associations of polymorphic CAG repeats in androgen receptor (AR) gene with PCOS risk, but with inconsistent results. So, the aim of present meta-analysis was to clarify such inconsistence, so as to provide more conclusive results.

Methods

PubMed was searched for the eligible reports published until February 2012 without language limitation. The studies reporting the relationship between CAG repeat length and PCOS were selected for the meta-analysis according to the inclusion criteria. Two reviewers independently extracted the data and evaluated the study quality.

Principal findings

As for the relationship between CAG repeat length and PCOS risk, the pooled results showed that the biallelic mean was not significantly different between PCOS and controls (SMD − 0.03, 95% CI − 0.16–0.10, P = 0.603), and that the ORs of PCOS were not demonstrated for the individuals with the biallelic mean less than median (OR 0.96, 95% CI 0.68–1.35, P = 0.794), with the short CAG allele (OR 0.94, 95% CI 0.80–1.10, P = 0.424), or with the X-weighted biallelic mean (OR 0.81, 95% CI 0.46–1.41, P = 0.447). Further, as for the relationship between CAG repeat length and T levels in PCOS patients, the biallelic mean was not significantly different between PCOS patients with high T and those with low T (SMD 0.79, 95% CI − 0.12–1.70, P = 0.088), while the summary correlation r indicated that the CAG biallelic mean appeared to be positively associated with T levels in PCOS (r 0.20, 95% CI 0.11–0.30, p = 0.000).

Conclusions

This meta-analysis demonstrates no evident association between the CAG length variations in AR gene and PCOS risk, while the CAG length appears to be positively associated with T levels in PCOS patients.     

Androgen receptor CAG repeat polymorphism in males of six non-human primate species

Background Androgen receptor [CAG]_n microsatellite has been linked to human diseases. Methods Six non‐human primates were genotyped for the [CAG]_n microsatellite. Results Marmosets and macaques are monomorphic, while mangabeys, baboons, and chimpanzees are polymorphic. Conclusions Non‐human primates that are polymorphic for the microsatellite are candidate animal models for CAG‐related diseases.     

GGC and StuI polymorphism on the androgen receptor gene in endometrial cancer patients

Androgens have an anti-proliferative effect on endometrial cells. Human androgen receptor (AR) gene contains two polymorphic short tandem repeats of GGC and CAG, and a single-nucleotide polymorphism on exon 1 that is recognized by the restriction enzyme, StuI. Prior studies have shown that the lengths of the CAG repeat are inversely and linearly related to AR activity and associated with endometrial cancer. However, little is known about the GGC repeat and the StuI polymorphism of the AR gene. Thus, we investigated whether these AR polymorphisms are risk factors for endometrial cancer. To test this hypothesis, the genetic distributions of these polymorphisms were investigated in blood samples from endometrial cancer patients and healthy controls. The allelic and genotyping profiles were analyzed by polymerase chain reaction (PCR), PCR-restriction fragment length polymorphism (PCR-RFLP), and direct DNA sequencing, and analyzed statistically. The GGC repeat was significantly longer in endometrial cancer patients as compared to normal healthy controls. In general, an increased risk of endometrial cancer was found with increasing GGC repeat. The relative risk for the 17 GGC repeat was greater than 4, as compared to controls. However, the StuI polymorphism was not significantly different between patients and controls. The findings suggest that increased numbers of GGC repeat on the AR gene may be a risk factor for endometrial cancer.