Repeats In Androgen Receptor Gene Research Articles

A pharmacogenetic approach to improve low ovarian response: The role of CAG repeats length in the androgen receptor gene

The AR (androgen receptor) polymorphism is associated with POR risk. Furthermore, the use of androgens in POR remains controversial. Our data could clarify the effectiveness of androgen pretreatment. AR genotyping could help us to identify patients at risk for POR and POR patients that will be benefited of androgen pretreatment. ObjectiveThe aim of this project was to investigate if the AR (androgen receptor) polymorphism could be used to identify patients at risk for POR and that will benefit from androgens pretreatment. Study DesignTo evaluate the POR risk we performed a cohort study including 231 patients (54 POR and 177 control). Moreover, we included 88 IVF-cycles performed by 44 POR-patients to assess the effect on ovarian response. All patients performed two cycles: a standard ovarian stimulation and a second one with androgen preparation. We compare the results in pair from each. ResultsPOR showed the highest frequency of CAG repeats at 24 vs 22 in controls. Only 33% of POR have alleles with a repeat number below 23, compared with 50% of controls (p < 0.05). According to AR polymorphism ovarian response differences were shown. Patients that carried CAG repeats in AR gene between 22 and 24 showed an increased in the number of oocytes (2.61 in cycles without androgens vs 5.11 when they were pretreated with androgens; p < 0.05). For the patients that carried repeats lower than 22 and higher than 24, no differences were reported in the number of oocytes obtained in the cycle with or without androgens (2.94 vs 2.56; p = 0.88). Similar results were obtained for mature oocytes in patients that carry a number of CAG repeats between 22 and 24 (1.86 MII in cycles without androgens vs 4.04 MII when they were pretreated with androgens; p < 0.05). No differences in the number of MII oocytes were found in patients that get out of 22 and 24 repeats between the two cycles (2.31 vs 2.13; p = 0.88). ConclusionThe AR polymorphism is associated with POR risk, patients with repeats greater than 22 show a higher risk. Our data suggest that AR genotype could play a role in natural ovarian aging. Furthermore, the use of androgens in POR remains controversial. Our data suggest that the AR genotype could clarify the effectiveness of the androgen pretreatment. AR genotyping could help us to identify patients at risk of POR and POR patients that could benefit from transdermal testosterone pretreatment.

Androgen receptor gene polymorphisms and risk of prostate cancer: a meta-analysis

Although the association between CAG and GGN repeats in the androgen receptor gene and prostate cancer risk has been widely studied, it remains controversial from previous meta-analyses and narrative reviews. Therefore, we performed this meta-analysis to provide more precise estimates with sufficient power. A total of 51 publications with 61 studies for CAG repeats and 14 publications with 16 studies for GGN repeats were identified in the meta-analysis. The results showed that short CAG repeats (<22 repeats) carriers presented an elevated risk of prostate cancer than long CAG repeats (≥22) carriers (OR = 1.31, 95% CI 1.16 to 1.47). Prostate cancer cases presented an average fewer CAG repeats (MD = −0.85, 95% CI −1.28 to −0.42) than controls. Short GGN repeats (≤16) carriers presented an increased risk of prostate cancer than long GGN repeats (>16) carriers (OR = 1.38, 95% CI 1.05 to 1.82). In subgroup analyses, the abovementioned significant association was predominantly observed in Caucasian populations. The meta-analysis showed that short CAG and GGN repeats in androgen receptor gene were associated with increased risk of prostate cancer, especially in Caucasians.

Shorter GGN Repeats in Androgen Receptor Gene Would Not Increase the Risk of Prostate Cancer.

The association between the polymorphic GGN repeat in androgen receptor gene and prostate cancer susceptibility has been studied extensively. But the results of these polymorphisms with prostate cancer risk remain inconclusive. Previous meta-analysis showed short GGN repeats (≤16 repeats) had high risks for prostate cancer compared with longer GGN repeats (>16 repeats). Many studies have been published since the release of the previous meta-analysis. Here, we conducted an updated meta-analysis to demonstrate whether short repeats have higher risks for prostate cancer compared to long repeats. Five databases (PubMed, EMBASE, Cochrane Library, The China National Knowledge Infrastructure, and Web of Science) were last searched until January 1, 2016. Random- or fixed-effects model was performed based on the heterogeneity among studies. The potential publication bias was assessed via Begg funnel plot and Egger regression test. Twelve out of 157 studies were extracted. The result indicated that there was no significant difference between short repeat group and long repeat group in the overall analysis ( I2 = 80.6%, P = .000, odds ratio = 1.31, 95% confidence interval: 0.93-1.83). There was no association between the length of GGN repeats and the occurrence of prostate cancer in both Caucasian and African American ( I2 = 6.7%, P = .359, odds ratio = 1.11, 95% confidence interval: 0.94-1.32; and I2 = 74.1%, P = .050, odds ratio = 0.963, 95% confidence interval: 0.36-2.58). Our result demonstrated that a shorter GGN repeat polymorphism cannot increase the risk of prostate cancer compared to the longer GGN repeats. That's different with previous meta-analysis.

Molecular pathogenesis in granulosa cell tumor is not only due to somatic

Granulosa cell tumors are rare ovarian malignancies. Their characteristics include unpredictable late recurrent and malignant behavior. Recent molecular studies have characterized the FOXL2 402C > G mutation in adult-type granulosa cell tumor. In this study, we report an 80-year-old woman with a granulosa cell tumor arising from ovary. She presented with a huge pelvic mass with postmenopausal bleeding. No obvious intraperitoneal tumor implants were observed during operation. Final diagnosis was granulosa-theca cell tumor without capsule invasion. No recurrent disease was noted during 3-year post-operation follow-up period. Molecular studies showed a heterozygous FOXL2 402C > G mutation in the tumor by direct gene sequencing. In addition, DNA replication error, on analysis of the lengths of CAG repeats in androgen receptor gene, revealed defective DNA mismatch repair system in the granulosa cell tumor. We propose that the 402C > G mutation in FOXL2 is critical to the development of adult granulosa cell tumor. However, the malignant behavior of this tumor is driven by DNA mismatch repair deficiency. Unequal DNA copy numbers were noted on array comparative genomic hybridization. This implies that there is malignant potential even in the early stage of the granulosa cell tumor. Late malignant recurrence may be a late event of DNA repair function disability, not directly related to pathognomonic FOXL2 mutation.

Effect of smoking on semen quality, FSH, testosterone level, and CAG repeat length in androgen receptor gene of infertile men in an Indian city

This study was conducted as part of an epidemiological survey of 126 nonsmokers and 178 smokers, showing primary infertility residing around Kolkata region of Eastern India. Their lifestyle history including smoking habits along with semen and blood were collected. The study examined the association of cigarette smoking with the risk of infertility, by determining the semen quality, follicle stimulating hormone (FSH), luteinizing hormone (LH), testosterone levels, and androgen receptor (AR)-CAG repeat length in a group of smokers compared with a control group (non smokers). Based on conventional WHO criteria, lower sperm motility (P < 0.001) and increased sperm morphological defects (P < 0.0001) were associated with smoking habits. Binary logistic regression analysis for the effect of smoking status on sperm DNA integrity demonstrated significant positive correlation (p = 0.006). Serum FSH and LH levels were higher for smokers compared with non-smokers while the testosterone level decreased significantly with the increasing smoking habit. The mean length of CAG repeats in AR gene was significantly higher for smokers with low testosterone compared to non-smokers. The study suggested that smoking is associated with altered semen quality, endocrine hormonal status, and number of CAG repeats in the AR gene.

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.

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

To investigate the role of CAG and GGN repeats as genetic background affecting androgen insensitivity syndrome (AIS) phenotype. 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. 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). 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.

Clinical manifestations and molecular genetics of spinal bulbar muscular atrophy: report of 5 cases

To study the clinical and molecular genetic characteristics of spinal bulbar muscular atrophy (SBMA). The clinical data, including case history, physical examination, biochemical analyses of blood, EMG, and muscle biopsy, of 5 Chinese patients with SBMA, all males, aged 29 - 58, with the onset age of 36 (17 - 49), were collected the information of in 5 cases. Four patients underwent PCR to examine the number of copies of CAG repeat region in androgen receptor (AR) gene. The clinical characteristics of the 5 patients included atrophy of lingualis, dysarthria, weakness and waste of the limbs, especially in the hands, and elevated creatine kinase (CK), fasting glucose, testosterone, and progesterone in the blood. EMG showed denervation motor potentials in all cases. The muscle biopsy in one case showed neurogenic atrophy. The number of (CAG) n repeat in AR gene was 50 - 62 in the, remarkably from that of 13 normal controls (19 - 20) without overlapping. SBMA affects the middle age males, shows a slowly progressing muscular atrophy in spinal and bulbar muscles. The different number of (CAG) n repeat of AR gene between the SBMA patients and the normal controls may be an important identification to differentiate SBMA from other motor neuron diseases.

Effectiveness of Finasteride on Patients with Male Pattern Baldness Who Have Different Androgen Receptor Gene Polymorphism

Finasteride is not necessarily effective on all of the male pattern baldness (MPB) patients. To know any factor which correlates with the effectiveness of finasteride, the polymorphism of androgen receptor (AR) gene was analyzed. Symptoms of the 488 MPB patients (18-62 y) before and after treatment with total dose of 10 mg or more of finasteride was typed by photographic method. The number of CAG and GGC repeats in AR gene of MPB patients was determined by DNA sequencing. When the number of the triplet repeats (CAG + GGC) was plotted against the degree of symptom improvement after treatment with this drug, a broad correlation between these variables was observed. The smaller the repeat number, the higher the improvement with finasteride. The group of patients with shorter repeat region in AR gene responded better to this drug than that with longer repeat region, although the former patients tended to reveal severe initial symptoms. Determination of such polymorphism is thought to be useful in the drug choice for MPB patients.

The polyglycine and polyglutamine repeats in the androgen receptor gene in Japanese and Caucasian populations

Human androgen receptor (AR) gene contains two polymorphic trinucleotide repeats of CAG and GGC, which code for polyglutamine and polyglycine tracts in the N-terminal domain in which the receptor activity resides. Longer repeats induce decrease of transactivation function in the AR receptor, weaken an anti-proliferative effect on various steroid-related tissues, and may promote the carcinogenesis of these cancers, such as breast, endometrial, and ovarian cancers. However, the incidences of these steroid-related cancers are remarkably lower in Japanese than in Caucasians. We hypothesize that the GGC and CAG repeats in AR gene correspond to lower incidence of steroid-related cancers in the Japanese population. To test this hypothesis, these two polymorphic trinucleotide repeats in AR gene were genotyped in 221 Japanese and 177 Caucasians. The results of genotyping in these loci clearly show that the distribution of GGC repeat is significantly different between these populations ( P<0.001). Japanese (73.7%) had 16 GGC repeats compared to 53.3% for Caucasians. Japanese (3.8%) also had 17 GGC repeats compared to 36.2% for Caucasians. No Japanese had more than 18 GGC repeats compared to 3.4% for Caucasians. The length of CAG repeats in the Japanese population was not significantly different than that of the Caucasian population, although the CAG repeats varied from 14 to 31 and 15 to 29 repeats in Japanese and German populations, respectively. This study demonstrates that the Japanese population has shorter GGC compared to the Caucasian population, which may explain the incidences of estrogen-related cancers in these populations.

Cytogenetic and molecular analysis of the Y chromosome: absence of a significant relationship between CAG repeat length in exon 1 of the androgen receptor gene and infertility in Indian men

The genetic basis of male infertility remains unclear in the majority of cases. Recent studies have indicated an association between microdeletions of the azoospermia factor a (AZFa)-AZFc regions of Yq and severe oligospermia or azoospermia. Increased (CAG)n repeat lengths in the androgen receptor (AR) gene have also been reported in infertile men. Therefore, in order to assess the prevalence of these genetic defects to male infertility, 183 men with non-obstructive azoospermia (n = 70), obstructive azoospermia (n = 33), severe oligospermia (n = 80) and 59 fertile men were examined cytogenetically and at molecular level for Yq deletions, microdeletions, and AR-CAG repeat lengths along with hormonal profiles [luteinizing hormone (LH), follicle-stimulating hormone (FSH) and testosterone (T)]. We used high resolution cytogenetics to detect chromosome deletions and multiplex polymerase chain reaction (PCR) involving 27 sequence-tagged site (STS) markers on Yq to determine the rate and extent of Yq microdeletions. PCR amplification with primers flanking exon 1 of AR gene was used to determine the AR-(CAG)n repeat lengths. Hormonal profiles (LH, FSH and T levels) were also analysed in infertile and fertile men. Testicular biopsies showed Sertoli cell only (SCO) morphology, maturation arrests (MA) and hypospermatogenesis. No chromosome aberrations were found in infertile men but there was a significant increase (p < 0.001) in the association of acrocentric chromosomes including the Y chromosome. Yq microdeletions were found in 16 non-obstructive azoospermic men (16 of 70; 22%) and seven severe oligospermic individuals (seven of 80; 8.7%) and most of them had deletions in the sY240 locus. No Yq microdeletions were detected in patients with obstructive azoospermia. No statistically significant difference in the mean length of CAG repeats in AR gene was observed between infertile and fertile men (22.2 +/- 1.5 and 21.5 +/- 1.4 respectively). No significant increase or decrease in levels of LH, FSH and T was observed in infertile and fertile men. In some infertile men, significantly elevated levels of FSH alone or in combination with LH were found to be indicative of failure of spermatogenesis and/or suggestive of testicular failure. Y-chromosome microdeletions contribute to infertility in some patients but no relationship could be established with the (CAG)n repeat lengths in exon 1 of the AR gene in infertile Indian men.

No association between mutations in the human androgen receptor GGN repeat and inter-sex conditions.

The functional role of the GGN repeat in the human androgen receptor gene is unknown, although mutations in this region have been found in patients with inter-sex conditions. We have investigated the prevalence of GGN mutations in the androgen receptor in the Swedish population and their relation to male reproductive function. A physical examination and semen analysis was carried out in 223 men under medical examination before military service and in 94 men referred due to infertility and having sperm concentrations <5 x 10(6)/ml. The GGN and CAG repeats in the androgen receptor gene were directly sequenced. Both populations contained two predominant alleles of 23 and 24 GGN repeats, 83.8 and 90.5% respectively. Four mutations, three in the conscripts and one among the infertile men, were found, resulting in three GGC to GGT substitutions and one GGT to GGC substitution. None of the men presented with genital abnormalities, but two conscripts had low ejaculate volumes (0.3 and 0.9 ml). All men carrying a mutation also had GGN lengths >or=24. Three subjects with GGN >24, with no mutations and with normal seminal volumes, were also found. Our findings indicate that point mutations in the GGN repeat are frequently found in the general male population (1.3%; 95% CI: 0.3-3.9%), but are usually not associated with profound changes in the male phenotype.

Detection of an Amadori product, 1-hexitol-lysine, in the anterior horn of the amyotrophic lateral sclerosis and spinobulbar muscular atrophy spinal cord: evidence for early involvement of glycation in motoneuron diseases.

Glycation is a series of non-enzymatic reactions initiated by addition of reducing sugars to epsilon-amino group of lysine residues and alpha-amino group of the N terminus of proteins, leading to the formation of advanced glycation end products (AGE). It is thought to be involved in aging and various neurodegenerative conditions. In the present study using anti-1-hexitol-lysine (1-HL) antibody, Amadori product, an early glycation product, was detected in axonal spheroids in the anterior horn of amyotrophic lateral sclerosis and in atrophic neurons of spinobulbar muscular atrophy (SBMA, Kennedy disease with abnormally expanded triplet repeats in androgen receptor gene) but not in other regions of the central nervous system. Furthermore, Amadori product was undetectable in the tissues from age-matched controls. Thus, 1-HL formation could not reflect physiological aging.

Measurement of polymorphic trinucleotide repeats in the androgen receptor gene by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry

Trinucleotide repeats are polymorphic in normal individuals. CAG repeats in the X-linked androgen receptor gene were counted by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI/TOF-MS). A region of approximately two hundred base-pairs containing the repeats was amplified by polymerase chain reaction, then measured after a simple purification procedure. The single-charged molecular ion species was detected using 0.1 pmol of DNA sample and the number of repeats was determined from the molecular mass. The results indicated that MALDI/TOF-MS is a high-throughput alternative to polyacrylamide gel electrophoresis for precise determination of polymorphic trinucleotide repeats. Copyright © 1999 John Wiley & Sons, Ltd.

Measurement of polymorphic trinucleotide repeats in the androgen receptor gene by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry.

Trinucleotide repeats are polymorphic in normal individuals. CAG repeats in the X-linked androgen receptor gene were counted by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI/TOF-MS). A region of approximately two hundred base-pairs containing the repeats was amplified by polymerase chain reaction, then measured after a simple purification procedure. The single-charged molecular ion species was detected using 0.1 pmol of DNA sample and the number of repeats was determined from the molecular mass. The results indicated that MALDI/TOF-MS is a high-throughput alternative to polyacrylamide gel electrophoresis for precise determination of polymorphic trinucleotide repeats.

CAG-repeat expansion in androgen receptor in Kennedy's disease is not a loss of function mutation

Expansion of CAG trinucleotide repeats in androgen receptor gene is present in patients with a rare X-linked inherited form of motor neuron disorder termed Kennedy's disease or spinal and bulbar muscular atrophy (SBMA). This is a late onset progressive disease often associated with mild signs of androgen insensitivity. Defects in androgen receptor (AR) action have been linked to the expansion of the CAG trinucleotide repeats and postulated to be the cause of the disease. We have identified a trinucleotide repeat of 45 in the N-terminus of the AR in two brothers with SBMA and several members in their family (range in the general population is 11–35). Treatment of the patients with androgens failed to improve their clinical symptoms and provided no hint of an anomalous function of the AR. Consistently, functional analysis of the mutant receptor showed hormone binding, transactivation and transrepression potentials identical to that of the wild-type receptor. These results together argue against SBMA being a loss of function mutation of the AR.

Aberrant androgen action and increased size of tandem CAG repeat in androgen receptor gene in X-linked recessive bulbospinal neuronopathy

Plasma levels of testosterone, luteinizing hormone (LH) and follicle-stimulating hormone (FSH) after 3 or 6 days of administration of the synthetic androgenic hormone fluoxymesterone (10 mg/day) were measured in 26 patients with X-linked recessive bulbospinal neuronopathy (X-BSNP) and 22 age-matched male controls. The testosterone, LH and FSH levels in the controls were markedly suppressed after administration, but in the patients with X-BSNP, they were suppressed significantly less. The level of suppression varied considerably with the patients, and those of plasma testosterone and FSH were significantly correlated with the number of CAG repeats in the androgen receptor gene. These findings suggest that the androgen action was aberrantly transduced in the target organs in the patients with X-BSNP and which is related to the elongated CAG repeat in the androgen receptor gene.

Very late onset X-linked recessive bulbospinal neuronopathy: mild clinical features and a mild increase in the size of tandem CAG repeat in androgen receptor gene.

Very late onset X-linked recessive bulbospinal neuronopathy: mild clinical features and a mild increase in the size of tandem CAG repeat in androgen receptor gene.

Severity of X‐linked recessive bulbospinal neuronopathy correlates with size of the tandem cag repeat in androgen receptor gene

The genetic mutation of X-linked recessive bulbospinal neuronopathy is amplification of a polymorphic tandem CAG repeat in the androgen receptor gene. We studied this CAG repeat in 26 Japanese patients from 21 families with X-linked recessive bulbospinal neuronopathy. The number of CAG repeats was significantly correlated with the age at onset of limb muscular weakness (r = -0.596, p < 0.001) and age-adjusted scored disability (r = 0.446, p < 0.03). The length of the CAG repeat therefore seems to be a determinant factor of clinical severity.