AR-CAG Repeat Length Research Articles

Preeclampsia and androgen receptor gene CAG repeat length: results from both children and women

We studied whether the CAG (encoding glutamine) repeat length polymorphism in the first exon of the androgen receptor (AR) gene is predictive of preeclampsia. Fifty-nine children born after preeclamptic pregnancy (PRE) and 58 control subjects born after normotensive pregnancy (non-PRE) were genotyped for the CAG repeat length of the AR gene. Secondly, the ARCAG repeat lengths of 133 unrelated preeclamptic women and 112 healthy controls were studied. The mean AR gene CAG lengths were compared between the preeclampsia and the control groups. The mean length of the CAG repeat segment among children was significantly shorter in the PRE group compared with the non-PRE group (p = 0.02). Interestingly, the difference between the PRE and the non-PRE boys was even more significant (p = 0.008). Also the distribution of allele frequencies was different, short repeat lengths being overrepresented in the PRE children. However, there were no significant differences in the mean CAG repeat lengths between the unrelated preeclamptic women and their controls, but the shortest CAG repeat lengths were found only in the preeclamptic women. The AR gene CAG repeat length is not a major determinant in the development of preeclampsia. The association of the shortest CAG repeats with preeclampsia is possible, but a larger study group is needed to confirm this finding.

Androgen receptor gene cytosine, adenine, and guanine trinucleotide repeats in patients with endometriosis.

A genetic variation in the androgen receptor (AR) has been associated with the risk of developing endometriosis. The AR gene is located on the X chromosome and contains a highly polymorphic trinucleotide repeat (cytosine, adenine, and guanine: CAG) in its first exon, whose length and methylation pattern affect both AR expression and function. Thus, we sought to further investigate the potential association between endometriosis and the AR-CAG polymorphism. Genomic DNA was obtained from a consecutive series of 197 white Italian women of reproductive age who underwent laparoscopy for benign gynecologic pathologies. Molecular analysis of AR-CAG repeats was performed by polymerase chain reaction amplification and Genescan evaluation. The pattern of CAG repeat distribution was compared between subjects with and without endometriosis. Endometriosis was documented in 105 women (stage I-II in 33 women and stage III-IV in 72 women). We found no difference in the number of AR-CAG repeats between women with endometriosis and controls. The CAG repeat length ranged from eight to 27 (mean +/- standard deviation, 17.4 +/- 1.9) for endometriosis patients and from 11 to 27 (mean +/- standard deviation, 17.4 +/- 2) for controls. Moreover, no association was found between AR gene polymorphisms and the various clinical manifestations of the disease. We conclude that AR-CAG repeat length does not constitute an important factor for the genetic predisposition to endometriosis.

Polymorphism in the androgen receptor and mammographic density in women taking and not taking estrogen and progestin therapy.

There is some evidence that women with a higher number of CAG repeat lengths on the androgen receptor (AR) gene have increased breast cancer risk. We evaluated the association between AR-CAG repeat length and mammographic density, a strong breast cancer risk factor, in 404 African-American and Caucasian breast cancer patients. In postmenopausal estrogen progestin therapy users, carriers of the less active AR-CAG had statistically significantly higher mean percentage of density (41.4%) than carriers of the more active AR-CAG (25.7%; P = 0.04). Our results raise the question of whether the number of AR-CAG repeats predicts breast cancer risk in estrogen progestin therapy users.

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.

Polymorphic CAG repeat length within the androgen receptor gene: identification of a subgroup of patients with increased risk of ovarian cancer

The CAG repeat (CAGn) present in the N-terminal region of the androgen receptor (AR) inversely correlates with AR transactivation activity. The aim of this study was to investigate whether polymorphic variation in the CAGn length is associated with the risk of developing ovarian cancer. Using a case-control study design 121 women with histologically confirmed ovarian cancer and 100 controls (healthy women) were genotyped for AR-CAG length. No marked difference in the mean length of CAGn was observed between ovarian cancer patients and controls. However, when considering patients with positive personal or family history of tumor (PPFHT), the mean lengths of the long allele, the short allele and the average of the 2 alleles were longer than in the controls. Odds ratios (OR) and their corresponding 95% confidence intervals (CI) were computed after allowance for age. We observed an increase in the risk of ovarian cancer, in terms of OR, in women with CAGn >or=22 (OR=2.17, 95% CI:1.10-4.27). The increase of relative risk was particularly high in women with CAGn >or=22 belonging to the PPFHT group: OR=3.52 (95% CI 1.18-10.47). We also found a statistically significant trend (chi2 trend=4.91; p=0.03) towards an increased risk of ovarian cancer with increasing CAGn length (from <or=21 to 22-23, 24-25 and >or=26). Again, a strong association between increase in CAGn and risk of ovarian cancer was observed in PPFHT patients (chi2 trend=6.38; p=0.01). The results suggest that AR-CAG repeat length could play a role as modifier of the ovarian cancer risk conferred by highly penetrant genes rather than itself conferring a low risk.

The androgen receptor CAG repeat: a modifier of carcinogenesis?

The first exon of the human androgen receptor (AR) contains a translated CAG (poly-glutamine) repeat. The repeat length is polymorphic in the normal population ranging from 8 to 35 repeats. Expansions to over 40 repeats lead to spinal bulbar muscular atrophy (SBMA), a late onset neurodegenerative disease. The repeat is located between the two parts of a bipartite amino-terminal transactivation function and the repeat length, also within in the normal range, is inversely correlated to the transactivation power of the receptor. P160 type co-activators bind more strongly to shorter repeats. A correlation between AR CAG repeat length and total risk, age at diagnosis, recurrence after surgery and aggressive growth has been reported for tumors of classical androgen target tissues. In the prostate, where androgens exert a mitogenic effect, the cancer risk increases with decreasing AR-CAG repeat length. In contrast, in the breast, where the hormone probably acts as anti-mitogen, a higher risk and earlier onset of breast cancer has been reported for carriers of BRCA1 mutations who also have long CAG repeats in the receptor gene. Somatic alterations during carcinogenesis appear to be frequent in endometrial and in colon cancer. In the endometrium the AR CAG repeat prevalently undergoes expansions consistent with the putative protective function of androgens in this tissue. Frequent repeat reductions during colon carcinogenesis would be consistent with a mitogenic effect of androgens. Analysis of AR protein expression by Western blot reveals expression of the AR in healthy and neoplastic colon tissues. Normal mucosa of the colon expresses both AR-isoforms of 110 and 87 kDa, while the tumor samples have lost the expression of the 110-kDa isoform. The 87-kDa isoform is devoid of the amino-terminal portion of the receptor molecule that also contains the poly-glutamine tract. The temporal and causal relation between isoform switch and somatic repeat reductions during colon carcinogenesis is as yet unclear, but the two events could both enhance p160 mediated androgen signaling. The recent finding that smad3 interacts with the AR in a way similar to p160 links the AR to TGFβ signaling. Interruption of this signaling pathway is a frequent event in colon carcinogenesis.

Lack of influence of the androgen receptor gene CAG-repeat polymorphism on sex steroid status and bone metabolism in elderly men.

Population means for serum testosterone (T) levels in healthy men decrease with ageing but there is considerable interindividual variability of serum T in elderly men. Ultimate androgen action is mediated through the androgen receptor. Subtle differences in androgen sensitivity might contribute to serum T variability through the T negative feedback regulation. The androgen receptor gene (AR) contains in exon 1 a polymorphic trinucleotide CAG-repeat, whose length modulates androgen receptor action. The aims of the study were to assess the potential contribution of the AR CAG-repeat polymorphism in the interindividual variability of serum T and in the determination of bone metabolism in ambulatory elderly men. We used cross-sectional baseline data of a longitudinal study investigating the process of ageing, in particular the changes in hormonal status and bone metabolism, in a cohort of 273 community-dwelling healthy men, between age 71 and 86 years. AR CAG-repeat length was determined by automated DNA sequencing of exon 1 of the AR gene. Serum T, sex hormone binding globulin, LH and oestradiol were measured by specific immunoassays. Bone mineral density (BMD) was determined by dual energy X-ray absorptiometry. Bone turnover was assessed by measurement of serum bone-specific alkaline phosphatase, serum osteocalcin, serum C-terminal type I procollagen peptide, serum and urinary C-terminal telopeptides of type I collagen and urinary deoxypyridinoline levels, with use of immunoassays. No significant association was found between the AR CAG-repeat length and either total or free T, LH or the androgen sensitivity index (LHxT). BMD measurements at the hip and the forearm were not associated with AR CAG-repeat length and there was no association of this AR polymorphism with any of the biochemical markers of bone turnover. Results were not different after adjustments for age and body mass index. The findings of the present study do not support the view that in community-dwelling, healthy elderly men the androgen receptor gene CAG-repeat polymorphism has a substantial impact on interindividual variability of serum testosterone levels or on the determination of bone turnover and bone mineral density.

The polymorphic CAG repeat in the androgen receptor gene in Jewish Israeli women with endometrial carcinoma.

Endometrial carcinoma is considered a hormonal-dependent tumor; estrogen induces endometrial cellular proliferation, whereas progestins display an antiproliferative effect on endometrial tissue. The role that androgen and its receptor (androgen receptor [AR]) play in the pathogenesis of endometrial carcinoma is less clear. Although androgen has an in vitro inhibitory effect on endometrial cell proliferation, up to 75% of endometrial carcinoma express AR somatically. A polymorphic CAG repeat within exon 1 of the AR encodes for a polyglutamine tract, with length range of 8 to 33 repeats, which is inversely correlated with the transcriptional activity of the AR. To gain insight into the role of AR in endometrial carcinoma, the authors analyzed the polymorphic CAG repeat in 79 Jewish Israeli patients with endometrial carcinoma as compared with 44 healthy Jewish women serving as controls. Analysis was conducted using germline DNA as template and using polymerase chain reaction primers flanking the CAG repeat with subsequent fluorescent determination of allele sizes. Allele size range of the longer of the two alleles in the patients was 11-33 (mean, 19.8 +/- 2.7) and in the controls 10-22 (mean, 17.9 +/- 1.9), a statistically significant difference (P < 0.01). Allele size variation within the patient group did not correlate with disease stage, grade, reproductive history, or age at diagnosis. The authors conclude that AR-CAG repeat length differs in Jewish patients with endometrial carcinoma as compared with healthy individuals in Israel, and this finding increases the possibility that the AR is involved in the predisposition to this neoplasm.