CAG Repeat Polymorphism Research Articles

Testosterone rapidly increases men’s emotion-based dehumanization of a conservatively dressed woman

Past research has found that sexualized women are often dehumanized (i.e., attributed reduced human qualities). However, the mechanisms contributing to such dehumanization remain poorly understood. In this pre-registered experiment involving a within-subject, placebo-controlled, cross-over design, we tested whether testosterone contributes to men’s (N = 120, age range: 18–38 years) dehumanization of women. After administration of intranasal testosterone or placebo gel, men watched a video of a woman wearing either modest (i.e., conservative) or revealing (i.e., sexualized) clothing (between-subjects factor) and then completed three subtle dehumanization tasks, measuring emotion-based, personality-based, and perceptual dehumanization. We hypothesized that testosterone would increase dehumanization, especially for men who watched the “sexualized-clothing” video. Instead, we found that, while men engaged in emotion-based dehumanization toward the sexualized woman both when they had testosterone and placebo, testosterone increased emotion-based dehumanization toward the conservatively dressed woman. Other forms of dehumanization were not affected by testosterone. We also explored whether personality (e.g., dominance) and biological (e.g., CAG repeat polymorphism) traits that have been found to moderate the effects of testosterone on some social behaviors also moderated the effects examined here, but we did not find any significant moderations. Overall, this experiment revealed a novel physiological mechanism affecting emotion-based dehumanization.

Polymorphic CAG and GGN repeats in Cryptorchidism patient risk: A meta-analytical study

Genetic mutations in the androgen receptor (AR) gene have been identified as the cause of androgen insensitivity syndrome. These mutations are linked to inconsistent development of the Wolffian duct and may result in conditions such as micropenis, hypospadias, and cryptorchidism. The androgen receptor has two polymorphic sites located in exon 1, which consists of varying amounts of CAG and GGN repeats. These repetitions lead to the formation of polyglutamine and polyglycine stretches of varied lengths. Increased CAG repeats lead to a decrease in androgen receptor transcriptional activity, but the impact of GGN triplets is less well understood. This research examined the CAG and GGN repeat lengths in males who had a past medical record of cryptorchidism. Prospective and retrospective observational studies from PubMed, Science Direct, and Embase were systematically searched up to 15th November 2020. Primary outcomes were analyzed using a fixed or random effect model regarding its heterogeneity and continued with multilevel modeling of each polymorphism and ethnicity. CAG and GGN repeat polymorphism was found to be significantly different compared to control in contributing to cryptorchidism (CAG: 0.55 [CI 95%=0.19-0.91]; p-value=0.003 and GGN 0.90 [CI95%=0.65-1.15]; p value<0.000). In conclusion, CAG and GGN repeat polymorphism have an essential role in the incidence of cryptorchidism.

Associations of CAG repeat polymorphism in the androgen receptor gene with steroid hormone levels and anthropometrics among men: the role of the ethnic factor.

Androgens are required for stimulation and maintenance of skeletal growth and bone homeostasis. Physiological functions of androgens are mediated through the androgen receptor (AR). The androgen receptor gene AR has a polymorphic trinucleotide CAG repeat and the length of AR CAG repeats determining the sensitivity of bone tissue to androgens is associated with skeleton formation and body proportions. This study aimed to investigate the relationship between AR CAG repeat polymorphism, circulating sex steroid hormones and the anthropometrics in males of different ethnic origins. Male volunteers of three ethnic groups (Slavs, Buryats, Yakuts) from urban Russian populations were recruited in a population-based study (n = 1078). Anthropometric indicators (height, arm span, leg length, the length of 2 and 4 digits of both hands) were measured and the following anthropometric indices were calculated: the ratio of height to leg length, the ratio of arm span to height, the ratio of lengths of second to fourth digit of the hand. Serum testosterone and estradiol were determined by enzyme immunoassay. Genotyping of the AR CAG repeats was performed using fragment analysis and capillary electrophoresis. Ethnic differences in all anthropometric and hormonal indicators have been established, with higher anthropometric indicators in Slavs than Buryats, and in most cases higher than in Yakuts. The testosterone level was higher among Slavs compared to Buryats, but did not differ from Yakuts; the estradiol level was lower among Slavs compared to Buryats, who did not differ from Yakuts. Buryats and Yakuts had a higher number of CAG repeats than Slavs (medians: Slavs, 23; Buryats, 24; Yakuts, 25). Positive correlations were found between the length of AR CAG repeats and estradiol levels in Buryats and testosterone levels in Yakuts, while longer CAG repeats were accompanied by higher estradiol levels in Buryats and testosterone levels in Slavs and Yakuts. Ethnic-specific correlations have been established between the steroid hormone levels and some anthropometric indicators in all ethnic groups. Available data suggest that the ethnic-specific associations of AR CAG repeats with anthropometrics can be mediated by sex steroid hormones as important regulators of skeletal growth and bone homeostasis.

Investigation of androgen receptor CAG repeats length in polycystic ovary syndrome diagnosed using the new international evidence-based guideline

BackgroundTo study whether CAG repeat polymorphism of androgen receptor (AR) contributes to the risk of polycystic ovarian morphology (PCOM) with antral follicle count (AFC) ≥ 20 in the context of new international guideline of polycystic ovary syndrome (PCOS).MethodsBlood of 109 PCOS cases and 61 controls were collected for the measurement of AR CAG repeats length by sequencing. The mean number and frequency distribution of CAG repeats length were observed. Detailed analysis was conducted by dividing PCOS cases into low AFC group (L-AFC, AFC < 20) and high AFC group (H-AFC, AFC ≥ 20) according to the new international evidence-based guideline.ResultsThe portion of individuals with lower CAG repeats length in H-AFC group was significantly larger than those with higher CAG repeats length. Logistic model revealed individuals with lower CAG length tended to develop H-AFC.ConclusionLower CAG repeats length in the AR gene of PCOS cases increases risk of PCOM.

The Association of CAG Polymorphism in the Androgen Receptor Gene with Nodulocystic Acne in Egyptians

Abstract Acne vulgaris is a pilosebaceous inflammatory condition with several etiologies. Hormones have a crucial role in the development of acne. Hypersensitivity of the androgen receptor gene (ARG), which is the sole receptor for androgens, was reported to share in the pathogenesis of acne. At the 5'end of exon 1 of chromosome X, ARG has a polymorphism of CAG triple loop that codes for the polyglutamine pathway. Aim of the Study The aim of this study was to investigate CAG repeat polymorphism in the ARG in Egyptian nodulocystic acne patients to clarify its relevance to the pathogenesis of nodulocystic acne. Patients and Methods Twenty-five patients with severe and very severe nodulocystic acne and 25 apparently healthy control subjects were included in the current study. Full general, dermatological assessment and acne severity determination were performed through GAGS score before genetic analysis to determine CAG repeat number in included participants. Results Genetic analysis of CAG repeats number revealed that male and female acne patients had significantly lower number of CAG repeats compared to control subjects. Moreover, after gender correction, acne patients still had significantly lower number of CAG repeats compared to control subjects. Conclusion the current study revealed that acne patients had significantly lower number of CAG repeats compared to controls.

CAG and GGN repeat polymorphisms in the androgen receptor gene of a Chilean pediatric cohort with idiopathic inguinal cryptorchidism.

Cryptorchidism is one of the most common congenital disorders in boys and it is associated with a higher risk of sub-fertility and testicular cancer. Testicular descent occurs during embryo-fetal development in two phases, transabdominal and inguino-scrotal. In the latter process, androgens play a leading role. The androgen receptor has in its N-terminal domain, two aminoacidic repeats encoded by polymorphic nucleotide repetitions: (CAG)nCAA and GGN. The number of repetitions of these trinucleotides has been associated with different transactivation capacities and sensitivities of the androgen receptor response. To determine whether pediatric Chilean individuals with idiopathic inguinal cryptorchidism have a different number of CAG and/or GGN repeats polymorphisms compared with controls. A total of 109 cases with idiopathic inguinal cryptorchidism (26 bilateral and 83 unilateral) were studied by polymerase chain reaction amplification from DNA extracted from peripheral blood, followed by fragment size analysis by capillary electrophoresis, which were compared with 140 controls. The CAG26 repeats allele was increased in the total cases (8.3%vs. 1.4%; p=0.012; odds ratio=6.21, 95% confidence interval 1.31-29.4), and in bilateral cases compared to controls (11.5%vs. 1.4%; p=0.028; odds ratio=9 CI 95% 1.43-56.8). Similarly, CAG>22 alleles were increased in the total cases (62.4%vs. 49.3%, p=0.041), and more significantly in bilateral cases (73.1%vs. 49.3%; p=0.032; odds ratio=2.79, 95% confidence interval 1.1-7.1). In addition, CAG<18 alleles were not observed among cases, but were present in 5.7% of controls (p=0.01). Regarding the GGN repeats, no differences were observed between cases and controls either when analyzing separately unilateral and bilateral cryptorchidism. The joint analysis of the distribution of CAG and GGN alleles showed that the CAG26 allele was present with GGN23, hence the combination CAG26/GGN23 alleles was equally increased in bilateral cases compared with controls (11.5%vs. 1.4%). In contrast, CAG<18 was preferably observed in the combination CAG<18/GGN≠23 and was absent in the total cases (4.3%vs. 0%; p=0.037). These results suggest that greater lengths of CAG alleles may contribute to a diminished androgen receptor function. The CAG26 allele alone or in combination with GGN23 was associated with a higher risk of bilateral cryptorchidism. On the other hand, CAG<18 and the CAG<18/GGN≠23 allele combination may reduce the probability of cryptorchidism.

Evaluation of X chromosome inactivation in endemic Tunisian pemphigus foliaceus.

Almost 5% of the world's population develops an autoimmune disease (AID), it is considered the fourth leading cause of disability for women, who represent 78% of cases. The sex ratio when it comes to the most prevalent AID varies from 9:1 in systemic lupus erythematosus (SLE) to 13:1 in endemic Tunisian pemphigus foliaceus (PF). To test the potential involvement of skewed x-inactivation in the pathogenesis of Tunisian PF, we analyzed the methylation status of a highly polymorphic CAG repeat in the androgen receptor gene and evaluated the x chromosome inactivation (XCI) patterns in peripheral blood-leukocyte-derived DNA samples of female patients with PF (n=98) compared to healthy control (HC) subjects (n=150), as well as female patients with SLE (n=98) were enrolled as a reference group. XCI status was informative for 50 of the 98 PF patients (51%) and 70 of the 150 HC women (47%). Extremely skewed XCI patterns were more frequent in PF and SLEwomen than HC, but the difference was statistically significant only in women with SLE. No statistical difference was observed in XCI patterns between PF and SLE patients. PF phenotype-XCI correlation analysis revealed that (i) skewed XCI patterns may be involved in the disease's subtype and (ii) it was more pronounced in the endemic group than the sporadic one. Furthermore, preferential XCI showed an increase in heterozygote genotypes of PF's susceptibility polymorphisms in immunity-related X genes (FOXP3, AR, and TLR7) in PF patients compared to HC. Our results suggest that skewed XCI could lead to hemizygosity of X-linked alleles that might unmask X-linked deleterious alleles.

Investigation of the role of X chromosome inactivation and androgen receptor CAG repeat polymorphisms in patients with recurrent pregnancy loss: a prospective case–control study

BackgroundPrevious research has revealed that skewed X chromosome inactivation (SXCI) and androgen receptor (AR) CAG polymorphisms are associated with increased risk of recurrent pregnancy loss (RPL); however, the results are conflicting, and the underlying mechanisms remain unclear. This study investigated the role of SXCI and AR CAG polymorphisms in patients with RPL and explored whether the underlying mechanisms were related to the ovarian reserve and preimplantation embryo aneuploidy.MethodsThis was a prospective case-control study carried out in a tertiary hospital-based reproductive medicine center. An external validation RPL cohort was recruited during the study period. Data on baseline and cycle characteristics were collected. X-chromosome inactivation (XCI) was measured using a human AR assay. AR polymorphisms were assessed using quantitative fluorescent polymerase chain reactions and direct sequencing. Blastocysts of the patients with RPL were tested by single nucleotide polymorphism microarray based preimplantation genetic testing for aneuploidy.ResultsIn total, 131 patients with idiopathic RPL and 126 controls were included for the case-control study. Patients with RPL exhibited a significantly more skewed XCI distribution pattern (67.71 ± 10.50 vs. 64.22 ± 10.62, p = 0.011), as well as significantly shorter bi-allelic mean (18.56 ± 1.97 vs. 19.34 ± 2.38, p = 0.005) and X-weighted bi-allelic mean (18.46 ± 2.02 vs. 19.38 ± 2.53, p = 0.001) of AR CAG repeats. Multivariate logistic regression models indicated that CAG repeat < 20, SXCI, and duration of stimulation were independently associated with the risk of RPL. However, SXCI and AR CAG polymorphisms were not associated with ovarian reserve or preimplantation embryo aneuploidy in the RPL group, and the same results were attained in a separate validation cohort of 363 patients with RPL.ConclusionSXCI and AR CAG polymorphisms are related to RPL; however, these two factors do not lead to RPL by affecting the ovarian reserve or increasing embryo aneuploidy. The roles of SXCI and AR CAG in RPL may involve other mechanisms that require further investigation.Trial registration:NCT02504281, https://www.clinicaltrials.gov (Date of registration, 21/07/2015; date of enrolment of the first subject, 30/07/2015).

Investigation of the relationship between Androgen Receptor Gene CAG Repeat Polymorphisms and Turkish gifted students’ science attitudes

This study aims to examine the AR gene CAG polymorphisms of gifted students, and to determine whether there is a relationship between this gene region and students' attitudes towards science. The research was conducted with randomly selected gifted students (N = 100) and normally developing students (N = 100) studying at the 5th grade level in Kocaeli, Turkey during the 2017-2018 and 2018-2019 school years. In order to determine students' attitudes towards science, science and technology lesson attitude scale was applied. According to the results of the study, while there was no significant difference in terms of "enjoyment" and "social content of science" from the science and technology lesson attitude scale factors, it was found that there was a statistically significant difference in favor of gifted students from the "scale total scores" and "desire to learn" factors (p&amp;lt;0,05). In the genetic dimension of the study, no statistically significant difference was found between the two groups in AR gene CAG polymorphisms. In the whole sample, there was no significant relationship between the AR gene CAG polymorphisms and the "scale total score" values.

COVID-19 Severity and Androgen Receptor Polymorphism.

Simple SummarySince the early stages of the COVID-19 pandemic, it was recognized that male patients risked a more severe form of the disease. This suggested that, among other factors, a genetic predisposition could justify this issue. Thus, we investigated the CAG repeat polymorphism of the Androgen Receptor gene in a group of 142 recovered patients. Reduced androgenic signaling predisposes men to a more severe form: low testosterone levels and reduced androgen receptor activity (CAG > 23) expose the host to an excessive inflammatory response, leading downstream to the multi-organ damage seen in severe COVID-19.During the COVID-19 pandemic, the most severe form of the disease was most often seen in male patients. The aim of this study was to identify any male predispositions that could be used to predict the outcome of the disease and enable early intervention. We investigated CAG polymorphism in the androgen receptor gene and serum levels of testosterone and LH, which were considered as probably responsible for this predisposition. The study involved 142 patients who had recovered from COVID-19 at least three months previously and were classified according to their disease severity using the World Health Organization (WHO) classification. We observed a significant increase in the number of CAG repeats with increasing disease severity: the percentage of patients with more than 23 repeats increased two-fold from Grade I to Grade IV. Furthermore, testosterone levels were significantly lower in patients with severe disease. Reduced androgenic signaling could predispose men to a more severe form: low testosterone levels and a reduced androgen receptor activity (CAG > 23) expose the host to an excessive inflammatory response, leading downstream to the multi-organ damage seen in severe COVID-19.

Color Vision Pathway Follows the Expansion Repeats in SCA7

Spinocerebellar ataxia type 7 (SCA7) is an autosomal dominant neurodegenerative disorder caused by gene ataxin7 mutation with a polymorphic CAG repeat tract that falls in first axon. The gene which encodes ataxin7 normally contains a ten CAG repeat tract starting a codon 30, in affected patients the CAG repeat tract expands from 37 to 250 triplets, decreasing the transcription of an antisense non-coding RNA. Clinically SCA7 is characterized by progressive cerebellar ataxia, slow saccadic eye movements and progressive blindness. SCA7 neurotoxicity can be showed by the cone-rod dystrophy which follows in the generations the CAG repeats expansions in the affected patients. As retinal disease progresses in SCA7, the photoreceptors cells do become involved, and then loss of central visual acuity proceeds to complete blindness. The presence in the long run of the altered cone function, allows SCA7 to be classified as a cone dystrophy type of retinal degeneration [1]. Considering the X-linked inheritance of color vision deficiency, fixed sampling of only males, that compensation’s phenomenon in the heterozygous females [2], which can hid a real acquired color vision deficiency. The acquired color vision deficiency is real in the males where the anomaly has not hidden, and due to this reason we suggest sampling only male patients when color vision has studied both in neurological and metabolic diseases [3].

A Novel Missense Mutation of Arginine Vasopressin Receptor 2 in a Chinese Family with Congenital Nephrogenic Diabetes Insipidus: X-Chromosome Inactivation in Female CNDI Patients with Heterozygote 814A>G Mutation.

Background To identify novel clinical phenotypic signatures of congenital nephrogenic diabetes insipidus (CNDI). Methods A Chinese family with CNDI was recruited for participation in this study. The proband and one of his uncles suffered from polydipsia and polyuria since infancy. The results of clinical testing indicated the diagnosis of CNDI. 10 family members had similar symptoms but did not seek medical advice. Genetic testing of mutations in the coding region of the aquaporin 2 (AQP2) gene and the arginine vasopressin receptor 2 (AVPR2) gene were carried out in 11 family members. Somatic DNA from 5 female family members was used to test for methylation of polymorphic CAG repeats in the human androgen receptor (AR) gene, as an index for X-chromosome inactivation pattern (XCIP). Results AQP2 gene mutations were not found in any family members, but a novel missense mutation (814th base A>G) in exon 2 of the AVPR2 gene was identified in 10 individuals. This mutation leads to a Met 272 Val (GAT-GGT) amino acid substitution. Skewed X-chromosome inactivation patterns of the normal X allele were observed in 4 females with the AVPR2 gene mutation and symptoms of diabetes insipidus, but not in an asymptomatic female with the AVPR2 gene mutation. Conclusions Met 272 Val mutation of the AVPR2 gene was identified as a novel genetic risk factor for CDNI. The clinical NDI phenotype of female carriers with heterozygous AVPR2 mutation may be caused by X-chromosome inactivation induced by dominant methylation of the normal allele of AVPR2 gene.

CAG repeat polymorphism in androgen receptor and infertility: A case-control study.

BackgroundAndrogens play a role in the development of male phenotype and spermatogenesis during puberty, the function of which is regulated by the androgen receptor (AR) gene. There is a polymorphism site in exon 1 of the gene encoding this receptor that can have different frequencies of CAG trinucleotide repeats and leads to the formation of polyglutamine chains of different lengths in the N-terminal domain of the AR protein and reduced sperm production by affecting spermatogenesis.Objective To investigate whether the cause of a group of unexplained infertilities could be the increased frequency of CAG repeats in the AR gene of patients with oligozoospermia and azoospermia.Materials and MethodsIn this case-control study, 84 men including 42 with unexplained infertility As a case group and 42 fertile men as a control group were selected. The frequency of CAG repeats was determined by the polymerase chain reaction method and then the difference in the frequency of these repeats was determined based on the difference in band size on the agarose gel.ResultsThe mean CAG repeat length in the azoospermia and oligozoospermia group was 17.5 0.63 and in the fertile group it was 16.11 0.75 (p = 0.46). In addition, most men (88.1% in the case group and 71.41% in the control group) had 13-23 repeats.Conclusion No significant correlation was found between CAG repeat length and the risk of male factor infertility in an ethnically defined population of Iranian men. The role of regulatory factors and epigenetic changes should be taken into account too.

Huntington's Chorea-a Rare Neurodegenerative Autosomal Dominant Disease: Insight into Molecular Genetics, Prognosis and Diagnosis.

Huntington's disease is a neurodegenerative autosomal disease results due to expansion of polymorphic CAG repeats in the huntingtin gene. Phosphorylation of the translation initiation factor 4E-BP results in the alteration of the translation control leading to unwanted protein synthesis and neuronal function. Consequences of mutant huntington (mhtt) gene transcription are not well known. Variability of age of onset is an important factor of Huntington's disease separating adult and juvenile types. The factors which are taken into account are-genetic modifiers, maternal protection i.e excessive paternal transmission, superior ageing genes and environmental threshold. A major focus has been given to the molecular pathogenesis which includes-motor disturbance, cognitive disturbance and neuropsychiatric disturbance. The diagnosis part has also been taken care of. This includes genetic testing and both primary and secondary symptoms. The present review also focuses on the genetics and pathology of Huntington's disease.

Letter to the Editor re: Baldassarri etal., 2021 "Shorter androgen receptor polyQ alleles protect against life-threatening COVID-19 disease in European males".

We would like to thank Baldassarri et al. for presenting their findings that short androgen receptor (AR) polyQ alleles confer protection against life-threatening COVID-19 infection among European males [[1]Baldassarri M et al.Shorter androgen receptor polyQ alleles protect against life-threatening COVID-19 disease in European males.EBioMedicine. 2021; 103246Summary Full Text Full Text PDF PubMed Scopus (33) Google Scholar]. Data previously presented by McCoy et al. suggests that longer AR CAG repeats are associated with more severe COVID-19 disease. In skeletal muscle, for example, long AR CAG repeats confer increased transcriptional activity in response to testosterone. In prostate cancer, short CAG repeats have been associated with a poor prognosis. This difference in skeletal muscle and prostate tissue could be explained by the tissue-dependent expression of co-factors that aid in activation of the androgen response element (ARE) [[2]McCoy J et al.Androgen receptor genetic variant predicts COVID-19 disease severity: a prospective longitudinal study of hospitalized COVID-19 male patients.J Eur Acad Dermatol. Venereol. 2021; 35: e15-e17Crossref PubMed Scopus (23) Google Scholar]. Baldassarri et al. suggested to initiate clinical trials of testosterone therapy in men expressing defective androgen signaling and having serologic evidence of hypoandrogenism [[1]Baldassarri M et al.Shorter androgen receptor polyQ alleles protect against life-threatening COVID-19 disease in European males.EBioMedicine. 2021; 103246Summary Full Text Full Text PDF PubMed Scopus (33) Google Scholar]. There is evidence that th lower AR activity caused by the longer CAG repeats is biologically compensated by increased testosterone levels. The response to testosterone therapy may be increased in patients with shorter CAG repeats, who have enhanced AR activity [[3]Tirabassi G Cignarelli A Perrini S et al.Influence of CAG repeat polymorphism on the targets of testosterone action.Int J Endocrinol. 2015; : 1-12Crossref Scopus (45) Google Scholar]. We suggest a more robust discussion in light of already published randomized clinical trials addressing the role of antiandrogen therapy in reducing disease severity by reducing expression of TMPRSS2. Randomized control trials with 5-alpha-reductase inhibitors and antiandrogens have shown accelerated viral clearance at 7 days and improvement in inflammatory markers in males infected with SARS-CoV-2 compared to males treated with a placebo as well as a reduction in COVID-19 symptoms and hospitalization rates among males [[4]Cadegiani FA McCoy J Gustavo Wambier C Goren A Early Antiandrogen Therapy With Dutasteride Reduces Viral Shedding, Inflammatory Responses, and Time-to-Remission in Males With COVID-19: A Randomized, Double-Blind, Placebo-Controlled Interventional Trial (EAT-DUTA AndroCoV Trial –Biochemical).Cureus. 2021; https://doi.org/10.7759/cureus.13047Crossref Google Scholar]. A single case report gives much information about how external androgens seem to exacerbate COVID-19 symptoms, and how blocking the androgen receptor with a strong antiandrogen such as proxalutamide, seems to resolve COVID-19 symptoms within the first 24 hours of therapy [[5]Cadegiani F Lin EM Goren A Wambier CG. Potential risk for developing severe COVID-19 disease among anabolic steroid users.BMJ Case Report. 2021; 14e241572Crossref PubMed Scopus (10) Google Scholar]. We expect the publication of the results of the NCT04728802 (Proxalutamide Treatment for Hospitalized COVID-19 Patients) soon, which may strongly discourage clinical trials with androgens in hospitalized COVID-19 patients. We are thankful to the authors for their contribution to current literature, and we look forward to more studies investigating genetic and hormonal predictors of COVID-19 disease severity, as well as results of ongoing studies of antiandrogen therapy for COVID-19 by other groups. None Declared

Identifying androgen receptor (AR) and genomic characteristics that define populations of patients with mHSPC who benefit from early PARP inhibition therapy with talazoparib.

TPS5097 Background: A minority of men with mCRPC, those with DNA repair mutations, can benefit from PARP inhibitor therapy. In addition to DNA repair, PARP is used by cancer cells to interact with other cellular mechanisms including androgen receptors (AR). The next generation PARP inhibitor talazoparib can, in addition to inhibiting DNA repair, trap PARP, preventing it from carrying out its other functions. As progression in mHSPC is based on AR escape mechanisms, we predict that early exposure to PARP inhibition will delay progression. In addition, AR characteristics and function vary by ethnic populations. AR expression is inversely related with the number of polymorphic CAG repeats. As African American (AfrAm) men commonly have shorter CAG repeats in their AR, they may experience different response duration, but have been under-represented in clinical trials. Furthermore, CAG repeats may be associated with greater signaling through pathways such as wnt and Myc, which is associated with aggressive disease. Thus, studying intensified up-front therapy in a diverse prostate cancer population is a critical unmet need. Methods: 70 subjects will be treated with ADT + abiraterone + talazoparib. Outreach by our Division of Health Equities and accrual at community satellites located near diverse populations will be enlisted to accrue a target of 30% African American. Talazoparib will be dosed at 1mg daily (0.75 mg in renal insufficiency). LHRH and abiraterone formulations will be left to physician’s choice. PSA and safety labs will be checked every 4 weeks for the first 12 weeks. Imaging will be performed every 12 weeks for the first year then every 24 weeks if PSA is decreasing, or 12 weeks if rising. Data safety monitoring for toxicity after every 10 subjects have been accrued. Diversity of accrual will be evaluated after 30 subjects are enrolled; amendments will be made if the diversity goal is not achieved. Tissue genomics and ctDNA will be measured at baseline; ctDNA will be repeated after 4 weeks and at castration resistance. Endpoints: Primary: PSA nadir at 7 months has been found to be associated with overall survival and is achieved by 55% of men with mHSPC with ADT + abiraterone. With 70 subjects there is 97% power to confirm improved nadir rate of 75%, and 83% power to determine a nadir rate &gt;70%. Secondary endpoints include objective response by RECIST 1.1 for subjects with measurable disease. radiographic progression free survival. Correlative objectives include comparing outcomes in subsets of men with high vs low number of AR CAG repeats, men with genomic alterations, and the change in ctDNA alteration fractions from baseline to 4 weeks and at progression. Progress: The trial is open to accrual as of Feb 2021. Sponsor: Pfizer/ Prostate Cancer Foundation RFP Clinical trial information: NCT04734730.

Not giving up: Testosterone promotes persistence against a stronger opponent

Recent research suggests that when we lack a sense of control, we are prone to motivational failures and early quitting in competitions. Testosterone, on the other hand, is thought to boost competitiveness. Here we investigate the interaction between these factors, testing the testosterone’s potential to enhance persistence in a competition against a stronger opponent, depending on experimentally manipulated perceived control. Healthy participants were administered a single dose of testosterone or placebo. They first underwent a task designed to either induce low or high perceived control and then entered a costly competition against a progressively stronger opponent that they could quit at any time. In the placebo group, men with low perceived control quitted twice as early as those with high perceived control. Testosterone countered this effect, making individuals with low control persist in the competition for as long as those with high perceived control, and did so also despite raising participants’ explicit awareness of the opponents’ advantage. This psychoendocrinological effect was not modulated by basal cortisol levels, CAG repeat polymorphism of the androgen receptor gene, or trait dominance. Our results provide the first causal evidence that testosterone promotes competitive persistence in humans and demonstrate that this effect depends on the psychological state elicited prior to the competition, broadening our understanding of the complex relationships between testosterone and social behaviors.

Association of the CAG repeat polymorphism in mitochondrial polymerase gamma (POLG1) with male infertility: a case-control study in an Algerian population.

Polymorphisms in the have been speculated to be associated with male infertility. The main objective of our study was to CAG repeat polymorphism in POLG1 gene and male mitochondrial DNA polymerase gamma (POLG) assess the possible association of infertility in Algerian population. Genomic DNA from 89 infertile men and 84 controls was extracted using salting-out method. CAG repeat polymorphism was analyzed by the automated direct sequencing protocol. Statistical analysis was performed by Epi-info(r) (v6.0) software. A significant association with male infertility was found for CAG repeat polymorphism in heterozygous genotypes (10/≠10 vs 10/10: OR = 2.00 [0.99 - 4.05], p=0.03; "infertile vs control groups"; 10/≠10 vs 10/10: OR = 3.75[1.20-11.96], p=0.01 "oligoasthenoteratospermic group"). ALso, the results showed a significant association between the mordib allele (≠10) and male infertility (2.07 [01.07 - 04.02], p=0.01). Our results showed that POLG1 CAG repeat polymorphism might be a risk factor for male infertility in Algerian population. Investigations with larger sample sizes and representative population-based cases and matched controls are needed to validate our results.

National Variations in CAG Repeats of Men’s Androgen Receptor Gene: A Tabulated Review

As the mediator of androgen actions, the androgen receptor (AR) plays a central role in establishing both physical and behavioral sex differences. The AR gene contains a CAG repeat polymorphism that is related to the strength of androgen actions on target tissues and that is correlated with various health-related conditions, especially prostate cancer and infertility. Some studies have also linked the number of AR CAG repeats with behavioral and mental health factors. The present study provides a tabulated summary of the average number of AR CAG repeats for males according to the countries in which each study was conducted, thereby allowing future research to correlate national average AR CAG repeats with national variations in physical, medical and behavioral traits. Findings are summarized in two tables. The first table lists results from each of 187 studies of a total of 57,826 research participants according to the country in which each study was conducted. In the second table, the results from the first table are condensed down to the average number of AR CAG repeats for each of the 78 countries from which samples were drawn.

Исследование влияния CAG-полиморфизма гена андрогенового рецептора (AR) на сперматологические показатели у российских мужчин

Полиморфизм CAG-повторов в экзоне 1 гена андрогенового рецептора (AR/HUMARA) ассоциирован с патозооспермией и нарушением мужской фертильности, однако его влияние на сперматогенез и показатели семенной жидкости недостаточно изучено. В статье представлены результаты исследования влияния количества CAG-повторов гена AR на показатели спермограммы у российских мужчин с бесплодием в браке, связанным с патозооспермией (n=451), и у мужчин с нормозооспермией - контрольная группа (n=131). Не выявлено зависимости концентрации и общего количества сперматозоидов в эякуляте, доли (%) прогрессивно подвижных (PR), морфологически нормальных и живых сперматозоидов от количества CAG-повторов гена андрогенового рецептора. У пациентов с тератозооспермией количество CAG-повторов статистически значимо выше, чем у мужчин без тератозооспермии (22,37±3,20 против 22,15±3,12; р=0,02). Polymorphism of CAG repeats in exon 1 of the androgen receptor gene (AR/HUMARA) is associated with pathozoospermia and male sub-/infertility, but its effect on spermatogenesis and seminal fluid parameters is under evaluated. The article presents the results of a study of CAG repeats in AR gene on semen parameters in Russian male patients from infertile couples with pathozoospermia (n = 451), and in normozoospermic men, a control group (n = 131). The analysis of the groups revealed no dependence of the concentration indices, the total amount and amount (%) of progressively motile («PR»), morphologically normal and live spermatozoa from the number of CAG repeats of the AR gene. Teratozoospermic patients have statistically significantly higher number of CAG repeats, than men without teratozoospermia (22.37 ± 3.20 versus 22.15 ± 3.12; p = 0.02).