Polycystic Ovary Syndrome Susceptibility Research Articles

IGF2BP2 and IGFBP3 Genotypes, Haplotypes, and Genetic Models Studies in Polycystic Ovary Syndrome.

Insulin resistance has been correlated with the genetic diversity within the insulin-like binding proteins genes. Moreover, insulin resistance is one of the key characteristics of the widespread reproductive endocrine condition known as polycystic ovarian syndrome (PCOS). Hence, this study is aimed to determine the association between IGFBP3 and IGF2BP2 gene variants and PCOS risk. A total of 300 subjects (150 PCOS cases diagnosed based on Rotterdam ESHRE/ASRM consensus criteria and 150 healthy subjects) were recruited in this case-control cross-sectional study. Tetra-primer amplification refractory mutation system polymerase chain reaction (ARMS-PCR) was used for genotyping rs11705701, whereas genotyping of rs1470579 and rs2854744 was done employing PCR-restriction fragment length polymorphism (PCR-RFLP) technique. The CC and AA+AC genotypes of rs1470579 conferred an increased risk of PCOS in our population. Regarding the rs2854744, an increased risk of PCOS was observed under the codominant homozygous (TT vs. GG) model by 2.54 fold. The C allele of rs1470579 and T allele of rs2854744 enhanced PCOS risk by 1.97 and 1.46 folds, respectively. Haplotype analysis showed that the Ars1470579Ars11705701 haplotype conferred a decreased risk of PCOS (odds ratio = 0.53, 95% confidence interval = 0.34-0.83, p = 0.006). The AC/GG/GT, AA/GA/GT, AC/GA/GG, and AC/GA/GT genotype combinations of rs1470579/rs11705701/rs2854744 were associated with a decreased risk of the disease. IGF2BP2 rs1470579 and IGFBP3 rs2854744 enhanced PCOS susceptibility in a Southeastern Iranian population. Further investigation involving larger cohorts representing diverse ethnic backgrounds is needed to confirm the current findings.

Genome-wide association study (GWAS) identified PCOS susceptibility variants and replicates reported risk variants.

Genetic predisposition and environmental factors are considered risk factors for polycystic ovary syndrome (PCOS). Genome-wide association studies (GWAS) have been reported from various subpopulations to evaluate SNPs associated with PCOS risk. No PCOS-associated GWAS study has been reported from India so far. The current study was conducted to identify the PCOS-susceptible loci among the North Indian population and to validate the significant loci reported by previous GWAS studies. A total of 272 participants with 134 PCOS patients and 138 age-matchedhealthy controls were recruited. Genomic DNA was isolated and genotyped by using Infinium Global Screening Array v3.0 microchip considering HWE 10e-5 statistically significant. A total of fifteen markers have been identified as candidate PCOS risk factors. Only two SNPs, namely rs17186366 and rs11171739 have been identified through replication analysis while comparing the previously reported PCOS GWAS data. In-silico analysis was performed to study the functional impact of identified significant genes for gene ontology, pathways related to gene set, and cluster analysis to determine protein-protein interaction among genes or gene products. The study suggests that multiple variants play an important role in PCOS pathogenesis and emphasizes the importance of further genetic studies among Indian subpopulations.The study also validates two previously reported SNPs in the Indian population. What this study adds to clinical work Study summarizes the importance of candidate gene markers validated by replication and in-silico functional study, significantly involved in PCOS pathogenesis in the studied population. These markers can be used in the future as diagnostic markers for clinical phenotype identification.

Susceptibility loci identified in Han Chinese influence genetic predisposition of PCOS in Indian women.

Polycystic ovary syndrome (PCOS) is a multifactorial disorder characterized by a broad spectrum of reproductive and metabolic perturbations, necessitating early timely diagnosis and management. PCOS is a multigenic disorder and ample evidence from family based, candidate gene and genome-wide association studies (GWAS) has implicated genetic factors in development and progression of PCOS. The first GWASs in Han Chinese population revealed prominent gene loci to be strong contenders in the etiopathogenesis of PCOS. However, different ethnic and geographical settings impact the genetic association pattern of PCOS. In the current case-control replication study, we have genotyped previously identified polymorphisms viz. rs2479106 and rs10818854 of DENND1A and rs13405728 of LHCGR, rs4385527 and rs3802457 of c9orf3, rs705702 of RAB5B and rs1894116 of YAP1 in control (N = 247) and PCOS (N = 504) women by Sanger sequencing, and their association with PCOS susceptibility and its related traits was investigated. We found significant association of rs4385527 of c9orf3 and rs1894116 of YAP1 with decreased and increased PCOS susceptibility respectively in non-hyperandrogenic women. Trend towards association was also noted for rs2479106 of DENND1A and rs705702 of RAB5B. Additionally, polymorphisms also showed association with metabolic and androgen related traits in both controls and hyper- and non-hyperandrogenic women with PCOS. Thus, this study shows that some, but not all polymorphisms previously identified in Han Chinese women, could contribute to the genetic pathophysiology of PCOS in Indian women, accentuating essentiality of conducting replication studies to elucidate the genetic predisposition profile of PCOS.

Investigating the association of previously identified genome-wide significant loci (rs10739076 and rs1784692) with PCOS susceptibility and its related traits in Indian women

Objective(s)Polycystic ovary syndrome (PCOS) is a multifactorial endocrinopathy with an enigmatic etiology. Hallmark features include irregular menstrual cycles, insulin resistance and hyperandrogenemia and affected women are prone to development of adverse reproductive and cardiometabolic outcomes like anovulatory infertility, impaired glucose tolerance, type 2 diabetes, dyslipidemia, metabolic syndrome and cardiovascular disease. Genetic underpinnings of PCOS have been investigated extensively using genome-wide association studies, which have led to the identification of several novel susceptibility loci. However, as ethnic diversity contributes to phenotypic and genetic heterogeneity, we undertook the first genetic association study to determine the association of rs10739076 of PLGRKT and rs1784692 of ZBTB16 with PCOS susceptibility and its related traits in Indian women. Study DesignThe present case-control study comprised 497 women with PCOS diagnosed according to the Rotterdam criteria and 233 age matched healthy women as controls. All participants were characterized in terms of anthropometric, hormonal and metabolic parameters and the variants were investigated by direct sequencing. Genotypic and genotype-phenotype association of these variants with PCOS susceptibility and its related biochemical and hormonal traits was analyzed with appropriate statistical tests. ResultsThe genotypic and allelic frequencies of rs1784692 of ZBTB16 were significantly decreased in lean women with PCOS only, and this variant was associated with lowered insulin levels, HOMA-IR, LH:FSH ratio along with increased ApoA1 levels and QUICKI in them. Although, the PLGRKT variant, rs10739076, showed similar frequency distribution in both lean and obese groups, it was found to be associated with reduced fasting glucose in all women with PCOS. Conclusion(s)To the best of our knowledge, this is the first study to demonstrate that ZBTB16 variant showed significant association with reduced PCOS susceptibility in lean rather than obese Indian women, highlighting the impact of obesity on determining genetic predisposition to PCOS in Indian women. In contrast, PLGRKT variant did not influence PCOS risk in lean or obese women. Importantly, both variants exerted a protective effect on glucose metabolism, insulin resistance, gonadotropin and lipid levels in women with PCOS. Determination of susceptibility variants for PCOS demand population specific replication studies to ascertain best candidate loci for PCOS.

Association between single nucleotide polymorphisms, TGF-β1 promoter methylation, and polycystic ovary syndrome.

Polycystic ovarian syndrome (PCOS) is a common endocrine and metabolic disease in women. Hyperandrogenaemia (HA) and insulin resistance (IR) are the basic pathophysiological characteristics of PCOS. The aetiology of PCOS has not been fully identified and is generally believed to be related to the combined effects of genetic, metabolic, internal, and external factors. Current studies have not screened for PCOS susceptibility genes in a large population. Here, we aimed to study the effect of TGF-β1 methylation on the clinical PCOS phenotype. In this study, three generations of family members with PCOS with IR as the main characteristic were selected as research subjects. Through whole exome sequencing and bioinformatic analysis, TGF-β1 was screened as the PCOS susceptibility gene in this family. The epigenetic DNA methylation level of TGF-β1 in peripheral blood was detected by heavy sulfite sequencing in patients with PCOS clinically characterised by IR, and the correlation between the DNA methylation level of the TGF-β1 gene and IR was analysed. We explored whether the degree of methylation of this gene affects IR and whether it participates in the occurrence and development of PCOS. The results of this study suggest that the hypomethylation of the CpG4 and CpG7 sites in the TGF-β1 gene promoter may be involved in the pathogenesis of PCOS IR by affecting the expression of the TGF-β1 gene. This study provides new insights into the aetiology and pathogenesis of PCOS.

Association between leptin receptor polymorphisms and polycystic ovary syndrome risk: a meta-analysis based on 11 studies

Objective Published evidence indicated that the leptin receptor (LEPR) gene polymorphisms are associated with polycystic ovary syndrome (PCOS) risk. However, studies on the association between the polymorphisms of LEPR gene are inconsistent or even controversial. Material and Methods We conducted this meta-analysis to explore the more precise relationship between LEPR polymorphisms and PCOS risk. Relevant articles were searched with five online databases up to March 1 2023. Odds ratios (OR) with 95% confidence intervals (CI) were selected to examine the statistical strength of each genetic model. Moreover, RNA secondary structure and variant effects of these loci were examined with in silico analysis. Results Overall, 11 publications were analyzed, and the pooled results did not present any significant association between rs1137101 A/G polymorphism and PCOS risk in general population and some subgroup analysis. But the significant association were observed in Asian population (AG vs. AA: OR = 0.51, 95%CI = 0.32–0.81, p = .01, I2=0%; AG + GG vs. AA: OR = 0.41, 95%CI = 0.26–0.65, p < .01, I2=25.9%). Moreover, similar positive associations were also observed in rs1805096 polymorphism with PCOS risk. Conclusion In summary, our meta-analysis suggested that the LEPR gene polymorphisms might be associated with PCOS susceptibility. Owing to the limited studies and small sample size in our meta-analysis, more well-designed studies from different races were needed to be conducted to verify the current results.

FRI455 Polycystic Ovary Syndrome-Associated DENND1A Non-Coding Risk Loci Alter Gene Expression

Abstract Disclosure: L. Sankaranarayanan: None. G. Johnson: None. A. Barrera: None. A.E. Dunaif: None. T. Reddy: None. Polycystic ovary syndrome (PCOS) is a leading cause of infertility and type 2 diabetes affecting 10-15% of menstruating people worldwide. PCOS is characterized by increased circulating testosterone levels, ovulatory dysfunction and insulin resistance. Genome wide association studies (GWAS) have identified ∼20 replicated common PCOS susceptibility loci in European and Han Chinese cohorts. The associated variants are predominantly non-coding and implicate neuroendocrine, reproductive, and metabolic causal pathways. Rare non-coding variants in DENND1A, a GWAS candidate gene that regulates androgen biosynthesis, were present in ∼50% of PCOS families by whole genome sequencing. These associations suggest non-coding genetic contributions to the development of PCOS. We tested the hypothesis that PCOS GWAS risk loci contribute to PCOS pathogenesis by altering gene regulation. We first identified ∼1500 functioning regulatory elements across the GWAS associated regions using a high throughput reporter assay, STARR-seq, in two different cell lines. We used H295R, an adrenal cell line model for testosterone production and COV434, an ovarian granulosa cell line. We identified cell-line specific and overlapping regulatory regions suggesting that there is context specific gene regulation. Sixty percent of the identified regions are in previously documented open chromatin regions from DNase-seq and ATAC-seq studies supporting our hypothesis that these regulatory regions are functional. We additionally experimentally tested the regulatory effect of five of the regulatory regions identified in the DENND1A locus in H295R cells using CRISPR-based epigenetic editing tools. This endogenous perturbation increases DENND1A gene levels (measured by qPCR) and also increased testosterone produced by the H295R cells (measured by ELISA), suggesting that these regions are biologically relevant to PCOS pathogenesis.We investigated allele-specific regulatory activity in a multi-ethnic pool of five genomes from healthy individuals. We identified 21 common genetic variants (minor allele frequency in the population &amp;gt;0.05) that alter regulatory activity in the DENND1A locus, including two that are ancestry-specific. Further, rs12237685 and rs28441318 are also eQTLS for DENND1A from the GTEX project and reside within open chromatin regions in ovarian cells. The functional consequences of non-coding genetic variants associated with complex traits has been exceptionally difficult to elucidate. Our findings suggest that both the common genetic variants and rare PCOS patient-associated DENND1A variants and altered gene expression. Further, some of those variants may contribute to allele-specific genetic risk for PCOS. Presentation Date: Friday, June 16, 2023

Interleukin 10 (IL-10) gene variants and haplotypes in Tunisian women with polycystic ovary syndrome (PCOS): a case-control study.

Polycystic ovary syndrome (PCOS) is a prevalent endocrine disorder that affects women in their child-bearing age, and is associated with insulin resistance and type 2 diabetes. The etiology of PCOS involves multiple factors including genetic, metabolic and immunological factors. Interleukin - 10 (IL-10), as an anti-inflammatory cytokine, plays a critical role in this regard. We investigated the potential role of IL-10 gene variants in the development of PCOS in Tunisian population. 115 cases and 120 controls were recruited in the current case control study. Rotterdam consensus criteria were used to diagnose PCOS patients. Genotyping for IL-10, rs1800896, rs1800871 and rs1800872 variants, was performed by real time PCR. The results obtained showed that the minor allele frequency of rs1800896, rs1800871and rs1800872 were comparable between PCOS cases and control subjects (P = 0.30, P = 0.71, and P = 0.57 respectively). The distribution analysis revealed an unsignificant association of the three tested variants, in all genetic models. Haplotype analysis identified one haplotype CCA with a protective role in PCOS development (P = 0.05; OR (95% CI) = 0.56 (0.32 - 0.99)). This association did not persist after adjustment for multiples covariates (Pc = 0.154). Our study is the first to show how ethnicity influences the association of IL-10 gene variants with PCOS susceptibility. No allelic nor genetic association were observed between the tested variants and PCOS in Tunisian women, however, a particular IL-10 haplotype with a protective effect for PCOS was identified.

CYP17A1 (rs74357) polymorphism and polycystic ovary syndrome risk: a systemic review and meta-analysis.

To investigate the association between CYP17A1 (rs74357) polymorphism and the risk of Polycystic Ovary Syndrome (PCOS). Literature on the association of CYP17rs74357 gene polymorphism and susceptibility to PCOS was retrieved by searching databases such as PubMed, Science Direct, Google Scholar and Embase from. The association measure was analyzed using an Odds Ratio (OR) and 95% Confidence Interval (CI). All the statistical analyses were executed using CMA 3.0 Software. In the present meta-analysis,24 studies including 3462 PCOS and 2898 controls were analyzed. The overall results validated that the 17 CYP17 T/C (rs74357) gene polymorphism was significantly associated with PCOS risk in 5 genetic models: recessive model (fixed and random effect), dominant model (random effect), CC vs. TT (fixed effect), CT vs. TT (fixed effect), and allele contrast (random effect). Stratified analyses by ethnicity/country also detected significant association between Asian and Caucasian under the recessive, dominant, CC vs. TT, CC vs. CT, and the allele contrast models. In the present study, CYP17 T/C (rs74357) gene polymorphism increase the susceptibility of PCOS, and the recessive C allele, can be proposed as a predictive factor for the risk of PCOS or an important pathway in PCOS associated metabolic and hormonal dysregulation especially insulin resistance.However, larger sample size andmultiracial studies are needed in the future to confirm the findings.

Vitamin D receptor gene polymorphism and polycystic ovary syndrome susceptibility

BackgroundPolycystic ovary syndrome (PCOS) is the most common endocrinopathy in women. This study was designed to investigate the associations of vitamin D receptor (VDR) gene variants with PCOS risk and the severity of the disease phenotype among Egyptian women.MethodsIn this study, 185 women with PCOS and 207 fertile women as controls were recruited. Cases were divided into phenotype groups based on their clinical and paraclinical features. Clinical and laboratory data were measured in the patient and control groups. All individuals were genotyped for nine single-nucleotide polymorphisms (SNPs) located across the VDR gene using TaqMan allelic discrimination real-time polymerase chain reaction.ResultsWomen with PCOS were significantly (P ≤ 0.001) higher body mass index (BMI) (22.77 ± 2.5) than controls (21.68 ± 1.85 kg/m2). Women with PCOS had significantly higher anti-Mullerian hormone, prolactin, luteinizing hormone (LH), LH/follicle-stimulating hormone (FSH), free testosterone, total testosterone, and dehydroepiandrosterone sulfate levels than the control group (P ≤ 0.001). The level of FSH was significantly lower in women with PCOS than in the control group (P ≤ 0.001). Analysis of the VDR rs4516035, rs2107301, rs1544410 (BsmI), and rs731236 (TaqI) SNPs showed a significant association with PCOS phenotype A. Furthermore, rs2228570 (FokI), rs3782905, rs7975232 (ApaI), and rs739837 SNPs showed a significant association with PCOS phenotype C. Furthermore, rs11568820 SNP showed a significant association with PCOS phenotype D (P < 0.05).ConclusionsThe findings of this study indicate that variations in the VDR gene were associated with an increased risk of PCOS in Egyptian women.

Genetic variations in OLR1 gene associated with PCOS and atherosclerotic risk factors.

Polycystic ovary syndrome (PCOS) is the most common endocrinopathy in women of reproductive age. The aim of this study was to investigate the association of oxidized low-density lipoprotein receptor 1 (OLR1) gene variations with the susceptibility of PCOS and to examine the relationship between the frequencies of OLR1 gene variations and atherosclerotic risk factors. Genomic DNA was extracted from blood samples collected from 49 patients with PCOS and 43 healthy controls. The variants in the OLR1 gene were identified using next-generation sequencing (NGS). Heterozygous rs11053646 (K167N), rs11611438, rs11611453, and rs35688880 genotype frequencies were significantly higher in the PCOS group than that of control group. Single nucleotide polymorphism (SNP) rs34163097 minor A allele increased the PCOS risk by ∼10-fold (p = 0.03). SNPs rs11053646, rs11611438, rs11611453, rs34163097, and rs35688880 were positively correlated with body mass index (BMI). The logistic regression model (area under the curve: 0.770, p = 0.000) further revealed a combination of 2-h plasma glucose (PG-2 h), dehydroepiandrosterone sulfate (DHEAS), and rs11053646 as predictors of PCOS phenotype. This is the first study reporting the NGS data of OLR1 gene variants which might be associated with the pathogenesis of PCOS and several atherosclerotic risk factors, particularly higher BMI and DHEAS. To fully understand the genetic basis of PCOS and the contribution of OLR1 gene variants to PCOS pathogenesis, additional large-scale studies are warranted.

HLA-B*0702 class-I allele, anti-FSH, anti-LH, and vitamin D3: Potential links with polycystic ovary syndrome in women of Erbil city, Iraq

Polycystic Ovary Syndrome (PCOS) is a widespread endocrine-reproductive-metabolic condition with severe implications for females’ health. The role of four essential parameters on PCOS, including Human Leukocyte Antigens (HLA) represented by the HLA-B*0702 allele, anti-Follicle Stimulating Hormone (anti-FSH) antibodies, anti-Luteinizing Hormone (anti-LH) antibodies, and vitamin D3 was investigated. A total of 100 samples were collected from Kurdish women attended the Maternity Teaching Hospital and some private hospitals/laboratories in Erbil City from October, 2021 to January, 2022. The samples were genotyped using a PCR-based technique with specific sequence primers. The levels of anti-FSH and anti-LH antibodies were determined using an Enzyme-Linked Immunosorbent Assay (ELISA), while vitamin D3 levels were measured by an Electrochemiluminescence (ECL) test on Cobas e411 immunoassay system. The Odds Ratio (OR) of 2.167 at a 95% Confidence Interval (CI) of 0.8167 to 6.330, indicated an essential link between the HLA-B*0702 allele and a risk of PCOS. Anti-FSH and anti-LH antibodies were significantly greater in PCOS patients, notably infertile women, than in healthy controls. A significant positive linear correlation was observed between antibodies against FSH and LH in patients. Most patients and controls had hypovitaminosis D3, with a significant difference (P-value  0.01). The results indicated that the HLA-B*0702 allele is associated with PCOS susceptibility and could be used as an immunogenetic marker. It also supported the idea that anti-FSH and anti-LH antibodies are naturally presence antibodies in PCOS patients instead of signs for autoimmunity. Women suffer from PCOS are also more prone to develop vitamin D3 deficiency.

A meta-analysis of the association of ApaI, BsmI, FokI, and TaqI polymorphisms in the vitamin D receptor gene with the risk of polycystic ovary syndrome in the Eastern Mediterranean Regional Office population.

BackgroundThe results of case-control studies on the association between vitamin D receptor gene (VDR) polymorphisms and polycystic ovary syndrome (PCOS) are inconclusive.ObjectiveWe aimed to more precisely evaluate the correlation between the ApaI, BsmI, FokI, and TaqI VDR gene polymorphisms and PCOS susceptibility.Materials and MethodsPubMed, Scopus, Science Citation Index, and Google Scholar databases were searched to retrieve related reports released up to the end of 2020. To evaluate the association strength of the VDR gene polymorphisms with PCOS risk, pooled odds ratios (OR) with a 95% confidence interval were determined.ResultsIn total, 1,119 subjects (560 PCOS cases and 559 controls) from 7 studies were included which met the inclusion criteria. A statistically significant association between the TaqI polymorphism and PCOS susceptibility was found in the Eastern Mediterranean Regional Office population (T vs. t: OR = 0.715; TT vs. tt: OR = 0.435, p 0.001; TT vs. Tt+tt: OR = 0.696, p = 0.01; tt vs. TT+Tt: OR = 1.791, p 0.001). It was found that the ApaI variant was a risk factor in the dominant inheritance model (AA vs. Aa+aa: OR = 1.466, p = 0.01) and the FokI polymorphism was a protective factor in the recessive inheritance model (ff vs. FF+Ff: OR = 0.669, p = 0.04). The VDR BsmI polymorphism did not show association with PCOS susceptibility.ConclusionOur meta-analysis revealed that the VDR ApaI in the dominant model, VDR FokI in the recessive model, and VDR TaqI polymorphisms in all genetic models are associated with vulnerability to PCOS. However, further studies with a larger sample size are required.

Clinical Implications of Krüpple-like Transcription Factor KLF-14 and Certain Micro-RNA (miR-27a, miR-196a2, miR-423) Gene Variations as a Risk Factor in the Genetic Predisposition to PCOS.

Polycystic ovary syndrome (PCOS) is a disorder with a symptomatic manifestation of an array of metabolic and endocrine impairments. PCOS has a relatively high prevalence rate among young women of reproductive age and is a risk factor for some severe metabolic diseases such as T2DM, insulin insensitivity, and obesity, while the most dominant endocrine malfunction is an excess of testosterone showing hyperandrogenism and hirsutism. MicroRNAs have been implicated as mediators of metabolic diseases including obesity and insulin resistance, as these can regulate multiple cellular pathways such as insulin signaling and adipogenesis. Genome-wide association studies during the last few years have also linked the Krüpple-like family of transcription factors such as KLF14, which contribute in mechanisms of mammalian gene regulation, with certain altered metabolic traits and risk of atherosclerosis and type-2 DM. This study has characterized the biochemical and endocrine parameters in PCOS patients with a comprehensive serum profiling in comparison to healthy controls and further examined the influence of allelic variations for miRNAs 27a (rs895819 A > G), 196a2 (rs11614913 C > T), 423 (rs6505162C > A), and transcription factor KLF14 (rs972283 A > G) gene polymorphism on the risk and susceptibility to PCOS. The experimental protocol included amplification refractory mutation-specific (ARMS)-PCR to detect and determine the presence of these polymorphic variants in the study subjects. The results in this case–control study showed that most of the serum biomarkers, both biochemical and endocrine, that were analyzed in the study demonstrated statistically significant alterations in PCOS patients, including lipids (LDL, HDL, cholesterol), T2DM markers (fasting glucose, free insulin, HOMA-IR), and hormones (FSH, LH, testosterone, and progesterone). The distribution of Krüppel-like factor 14 rs972283 G > A, miR-27a rs895819 A > G, and miR-196a-2 rs11614913 C > T genotypes analyzed within PCOS patients and healthy controls in the considered population was significant (p < 0.05), except for miR-423 rs6505162 C > A genotypes (p > 0.05). The study found that in the codominant model, KLF14-AA was strongly associated with greater PCOS susceptibility (OR 2.35, 95% CI = 1.128 to 4.893, p < 0.022), miR-27a-GA was linked to an enhanced PCOS susceptibility (OR 2.06, 95% CI = 1.165 to 3.650, p < 0.012), and miR-196a-CT was associated with higher PCOS susceptibility (OR 2.06, 95% CI = 1.191 to 3.58, p < 0.009). Moreover, allele A of KLF-14 and allele T of miR-196a2 were strongly associated with PCOS susceptibility in the considered population.

Thada Is Dispensable for Female Fertility in Mice.

Genome-wide association studies (GWAS) have identified THADA as one of the susceptibility genes for polycystic ovary syndrome (PCOS). Single nucleotide polymorphisms (SNPs) in the THADA gene showed significant over-transmission in PCOS and strong correlations with testosterone level. However, there was insufficient evidence to verify the effect of THADA in vivo on female reproductive system. In this study, we investigated the impacts of Thada ablation on ovarian function and reproductive outcomes with knockout (KO) mice. The results showed that the Thada deletion was insufficient to affect ovarian folliculogenesis, steroidogenesis, and female fertility. Additionally, we stressed the mice with high-fat-high-sugar diet (HFHS). In this case, the KO mice still merely had a negligible impact on ovarian function. These findings indicated that Thada deficiency was dispensable for female fertility in mice, which enriched our knowledge about in vivo functions of PCOS susceptibility genes.

Biochemical Characterization and Molecular Determination of Estrogen Receptor-α (ESR1 PvuII-rs2234693 T>C) and MiRNA-146a (rs2910164 C>G) Polymorphic Gene Variations and Their Association with the Risk of Polycystic Ovary Syndrome

Polycystic ovary syndrome (PCOS) is regarded as one of the most frequently encountered endocrine disorders and affects millions of young women worldwide, resulting in an array of complex metabolic alterations and reproductive failure. PCOS is a risk factor for diabetes mellitus, obstructive sleep apnea, obesity and depression in patients. Estrogen receptors (ESRs) are significant candidates in endocrine function and ovarian response in women. Moreover, microRNAs and long non-coding RNAs are emerging as principal mediators of gene expression and epigenetic pathways in various disease states. This study has characterized the clinical parameters in PCOS patients with comprehensive biochemical profiling compared to healthy controls and further examined the influence of allelic variations for estrogen receptor-α (ESR1 PvuII-rs2234693 T>C) and miRNA-146a (rs2910164 C>G) gene polymorphism on the risk of and susceptibility to PCOS. In this case-control study, we have used amplification refractory mutation specific (ARMS)-PCR to detect and determine the presence of these polymorphic variants in the study subjects. Our results demonstrated that most of the biochemical markers, which were analyzed in the study, show statistically significant alterations in PCOS patients, including fasting glucose, free insulin, HOMA-IR, LDL, HDL, cholesterol and hormones such as FSH, LH, testosterone and progesterone, which correlate with the established biochemical alterations in the disorder. Further, it is reported that for estrogen receptor-α (ESR1 PvuII-rs2234693 T>C), the frequency of the T allele (fT) was significantly higher among patients (0.64 vs. 0.44) compared to controls, while the frequency of the C allele (fC) was lower in patients (0.36 vs. 0.56) compared to controls. However, it was found that there was no association of an increased risk of PCOS with the ESR1 PvuII-rs2234693 C>T gene polymorphism. On the contrary, the study found strong association of miRNA-146a (rs2910164 C>G) gene polymorphism with an enhanced risk of PCOS. The frequency of the C allele (fC) was significantly higher among patients (0.52 vs. 0.36) compared to controls. The frequency of the G allele (fG) was found to be lower in patients (0.48 vs. 0.64) compared to controls. The codominant, dominant and recessive models display a statistically significant association of polymorphic variations with PCOS. Moreover, the G allele was associated strongly with PCOS susceptibility with an OR = 1.92 (95%) CI = (1.300–2.859), RR = 1.38 (1.130–1.691) p-value < 0.001.

The Association of STR markers on 19p13.2 region and polycystic ovarian syndrome susceptibility in Iranian population

Polycystic ovary syndrome (PCOS) is one of the most common endocrine complex and heterogeneous disorders in women. In this case-control study, we investigated the association of 9 short tandem repeats (STRs) located on 19p13.2 and susceptibility of PCOS. This study consisted of 66 women with PCOS as the case group as well as 44 age and ethnically matched healthy women as control groups from Qom province, Iran. The genomic DNA was extracted using a salting-out method from peripheral blood leukocytes. Genotyping was performed using polymerase chain reaction and electrophoresed on the polyacrylamide gel. Some samples with the same size bands on polyacrylamide gel were directly sequenced to confirm repeat numbers. The obtained results indicated that the target STRs are significantly different between patients and healthy controls. However, 19-CA repeat in D19S865 STR was identified as the only disease allele. Clinical analysis indicated that the levels of the anti-mullerian hormone, fasting blood sugar, and body mass index in the case group were significantly more than healthy controls. In conclusion, our study indicated that susceptibility to PCOS is associated with STRs on chromosome 19p13.2. A study with more sample size is needed to clear up this association in the Iranian population. However, more studies on different races and geographic areas are required to determine the exact role of these STRs in the susceptibility of PCOS.

Molecular determination of progesterone receptor's PROGINS allele (Alu insertion) and its association with the predisposition and susceptibility to polycystic ovary syndrome (PCOS).

Polycystic ovary syndrome, previously known as Stein-Leventhal syndrome, is associated with altered reproductive endocrinology, predisposing a young woman towards the risk of PCOS. It has a prevalence of 6-20% among the reproductive-age women. Progesterone is a key hormone in the pathophysiology of PCOS and patients show diminished response (progesterone resistance), implicating the role of progesterone receptor (PR) as a factor in the disease etiology and prognosis. In this case-control study, we have used mutation-specific PCR (confirmed by Sanger sequencing) to detect the presence of a pathologically significant PR polymorphic variant called as PROGINS. The variant has an Alu insertion in intron G and has two SNPs in exon 4 and exon 5, with all the three aberrations in complete disequilibrium. Our results demonstrated a statistically significant difference in the frequencies of PROGINS between the PCOS patients and healthy controls (p = 0.047). The frequencies of the genotypes CC (A1/A1), CT (A1/A2), and TT (A2/A2) in patients were 74.50%, 20.58%, and 4.90%, and in healthy controls they were 87.28%, 11%, and 1.69%, respectively. Our results put forward two determining factors with regard to PCOS: (i) the frequency of PROGINS allele was significantly higher among PCOS patients compared to the healthy matched controls (0.15 vs 0.07) in the studied population, (ii) the PROGIN allele was significantly associated with the lower levels of serum progesterone in PCOS patients (p < 0.003). The findings are conspicuous as these relate the PROGINS variant to the increased susceptibility of PCOS and might explain the progesterone resistance in patients.

Association of eNOS and STAT6 Gene Polymorphisms with the Susceptibility of Polycystic Ovary Syndrome in South Indian Women

Purpose: Polycystic Ovary Syndrome (PCOS) is a complex multifactorial endocrine metabolic disorder of reproductive-aged women characterized by hyperandrogenism, hirsutism, anovulation, hyperinsulinemia and polycystic ovaries. The main aim of this study was to investigate the association of eNOS and STAT6 gene Single Nucleotide Polymorphisms (SNPs) with the susceptibility of PCOS in South Indian Women. Research question: What is the association status of eNOS and STAT6 SNPs with PCOS? Methods: The present genetic association study involves clinically confirmed PCOS patients (n = 105) and non-PCOS controls (n = 110) of the Dravidian linguistic group. Genotyping of +894G/T (Glu298Asp) SNP of eNOS and 2964G/A SNP of STAT6 was performed by Polymerase Chain Reaction (PCR) and sequencing analysis. Results: There were statistically significant differences in the genotype and allele frequencies of eNOS+894G/T (p = 0.1110) and STAT62964G/A (0.0019) between the cases and controls, according to codominant, dominant and recessive genotype models. Conclusion: In conclusion, the eNOS and STAT6 gene polymorphisms may constitute an inheritable risk factor for PCOS in South Indian women.

CYP17 T/C (rs74357) gene polymorphism contributes to polycystic ovary syndrome susceptibility: evidence from a meta-analysis.

The cytochrome P450 family 17 (CYP17) is associated with hyperandrogenism in women, and the association between CYP17 gene polymorphism and the risk of polycystic ovary syndrome (PCOS) is not definitive. In order to determine whether the CYP17 T/C (rs74357) gene polymorphism is an exposure risk for PCOS, a comprehensive meta-analysis summarizing 19 studies was performed. The pooled odds ratio (OR) and the corresponding 95% CI were measured under five genetic models, and the stratified analyses by ethnicity, Hardy–Weinberg equilibrium, testosterone levels and BMI in controls were carried out to identify the causes of substantial heterogeneity. The overall results validated that the CYP17 T/C (rs74357) gene polymorphism was significantly associated with PCOS risk in four genetic models. Moreover, the outcomes of subgroup analysis by ethnicity indicated that the frequencies of the C allele of CYP17 T/C (rs74357) polymorphism were markedly higher in women from Asia than in Caucasians (T vs C: OR 0.85, 95% CI = 0.74–0.99, P < 0.05). Therefore, these findings suggested that the CYP17 T/C (rs74357) gene polymorphism played an indispensable part in increasing the susceptibility of PCOS when carrying the C allele, which proposed that the polymorphism of the CYP17 gene may be a predictive factor for the risk of PCOS or an important pathway in PCOS-associated metabolic and hormonal dysregulation.