Clinical-exome sequencing unveils the genetic landscape of polycystic ovarian syndrome (PCOS) focusing on lean and obese phenotypes: implications for cost-effective diagnosis and personalized treatment.

Polycystic ovarian syndrome (PCOS) is one of the most common endocrinopathies among reproductive women worldwide, contributing greatly on the incidence of female infertility and gynecological cancers. It is a complex health condition combining of multiple symptoms like androgen excess, uncontrolled weight gain, alopecia, hirsutism, etc. Conventionally PCOS was associated with obesity while it is often found among lean women nowadays, making the disease more critical to diagnose as well treatment. The disorder has an impact on several signal transduction pathways, including steroidogenesis, steroid hormone activity, gonadotrophin regulation, insulin secretion, energy balance, and chronic inflammation. Understanding the aetiology and pathophysiology of PCOS is difficult due to its multiple causes, which include environmental factors, intricate genetic predisposition, and epigenetic modifications. Despite research supporting the role of familial aggregations in PCOS outcomes, the inheritance pattern remains unknown. Henceforth, to reduce the burden of PCOS, it is inevitably important to diagnose at early ages as well as intervene through personalized medicine. With this brief background, it was imperative to elucidate the genetic architecture of PCOS considering BMI as an controlling factor. This study aims to investigate the genetic basis behind obesity-mediated PCOS, focusing on both obese and lean individuals. It uses a comprehensive bioinformatics methodology to depict pathways and functionality enrichment, allowing for cost-effective risk prediction and management. In the present research, the representative study participants (N = 2) were chosen from a cross-sectional epidemiological survey, based on their anthropometric parameters and confirmation of PCOS. Upon voluntary participation and written consent, biological fluids (whole blood and buccal swab) were taken from where DNA was extracted. The clinical-exome sequencing was performed by the Next-generation Illumina platform using the Twist Human Comprehensive Exome Kit. A comprehensive bioinformatics methodology was employed to identify the most important, unique, and common genes. A total of 26,550 variants were identified in clinically important exomes from two samples, with 5170 common and 2232 and 2322 unique among PCOS lean and obese phenotypes, respectively. Only 262 and 94 variants were PCOS-specific in lean and obese PCOS. Three filters were applied to shortlist the most potent variants, with 4 unique variants in lean PCOS, 2 unique variants in obese PCOS, and 5 common variants in both. The study found that leptin signalling impairment and insulin resistance, as well as mutations in CYP1A1, CYP19A1, ESR1, AR, AMH, AdipoR1, NAMPT, NPY, PTEN, EGFR, and Akt, all play significant roles in PCOS in the studied group. Young women in West Bengal, India, are more likely to have co-occurring PCOS, which includes estrogen resistance, leptin receptor insufficiency, folate deficiency, T2DM, and acanthosis nigricans, with obesity being a common phenotypic expression.

Causal relationship between fertility nutrients supplementation and PCOS risk: a Mendelian randomization study.

Background: Polycystic ovary syndrome (PCOS), a prevalent endocrine disorder in women of reproductive age, is mainly ameliorated through drugs or lifestyle changes, with limited treatment options. To date, numerous researchers have found that fertility nutrient supplements may benefit female reproductive health, but their direct impact on polycystic ovary syndrome risk remains unclear. Methods: Our research employs Mendelian Randomization to assess how fertility nutrients affect PCOS risk. Initially, we reviewed 49 nutrients and focused on 10: omega-3 fatty acids, calcium, dehydroepiandrosterone, vitamin D, betaine, D-Inositol, berberine, curcumin, epigallocatechin gallate, and metformin. Using methodologies of Inverse Variance Weighting and Mendelian Randomization-Egger regression, we examined their potential causal relationships with PCOS risk. Results: Our findings indicate omega-3 fatty acids reduced PCOS risk (OR=0.73, 95% CI: 0.57-0.94, P=0.016), whereas betaine increased it (OR=2.60, 95% CI: 1.09-6.17, P=0.031). No definitive causal relations were observed for calcium, dehydroepiandrosterone, vitamin D, D-Inositol, and metformin (P>0.05). Drug target Mendelian Randomization analysis suggested that increased expression of the berberine target gene BIRC5 in various tissues may raise PCOS risk (OR: 3.00-4.88; P: 0.014-0.018), while elevated expressions of curcumin target gene CBR1 in Stomach and epigallocatechin gallate target gene AHR in Adrenal Gland were associated with reduced PCOS risk (OR=0.48, P=0.048; OR=0.02, P=0.018, respectively). Conclusions: Our research reveals that specific fertility nutrients supplementation, such as omega-3 fatty acids, berberine, and curcumin, may reduce the risk of PCOS by improving metabolic and reproductive abnormalities associated with it.

Shared diagnostic genes and potential mechanisms between polycystic ovary syndrome and recurrent miscarriage revealed by integrated transcriptomics analysis and machine learning.

Objective: More and more studies have found that polycystic ovary syndrome (PCOS) is significantly associated with recurrent spontaneous abortion (RSA), but the specific mechanism is not yet clear. Methods: Based on the GEO database, we downloaded the PCOS (GSE10946, GSE6798 and GSE137684) and RSA (GSE165004, GSE26787 and GSE22490) datasets and performed differential analysis, weighted gene co-expression network (WGCNA), functional enrichment, and machine learning, respectively, on the datasets of the two diseases, Nomogram and integrated bioinformatics analysis such as immune infiltration analysis. Finally, the reliability of the diagnostic gene was verified by external verification and collection of human specimens. Results: In this study, PCOS and RSA datasets were obtained from Gene Expression Omnibus (GEO) database, and a total of 23 shared genes were obtained by differential analysis and WGCNA analysis. GO results showed that the shared genes were mainly enriched in the functions of lipid catabolism and cell cycle transition (G1/S). DO enrichment revealed that shared genes are mainly involved in ovarian diseases, lipid metabolism disorders and psychological disorders. KEGG analysis showed significant enrichment of Regulation of lipolysis in adipocytes, Prolactin signaling pathway, FoxO signaling pathway, Hippo signaling pathway and other pathways. A diagnostic gene FAM166 B was obtained by machine learning and Nomogram screening, which mainly played an important role in Cellular component. GSEA analysis revealed that FAM166B may be involved in the development of PCOS and RSA by regulating the cell cycle, amino acid metabolism, lipid metabolism, and carbohydrate metabolism. CIBERSORT analysis showed that the high expression of FAM166 B was closely related to the imbalance of multiple immune cells. Further verification by qPCR suggested that FAM166 B could be used as a common marker of PCOS and RSA. Conclusions: In summary, this study identified FAM166B as a common biomarker for PCOS and RSA, and conducted in-depth research and analysis of this gene, providing new data for basic experimental research and early prognosis, diagnosis and treatment of clinical diseases.

REMEDIAL INTERVENTION OF FERTILITY AGENT AND GENE 35 ON INDUCED CYSTIC OVARY IN RATS.

Infertility is a condition with a negative health state and cystic ovary disorder is one of it is causes. PCOS is a prevalent derange till now. Therefore, current study is designed to estimate the role of Gene 35 and fertility supplements (composed from chasteberry, green tea extracts and L-arginine along with some elements),as alternative therapy for induced cystic ovary with letrozole in rats. Thirty female rats were divided erratically into four groups: G1 negative control, G2 positive group, G3 fertility group, G4 Gene 35 group and G5 combination of both Gene 35 with fertility. Vaginal smear examination was done to ensure the occurrence of PCOS. Blood samples were obtained, and sera were separated for hormonal evaluation of luteinizing hormone (LH), testosterone (T), anti mullerian hormone (AMH), follicle-stimulating hormone (FSH), prolactin (PRL) as well as insulin and ovary samples were obtained for histopathological study. Current study reveals a significant (p<0.05) increase in serum AMH, FT, LH, PRL as well as insulin and significant (p<0.05) decrease in serum FSH in PCOS groups when compared to treated groups. However, treated groups experienced significant (p<0.05) decrease in serum AMH, FT, LH, PRL with insulin and significant (p<0.05) increase in in serum FSH in comparison to positive control. Histopathological study showed marked reduction of cystic follicle along with corpora lutea predominance that reflect a good response as compared to PCOS group. From the current result, there is a noticeable improvement in number of ovarian cysts and hormones levels. Therefore, it is recommended that Gene 35 and fertility supplement can be used in the treatment of PCOS patients as supporting and treatment.

ER stress-induced LINC00173 promotes the apoptosis of ovarian granulosa cells by regulating the HRK/PI3K/AKT pathway in polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is a prevalent endocrine disorder and metabolic abnormality disease that mainly affects women of reproductive age. LINC00173, a novel long noncoding RNA (lncRNA), has emerged as an important factor in the development of PCOS. However, the role of LINC00173 in PCOS development and its specific upstream and downstream mechanisms remain to be further clarified. Here, we found that LINC00173 was significantly upregulated in granulosa cells (GCs) of PCOS patients, and played a crucial role in promoting apoptosis of GCs. Mechanistically, we observed the activation of endoplasmic reticulum (ER) stress in the GCs of PCOS patients, and the ER stress sensor ATF4 could directly induce LINC00173 expression by binding to its promoter. LINC00173 further upregulated the expression of Harakiri (HRK) and subsequently inhibited downstream PI3K/AKT pathway. In conclusions, our study uncovered that ER stress-induced upregulation of LINC00173 leads to increased HRK expression and inhibition of the PI3K/AKT pathway, thereby promoting the progression of PCOS. These findings provide a new therapeutic strategy for the treatment of PCOS.

Unveiling the shared genetic architecture between testosterone and polycystic ovary syndrome.

Testosterone (T) is a critical predictor of polycystic ovary syndrome (PCOS) but the genetic overlap between T and PCOS has not been established. Here by leveraging genetic datasets from large-scale genome-wide association studies, we assessed the genetic correlation and polygenic overlap between PCOS and three T-related traits using linkage disequilibrium score regression and the bivariate causal mixture model methods. The conjunctional false discovery rate (conjFDR) method was employed to identify shared causal variants. Functional annotation of variants was conducted using FUMA. Total T and bioavailable T exhibited positive correlations with PCOS, while sex hormone-binding globulin (SHBG) showed a negative correlation. All three traits demonstrated extensive genetic overlap with PCOS, with a minimum of 68% of T-related variants influencing PCOS. The conjFDR revealed 4 to 6 causal variants within joint genomic loci shared between PCOS and T-related traits. Functional annotations suggested that these variants might impact PCOS by modulating nearby genes, such as FSHB. Our findings support the hypothesis that PCOS is significantly influenced by androgen abnormalities. Additionally, this study identified several causal variants potentially involved in shared biological mechanisms between PCOS and T regulation.

Unraveling the pathogenic interplay between SARS-CoV-2 and polycystic ovary syndrome using bioinformatics and experimental validation.

The prevalence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) among polycystic ovary syndrome (PCOS) is significantly higher than in the general population. However, the mechanisms underlying this remain obscure. This study aimed to explore the mechanisms by identifying the genetic signature of SARS-CoV-2 infection in PCOS. In the present study, a total of 27 common differentially expressed genes (DEGs) were selected for subsequent analyses. Functional analyses showed that immunity and hormone-related pathways collectively participated in the development and progression of PCOS and SARS-CoV-2 infection. Under these, 7 significant hub genes were identified, including S100A9, MMP9, TLR2, THBD, ITGB2, ICAM1, and CD86 by using the algorithm in Cytoscape. Furthermore, hub gene expression was confirmed in the validation set, PCOS clinical samples, and mouse model. Immune microenvironment analysis with the CIBERSORTx database demonstrated that the hub genes were significantly correlated with T cells, dendritic cells, mast cells, B cells, NK cells, and eosinophils and positively correlated with immune scores. Among the hub genes, S100A9, MMP9, THBD, ITGB2, CD86, and ICAM1 demonstrated potential as possible diagnostic markers for COVID-19 and PCOS. In addition, we established the interaction networks of ovary-specific genes, transcription factors, miRNAs, drugs, and chemical compounds with hub genes with NetworkAnalyst. This work uncovered the common pathogenesis and genetic signature of PCOS and SARS-CoV-2 infection, which might provide a theoretical basis and innovative ideas for further mechanistic research and drug discovery of the comorbidity of the two diseases.

Association of SOGPI in mediating the effect of Phosphatidylcholine on polycystic Ovary Syndrome.

BACKGROUND: Polycystic ovary syndrome (PCOS) is a prevalent endocrine disorder in women of reproductive age, marked by hormonal imbalances and disruptions in glucose and lipid metabolism. Emerging research has indicated a correlation between lipids and PCOS, yet the specific lipid profiles or associated genes identified in various studies vary, and observational data alone cannot establish causation. Therefore, our study seeks to establish a causal association between lipidome and PCOS. METHODS: Data from genome-wide association studies, liposomes, metabolites, and PCOS-related information were collected. Four rounds of double-sample bidirectional intermediate Mendelian Randomization analyses including liposomes to disease, liposomes to metabolites, metabolites to disease, and reverse Mendelian Randomization analysis of lipids, total effect values and intermediary effect values were calculated. The proportion mediated by the intermediary effect was determined by dividing the intermediary effect value by the total effect value. RESULTS: The analyses revealed that three liposomes and nine metabolites were causally associated with PCOS. Specifically, phosphatidylcholine and 1-Stearoyl-2-Oleoyl-Glycosylphosphatidylinositol were identified as independent risk factors for PCOS through further Mendelian Randomization analysis. The risk of developing PCOS increased by 32% for every one standard deviation increase in phosphatidylcholine and by 17% for every one standard deviation increase in 1-Stearoyl-2-Oleoyl-Glycosylphosphatidylinositol. Furthermore, the study revealed that phosphatidylcholine can influence the development of PCOS with 1-Stearoyl-2-Oleoyl-Glycosylphosphatidylinositol acting as a mediator, explaining 4.97% of the effect. CONCLUSIONS: This study confirmed a causal relationship between phosphatidylcholine and 1-Stearoyl-2-Oleoyl-Glycosylphosphatidylinositol with PCOS, where phosphatidylcholine can influence the occurrence of PCOS with 1-Stearoyl-2-Oleoyl-Glycosylphosphatidylinositol as a mediator.

Identification and validation of novel genes related to immune microenvironment in polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is one of the most complicated chronic inflammatory diseases in women of reproductive age and is one of the primary factors responsible for infertility. There is substantial dispute relating to the pathophysiology of PCOS. Consequently, there is a critical need for further research to identify the factors underlying the pathophysiology of PCOS. Three transcriptome profiles of granulosa cells from patients with PCOS and normal controls were obtained from the gene expression integration database. We also obtained relevant microarrays of granulocytes prepared from PCOS patients and normal controls from the gene expression integration database. Then, we used the R package to perform correlations and identify differences between PCOS and normal controls with regard to immune infiltrating cells and functionality. Subsequently, intersecting genes were identified and risk models were constructed. Finally, the results were validated by enzyme linked immunosorbent assay and real-time PCR. We identified 8 genes related to cuproptosis (SLC31A1, PDHB, PDHA1, DLST, DLD, DLAT, DBT, and ATP7A) and 5 genes related to m7G (SNUPN, NUDT16, GEMIN5, DCPS, and EIF4E3) that were associated with immune infiltration. Furthermore, the expression levels of DLAT (P = .049) and NUDT16 (P = .024) differed significantly between the PCOS patients and normal controls, as revealed by multifactorial analysis. Both DLAT and NUDT16 were negatively correlated with immune cell expression and function and expression levels were significantly lower in the PCOS group. Finally, real-time PCR and enzyme linked immunosorbent assay demonstrated that the expression levels of DLAT and NUDT16 were significantly reduced in the granulosa cells of PCOS patients. In conclusion, our findings shed fresh light on the roles of immune infiltration, cuproptosis, and m7G alternations in PCOS. We also provide a reliable biomarker for the pathological classification of PCOS patients.

Identification and validation of core genes associated with polycystic ovary syndrome and metabolic syndrome.

Polycystic ovary syndrome (PCOS) is a common endocrine and metabolic disorder affecting women of reproductive age, affecting reproductive health, and increasing the incidence of diabetes mellitus and hypertension. Metabolic syndrome (MetS) is the most common metabolic disorder. Although clinical studies have shown a close association between PCOS and MetS, the molecular mechanisms are unknown. In this study, datasets of PCOS and MetS were obtained from the Gene Expression Omnibus database; differential expression analysis and weighted gene coexpression network analysis (WGCNA) were performed; and gene ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses also performed of differentially expressed genes (DEGs). The PCOS- and MetS-coexpressed DEGs were subsequently intersected with the coexpressed genes in the WGCNA module to obtain the core genes. By constructing receiver operating characteristic curves, we verified the predictive effects of the core genes. We also validated the expression of the core genes in the datasets. Finally, we verified the expression of the core genes by quantitative polymerase chain reaction in human follicular fluid granulosa cells. In addition, we used Cell-type Identification By Estimating Relative Subsets Of RNA Transcripts to analyze the immune infiltration of immune cells in PCOS and MetS. Finally, we obtained 52 coexpressed DEGs of PCOS and MetS and 3 coexpressed genes in the WGCNA module. By taking the intersection of coexpressed DEGs and coexpressed genes of the WGCNA module, we get ELOVL fatty acid elongase 7 (ELOVL7) as the core gene. Receiver operating characteristic curve analysis showed that ELOVL7 is a reliable biological marker for PCOS and MetS. The expression level of ELOVL7 in human follicular fluid granulosa cells from PCOS patients was significantly higher than that of controls, as verified by quantitative polymerase chain reaction. This study provides the first evidence of the role of ELOVL7 in developing PCOS and MetS. This gene may serve as a potential diagnostic marker and therapeutic target for both conditions.

Exploring the causal pathway from gut microbiota to polycystic ovary syndrome: A network Mendelian randomization study.

Polycystic ovary syndrome (PCOS) is a complicated endocrine and metabolic syndrome with unclear pathogenesis. The gut microbiota sheds light on the etiology and pathophysiology of PCOS. We used Mendelian randomization (MR) studies to systematically evaluate the pathological mechanism gut microbiota causally associated with PCOS risk. A network MR analysis was performed to estimate the causal effects of gut microbiota and risk factors on PCOS, as well as the mediation effect of risk factors linking gut microbiota to PCOS. The investigation of side effects for the important gut microbiota was subsequently broadened to include phenotypes by performing Phenowide-MR analysis for a range of diseases. Genus Sellimonas id.14369 were causally associated with reduced PCOS risk (odds ratio [OR] = 0.69, 95% confidence interval [CI]: 0.58-0.84, P = 1.22 × 10-4) after multiple testing correction. And Sellimonas retained consistent causal effect estimates after a series of sensitivity analyses. In addition, we observed an indirect effect of Sellimonas on PCOS through body mass index (BMI) using network MR (b = -0.05, 95% CI: -0.09 to -0.01), with a mediated proportion of 12.82% of the total effect. Further, Phenowide-MR analyses showed that the protective effects of Sellimonas on type 2 diabetes and depression (for type 2 diabetes: OR = 0.95, 95% CI: 0.90-0.99, P = .0366; for depression: OR = 0.99, 95% CI: 0.98-1.00, P = .0210). We summarized that the causal path between gut microbiota and type 2 diabetes are also jointly mediated by BMI. Sellimonas may be a protective factor of PCOS, which can affect the occurrence of PCOS through BMI, supporting future studies on the importance of addressing obesity and metabolic issues in preventing and managing PCOS.

GDF-15 and mtDNA Deletions Are Useful Biomarkers of Mitochondrial Dysfunction in Insulin Resistance and PCOS.

There is no literature available about the growth differentiation factor-15 (GDF-15) biomarker in combination with mitochondrial DNA (mtDNA) deletions in insulin resistance (IR), and polycystic ovary syndrome (PCOS); however, it would be useful to achieve optimal metabolic status and improve pregnancy success. In this study, the role of GDF-15 and mtDNA deletions as biomarkers in the pathogenesis of IR and PCOS was investigated. In our study, 81 female patients who were treated for IR and/or PCOS and 41 healthy controls were included. GDF-15 levels in patients showed a marked increase compared to controls. Elevated GDF-15 levels were found in 12 patients; all of them had a BMI > 25 kg/m2, which is associated with reactive hyperinsulinemia. The presence of mitochondrial dysfunction was mainly observed in the IR-only subgroup. The increase in plasma levels of GDF-15 and the prevalence of mtDNA deletions is directly proportional to body mass index. The more marked metabolic abnormalities required more intensive drug therapy with a parallel increase in plasma GDF-15 levels. Elevated levels of GDF-15 and the presence of mitochondrial DNA deletions may be a consequence of carbohydrate metabolism disorders in patients and thus a predictor of the process of accelerated aging.

Metabolic and hormonal profiling in polycystic ovarian syndrome: insights into INSR gene variations.

BACKGROUND: Polycystic Ovary Syndrome (PCOS) is a hormonal disorder characterized by irregular periods, excess androgen levels, and polycystic ovaries, affecting many women of reproductive age. METHODS AND RESULTS: This study employed statistical and molecular analyses to compare hormone and metabolic markers between PCOS patients and controls. Sanger sequencing identified two INSR gene variants linked to high insulin and pre-diabetic conditions. Statistically, no significant age differences were detected (p = 0.492) between the overall PCOS patient pool and controls. However, a substantial variation in Vitamin D levels was observed within PCOS patients compared to controls (p = 0.0006), suggesting an association with PCOS. Correlations between Vitamin D and insulin, as well as HbA1c levels (R2 = 0.141 and 0.143, respectively), suggest Vitamin D's potential impact on glycemic control. Significant differences were found in HbA1c (p < 0.0001), insulin (p < 0.0001), and LDL (p = 0.0004) levels between PCOS patients and controls, highlighting marked disparities in these metabolic markers. LH levels also showed a significant contrast (p < 0.0001), while progesterone levels displayed a notable difference (p = 0.007) between the two groups. Correlation analyses within PCOS patients demonstrated associations among LDL, HbA1c, and insulin, with no such correlations observed in control cases. Additionally, Sanger sequencing identified two INSR gene variants, c.3614C > T (p.Pro1205Leu) and c.3355C > T (p.Arg1119Trp), associated with high insulin, LH, and pre-diabetic conditions. These amino acid changes may trigger metabolic imbalances and hormonal irregularities, potentially contributing to the development of PCOS. CONCLUSIONS: The findings highlight the multifaceted nature of PCOS, revealing significant metabolic, hormonal, and genetic differences compared to controls. These insights may inform tailored interventions and management strategies for the complex associations characteristic of PCOS.

From proteome to pathogenesis: investigating polycystic ovary syndrome with Mendelian randomization analysis.

Background: Polycystic ovary syndrome (PCOS) is defined by oligo/anovulation, hyperandrogenism, and polycystic ovaries with uncertain pathogenesis. The proteome represents a substantial source of therapeutic targets, and their coding genes may elucidate the mechanisms underlying PCOS. However, reports on the profiles of the human plasma protein-coding genes and PCOS are limited. Here, we aimed to investigate novel biomarkers or drug targets for PCOS by integrating genetics and the human plasma proteome. Methods: Our study acquired the protein quantitative trait loci from DECODE Genetics, offering 4,907 proteins in 35,559 individuals while obtaining PCOS summary statistics by accessing the FinnGen biobank (1,639 cases and 218,970 controls) and the genome-wide association study catalog (797 cases and 140,558 controls). Herein, we sequentially used two-sample Mendelian randomization (MR) analyses and colocalization to verify the causal link between candidate proteins, their coding genes, and PCOS. Further PCOS data download was conducted by accessing the Gene Expression Omnibus and Zenodo platforms. Gene expression level analysis, pathway enrichment analysis, immune cell infiltration, and transcription factor prediction were performed, aiming at detecting specific cell types with enriched expression and exploring potential optimized treatments for PCOS. Results: MR analysis revealed 243 protein-coding genes with a causal relationship to PCOS risk, of which 12 were prioritized with the most significant evidence. Through colocalization analysis, three key genes, CUB domain-containing protein 1 (CDCP1), glutaredoxin 2 (GLRX2), and kirre-like nephrin family adhesion molecule 2 (KIRREL2), were identified. Subsequently, the three genes were strongly related to immune function and metabolism in terms of biological significance. In single-cell analysis, the expression levels of genes in ovarian theca cells were explored. Conclusion: Overall, three protein-coding genes (CDCP1, GLRX2, and KIRREL2) may be related to a higher PCOS risk, suggesting that they may be entry points for exploration of PCOS pathogenesis and treatment, warranting further clinical investigations.

Transcription factor YY1 adversely governs ovarian granulosa cell growth in PCOS by transcription activation-mediated CDKN1C upregulation.

BACKGROUND: Polycystic ovary syndrome (PCOS) is a common endocrine and metabolic disease in women of childbearing age, making it imperative to explore more biomarkers for PCOS. Furthermore, previous studies have reported that cyclin dependent kinase inhibitor 1 C (CDKN1C) might be associated with PCOS progression. However, the molecular mechanism of CDKN1C involved in PCOS is poorly defined. METHODS: CDKN1C and Yin-Yang-1 (YY1) expression levels were determined using real-time quantitative polymerase chain reaction (RT-qPCR) and Western blot assay. Cell viability, proliferation, cell cycle progression, and cell apoptosis were analyzed using 3-(4, 5-dimethyl-2-thiazolyl)-2, 5-diphenyl-2-H-tetrazolium bromide (MTT), 5-ethynyl-2'-deoxyuridine (EdU), and flow cytometry assays. Caspase 3 activity was examined using a commercial kit. Binding between YY1 and CDKN1C promoter was predicted by JASPAR and verified using Chromatin immunoprecipitation (ChIP) and dual-luciferase reporter assays. RESULTS: CDKN1C and YY1 were highly expressed in PCOS granulosa cells (GCs). Furthermore, CDKN1C silencing could promote cell proliferation and cell cycle process and repress cell apoptosis in human ovarian granulosa cell line KGN cells. For mechanistic analysis, YY1 is directly bound to the promoter of CDKN1C and transcriptional-regulated CDKN1C expression. CONCLUSION: YY1-activated CDKN1C might block KGN cell proliferation and induce cell apoptosis, providing a possible therapeutic target for PCOS treatment.

The Impact of Vitamin D Receptor Gene Polymorphisms (FokI, ApaI, TaqI) in Correlation with Oxidative Stress and Hormonal and Dermatologic Manifestations in Polycystic Ovary Syndrome.

Background and Objectives: Polycystic ovary syndrome (PCOS) is a frequent and complex multidisciplinary disorder. Data regarding the role of genes involved in vitamin D metabolism in PCOS are as-yet elusive but suggest an association of VDR (vitamin D receptor) and vitamin D levels with metabolic, endocrine and cutaneous manifestations. The aim of this study was to evaluate the association between VDR gene polymorphisms and cutaneous manifestations, to find a correlation between hormonal parameters, oxidative stress and skin manifestations in women with PCOS, and to determine the impact of VDR gene polymorphisms on these parameters. Materials and Methods: This case-control study included 39 controls and 46 women with PCOS, matched by age and BMI distribution. Acne, hirsutism, seborrhea, androgenetic alopecia, oxidative stress and androgen hormones were recorded. VDR gene polymorphisms ApaI, FokI and TaqI were examined by polymerase chain reaction restriction fragment length polymorphism, and the androgen hormone (total testosterone, DHEAS), SHBG and malondialdehyde levels were assessed. Results: The most frequent skin manifestations in PCOS cases were acne followed by seborrhea, hirsutism and androgenic alopecia. The VDR-FokI polymorphism CC genotype had a significant protective role in the odds of acne (OR = 0.11, 95% CI: [0.02, 0.70], p = 0.015, p-corrected = 0.040) and seborrhea (OR = 0.15, 95% CI: [0.03, 0.75], p = 0.019, p-corrected = 0.039). The results demonstrated a significant protective effect of the C allele on the odds of acne and seborrhea in PCOS cases. Moreover, the dominant genotype of VDR-TaqI could have a protective role against oxidative stress (lower MDA levels) compared to patients carrying the TT genotype. Conclusions: In summary, this is the first study to demonstrate that the FokI CC genotype may have a protective role against both acne and seborrhea in women with PCOS, while the VDR-TaqI dominant genotype is associated with diminished oxidative stress in PCOS patients.

Helsmoortel-Van der Aa syndrome in a 13-year-old girl with autistic spectrum disorder, dysmorphism, a right solitary kidney, and polycystic ovaries: a case report.

BACKGROUND: Helsmoortel-Van der Aa syndrome was officially documented in 2014. Helsmoortel-Van der Aa syndrome is an extremely rare complex neurodegenerative disorder characterized by reduced intellectual capacity, motor dysfunction, facial dysmorphism, impaired development, and an increased predisposition to autism spectrum disorder. In addition, many patients also present with neuropsychiatric disorders, including attention deficit hyperactivity disorder, anxiety disorders, and various behavioral abnormalities. Helsmoortel-Van der Aa syndrome is challenging to identify solely on the basis of symptoms, and genetic investigations, including exome sequencing, may facilitate diagnosis. CASE PRESENTATION: We report a case of 13-year-old Saudi patient who presented with dysmorphic features as illustrated in Fig. 1, severe mental retardation, autism spectrum disorder, and attention deficit hyperactivity disorder. Initial genetic testing was unremarkable; thus, a clinical exome analysis was performed to identify the genetic basis of the condition. CONCLUSIONS: Clinical exome analysis indicated an autosomal dominant Helsmoortel-Van der Aa syndrome with a likely pathogenic de novo variant within the activity-dependent neuroprotector homeobox (ADNP) gene not previously reported in Helsmoortel-Van der Aa syndrome. The patient had a right-sided solitary kidney and polycystic ovaries, conditions that were not previously associated with HVDAS.

miR-151a-3p regulates the TNIK/PI3K/Akt axis and influences the progression of polycystic ovary syndrome.

OBJECTIVES: Polycystic ovarian syndrome (PCOS) is a common reproductive endocrine disease in women of childbearing age, and the incidence of PCOS has increased in recent years. However, the pathogenesis of this disease has not been fully elucidated. METHODS: The expression of miR-151a-3p in ovarian granulosa cells (KGN) was determined using real-time fluorescent quantitative polymerase chain reaction (RT-qPCR). Cell Counting Kit-8 (CCK-8), colony formation and flow cytometric assays were used to investigate the effect of miR-151a-3p on KGN cells. Luciferase reporter analysis and western blotting were used to verify the targeting of miR-151a-3p by Traf and Nck interacting kinase (TNIK). Western blotting (WB) was used to evaluate the protein levels. RESULTS: We found that miR-151a-3p was downregulated and TNIK was upregulated in the serum of PCOS patients. Low expression of miR-151a-3p promoted cell proliferation, colony formation and the G0/G1 transition and reduced apoptosis. Our results showed that low expression of miR-151a-3p promoted the expression of TNIK, which activated the phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) pathway. Overexpression of TNIK rescued the effect of miR-151a-3p in ovarian granulosa cells. Finally, our results showed that there was a significant correlation between the expression of miR-151a-3p and the expression of the target TNIK in PCOS patients and that miR-151a-3p promoted disease occurrence by activating the PI3K/AKT signaling pathway. CONCLUSIONS: Low expression of miR-151a-3p promoted KNG cell proliferation by activating the TNIK-mediated PI3K/AKT signaling pathway. The miR-151a-3p/TNIK/PI3K/AKT signaling axis may be a potential therapeutic target for preventing the progression of PCOS.

CTBP1 links metabolic syndrome to polycystic ovary syndrome through interruption of aromatase and SREBP1.

Some patients with polycystic ovarian syndrome (PCOS) suffered from metabolic syndrome (MetS) including dyslipidemia, hyperinsulinism, but the underlying mechanism is unclear. Although C-terminal Binding Protein 1 (CTBP1) is a transcriptional co-repressor frequently involved in hormone secretion disorders and MetS-associated diseases, the role of CTBP1 in PCOS is rarely reported. In the present study, we found that CTBP1 expression was significantly elevated in primary granulosa cells (pGCs) derived from the PCOS with MetS patients and was positively associated with serum triglyceride, but negatively correlated with serum estradiol (E2) or high-density lipoprotein. Mechanistic study suggested that CTBP1 physically bound to the promoter II of cytochrome P450 family 19 subfamily A member 1 (CYP19A1) to inhibit the aromatase gene transcription and expression, resulting in the reduced E2 synthesis. Moreover, CTBP1 interacted with the phosphorylated SREBP1a at S396 in nuclei, leading to the FBXW7-dependent protein degradation, resulting in the reduced lipid droplets formation in pGCs. Therefore, we conclude that CTBP1 in GCs dysregulates the synthesis of steroid hormones and lipids through suppression of aromatase expression and promotion of SREBP1a protein degradation in PCOS patients, which may offer some fresh insights into the potential pathological mechanism for this tough disease.

Exploring Genetic Interactions in Colombian Women with Polycystic Ovarian Syndrome: A Study on SNP-SNP Associations.

Polycystic ovary syndrome (PCOS) is an endocrine and metabolic disorder with high prevalence in women around the world. The identification of single-nucleotide polymorphisms (SNPs) through genome-wide association studies has classified it as a polygenic disease. Most studies have independently evaluated the contribution of each SNP to the risk of PCOS. Few studies have assessed the effect of epistasis among the identified SNPs. Therefore, this exploratory study aimed to evaluate the interaction of 27 SNPs identified as risk candidates and their contribution to the pathogenesis of PCOS. The study population included 49 control women and 49 women with PCOS with a normal BMI. Genotyping was carried out through the MassARRAY iPLEX single-nucleotide polymorphism typing platform. Using the multifactor dimensionality reduction (MDR) method, the interaction between SNPs was evaluated. The analysis showed that the best interaction model (p < 0.0001) was composed of three loci (rs11692782-FSHR, rs2268361-FSHR, and rs4784165-TOX3). Furthermore, a tendency towards synergy was evident between rs2268361 and the SNPs rs7371084-rs11692782-rs4784165, as well as a redundancy in rs7371084-rs11692782-rs4784165. This pilot study suggests that epistasis may influence PCOS pathophysiology. Large-scale analysis is needed to deepen our understanding of its impact on this complex syndrome affecting thousands of women.