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1.
PLoS Med ; 17(6): e1003132, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32574161

RESUMO

BACKGROUND: Polycystic ovary syndrome (PCOS) is a common, complex genetic disorder affecting up to 15% of reproductive-age women worldwide, depending on the diagnostic criteria applied. These diagnostic criteria are based on expert opinion and have been the subject of considerable controversy. The phenotypic variation observed in PCOS is suggestive of an underlying genetic heterogeneity, but a recent meta-analysis of European ancestry PCOS cases found that the genetic architecture of PCOS defined by different diagnostic criteria was generally similar, suggesting that the criteria do not identify biologically distinct disease subtypes. We performed this study to test the hypothesis that there are biologically relevant subtypes of PCOS. METHODS AND FINDINGS: Using biochemical and genotype data from a previously published PCOS genome-wide association study (GWAS), we investigated whether there were reproducible phenotypic subtypes of PCOS with subtype-specific genetic associations. Unsupervised hierarchical cluster analysis was performed on quantitative anthropometric, reproductive, and metabolic traits in a genotyped cohort of 893 PCOS cases (median and interquartile range [IQR]: age = 28 [25-32], body mass index [BMI] = 35.4 [28.2-41.5]). The clusters were replicated in an independent, ungenotyped cohort of 263 PCOS cases (median and IQR: age = 28 [24-33], BMI = 35.7 [28.4-42.3]). The clustering revealed 2 distinct PCOS subtypes: a "reproductive" group (21%-23%), characterized by higher luteinizing hormone (LH) and sex hormone binding globulin (SHBG) levels with relatively low BMI and insulin levels, and a "metabolic" group (37%-39%), characterized by higher BMI, glucose, and insulin levels with lower SHBG and LH levels. We performed a GWAS on the genotyped cohort, limiting the cases to either the reproductive or metabolic subtypes. We identified alleles in 4 loci that were associated with the reproductive subtype at genome-wide significance (PRDM2/KAZN, P = 2.2 × 10-10; IQCA1, P = 2.8 × 10-9; BMPR1B/UNC5C, P = 9.7 × 10-9; CDH10, P = 1.2 × 10-8) and one locus that was significantly associated with the metabolic subtype (KCNH7/FIGN, P = 1.0 × 10-8). We developed a predictive model to classify a separate, family-based cohort of 73 women with PCOS (median and IQR: age = 28 [25-33], BMI = 34.3 [27.8-42.3]) and found that the subtypes tended to cluster in families and that carriers of previously reported rare variants in DENND1A, a gene that regulates androgen biosynthesis, were significantly more likely to have the reproductive subtype of PCOS. Limitations of our study were that only PCOS cases of European ancestry diagnosed by National Institutes of Health (NIH) criteria were included, the sample sizes for the subtype GWAS were small, and the GWAS findings were not replicated. CONCLUSIONS: In conclusion, we have found reproducible reproductive and metabolic subtypes of PCOS. Furthermore, these subtypes were associated with novel, to our knowledge, susceptibility loci. Our results suggest that these subtypes are biologically relevant because they appear to have distinct genetic architecture. This study demonstrates how phenotypic subtyping can be used to gain additional insights from GWAS data.


Assuntos
Síndrome do Ovário Policístico/genética , Adulto , Análise por Conglomerados , Feminino , Estudos de Associação Genética , Estudo de Associação Genômica Ampla , Humanos , Fenótipo , Síndrome do Ovário Policístico/classificação , Síndrome do Ovário Policístico/patologia
2.
DNA Cell Biol ; 39(8): 1458-1466, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32513025

RESUMO

Polycystic ovary syndrome (PCOS) is a multifactorial disorder characterized by irregular menstrual problems, hyperandrogenism, and presence of polycystic ovaries. Till date, molecular mechanism underlying PCOS remains elusive. Recently mitochondrial displacement loop (D-loop) variants have been identified to be novel players in the pathogenesis of PCOS. At present, rare variants, besides common variants, are also the focus of research as it is believed to make essential contribution to the risk of complex diseases. However, rare and low hetroplasmic variants in mitochondrial D-loop are still not investigated in PCOS women. Furthermore, variants in light-strand origin of DNA replication (OriL) of mitochondrial DNA (mtDNA) have not been explored in PCOS. Hence, in this study, we investigated rare to common mitochondrial D-loop and OriL region variants obtained using mtDNA next-generation sequencing in women with PCOS. Furthermore, we also assessed mtDNA copy number, a biomarker of mitochondrial dysfunction (MD) in women with PCOS, as the variants in mtDNA are known to be associated with low mtDNA copy number in PCOS women. A total of 67 D-loop variants including 6 novel variants were identified in 30 PCOS women. Among 67 variants, 29 variants were reported in PCOS women. A single variant, 5746A was found in OriL region in two PCOS women. Both transition and transversion variants were found but transition variants occur at very high frequency compared with transversions (82.35% vs. 17.64%, respectively). As transition variants in mtDNA are known to arise because of polymerase γ errors, occurrence of high transition rates indicates that most mutation arises because of defect in replication errors that causes mtDNA damage leading to MD. Furthermore, mtDNA copy number was found to be low in women with PCOS compared with healthy control women suggesting that MD may be the contributing factor in the pathogenesis of PCOS.


Assuntos
Variações do Número de Cópias de DNA/genética , DNA Mitocondrial/genética , Mitocôndrias/genética , Síndrome do Ovário Policístico/genética , Adolescente , Adulto , Replicação do DNA/genética , DNA Mitocondrial/sangue , Feminino , Hormônio Foliculoestimulante/sangue , Humanos , Hormônio Luteinizante/sangue , Mitocôndrias/patologia , Síndrome do Ovário Policístico/sangue , Síndrome do Ovário Policístico/patologia , Testosterona/sangue , Tireotropina/sangue , Adulto Jovem
3.
Gene ; 754: 144903, 2020 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-32540374

RESUMO

Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders among reproductive-age women. The circRNA-miRNA axis functions in various diseases progression have been partially revealed in the past two decades. However, little is known about the role of the circRNA-miRNA axis in PCOS progression. MicroRNA miR-760, which is characterized by tissue-specific, has been studied in several cancers. Firstly, we found that miR-760 expression was decreased in PCOS tissues insulin treated GCs, KGN and SVOG cells. Secondly, The CCK-8 and apoptosis experiment results suggested that downregulated miR-760 promoted cell proliferation ability and suppressed apoptosis activity in KGN and SVOG cells. Then, the bioinformatic analysis result indicated that circPUM1 was a potential sponge to miR-760. By performing AGO2-RIP, RNA pull-down, Luciferase reporter, and qRT-PCR experiments, we demonstrated that circPUM1 acted as a molecular sponge to miR-760, and decreased miR-760 expression. Moreover, it was found that the promotive effect of circPUM1 was mediated by regulating miR-760. Collectively, our findings suggest that circPUM1 promotes PCOS progression through sponging to miR-760. We may provide a promising therapeutic target for PCOS.


Assuntos
Regulação da Expressão Gênica , Células da Granulosa/patologia , MicroRNAs/genética , Síndrome do Ovário Policístico/patologia , RNA Circular/genética , Apoptose , Proliferação de Células , Células Cultivadas , Progressão da Doença , Feminino , Células da Granulosa/efeitos dos fármacos , Células da Granulosa/metabolismo , Humanos , Hipoglicemiantes/farmacologia , Insulina/farmacologia , Síndrome do Ovário Policístico/genética , Síndrome do Ovário Policístico/metabolismo
4.
BMC Bioinformatics ; 21(1): 177, 2020 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-32366216

RESUMO

BACKGROUND: Feature screening plays a critical role in handling ultrahigh dimensional data analyses when the number of features exponentially exceeds the number of observations. It is increasingly common in biomedical research to have case-control (binary) response and an extremely large-scale categorical features. However, the approach considering such data types is limited in extant literature. In this article, we propose a new feature screening approach based on the iterative trend correlation (ITC-SIS, for short) to detect important susceptibility loci that are associated with the polycystic ovary syndrome (PCOS) affection status by screening 731,442 SNP features that were collected from the genome-wide association studies. RESULTS: We prove that the trend correlation based screening approach satisfies the theoretical strong screening consistency property under a set of reasonable conditions, which provides an appealing theoretical support for its outperformance. We demonstrate that the finite sample performance of ITC-SIS is accurate and fast through various simulation designs. CONCLUSION: ITC-SIS serves as a good alternative method to detect disease susceptibility loci for clinic genomic data.


Assuntos
Predisposição Genética para Doença , Síndrome do Ovário Policístico/diagnóstico , Síndrome do Ovário Policístico/genética , Estudos de Casos e Controles , Feminino , Genoma , Estudo de Associação Genômica Ampla/métodos , Humanos
5.
Gene ; 752: 144760, 2020 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-32416252

RESUMO

BACKGROUND: PCOS is a common endocrine disorder that is characterized by hyperandrogenism and chronic anovulation and is the leading cause of female infertility. It is a heterogeneous disorder with the involvement of multiple gene and environmental interactions. This study identified variants that are known to confer susceptibility identified by Genome wide association studies (GWAS) in other ethnicities and replicated the same in individuals with PCOS of Indian ethnicity. METHODS: Study subjects (n = 600) were recruited. Blood samples, demographic and clinical details were collected after obtaining informed consent. Fifteen variants were selected from GWA studies from other ethnicities and genotyped in half of the recruited samples (n = 300) using MassARRAYiPLEX™. Replication of significant variants generated from preliminary data was carried out by PCR and direct sequencing in remainder of the samples (n = 300). Insilco analysis for significant variants was performed using software namely CADD, GWAVA, FATHMM-MKL. Relevant statistics were used to ascertain significance. RESULTS: The mean age of patients and controls was 24.26 ± 3.22 and 30.19 ± 11.21 years respectively. Of the 15 variants, 3 variants (rs13405728 in LHCGR; rs13429458 in THADA and rs2209972 IDE genes) were found to be associated with PCOS. The association was successfully replicated in an independent cohort. Insilico analysis categorized two variants (rs13429458-THADA and rs2209972-IDE genes) as deleterious. CONCLUSION: We demonstrate the association of variants in genes namely LHCGR, THADA and IDE with an increased risk of PCOS. Genotyping for these variants aids in identifying at-risk individuals which is crucial as appropriate early interventions may benefit the patient.


Assuntos
Insulisina/genética , Proteínas de Neoplasias/genética , Síndrome do Ovário Policístico/genética , Receptores do LH/genética , Adulto , Alelos , Grupo com Ancestrais do Continente Asiático/genética , Estudos de Casos e Controles , Estudos de Coortes , Grupos Étnicos/genética , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Frequência do Gene/genética , Predisposição Genética para Doença/genética , Testes Genéticos , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Índia/epidemiologia , Insulisina/metabolismo , Proteínas de Neoplasias/metabolismo , Síndrome do Ovário Policístico/metabolismo , Polimorfismo de Nucleotídeo Único/genética , Receptores do LH/metabolismo , Análise de Sequência de DNA/métodos
6.
Pediatrics ; 145(Suppl 2): S210-S218, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32358213

RESUMO

Polycystic ovary syndrome (PCOS) is a common female reproductive disorder that often manifests during adolescence and is associated with disruptions in health-related quality of life. Prompt evaluation and clinical support after diagnosis may prevent associated complications and optimize overall health management. This article incorporates the most recent evidence and consensus guidelines to provide an updated review of the pathogenesis, clinical presentation, diagnostic evaluation, and management strategies for adolescents with this complex condition. We will review the recent international guidelines on PCOS; because the diagnosis of PCOS remains controversial, management of this condition is inconsistent. In 2019, PCOS remains a common, yet neglected, condition, in part, because of the lack of agreement around both diagnosis and management.


Assuntos
Síndrome do Ovário Policístico/diagnóstico , Qualidade de Vida/psicologia , Adolescente , Androgênios/sangue , Feminino , Seguimentos , Fidelidade a Diretrizes , Humanos , Insulina/sangue , Hormônio Luteinizante/sangue , Síndrome do Ovário Policístico/genética , Síndrome do Ovário Policístico/psicologia , Síndrome do Ovário Policístico/terapia , Fatores de Risco
7.
Metabolism ; 107: 154241, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32304754

RESUMO

BACKGROUND: Hyperandrogenism is one of the major characteristics of polycystic ovary syndrome (PCOS). Abnormal miR-125b-5p expression has been documented in multiple diseases, but whether miR-125b-5p is associated with aberrant steroidogenesis in preantral follicles remains unknown. METHODS: Steriod hormone concentrations and miR-125b-5p expression were measured in clinical serum samples from PCOS patients. Using a mouse preantral follicle culture model and a letrozole-induced PCOS mouse model, we investigated the mechanism underlying miR-125b-5p regulation of androgen and oestrogen secretion. RESULTS: The decreased miR-125b-5p expression was observed in the sera from hyperandrogenic PCOS (HA-PCOS) patients. In mouse preantral follicles, inhibiting miR-125b-5p increased the expression of androgen synthesis-related genes and stimulated the secretion of testosterone, while simultaneously downregulating oestrogen synthesis-related genes and decreasing oestradiol release. Ectopically expressed miR-125b-5p reversed the effects on steroidogenesis-related gene expression and hormone release. Mechanistic studies identified Pak3 as a direct target of miR-125b-5p. Furthermore, inhibiting miR-125b-5p facilitated the activation of ERK1/2 in mouse preantral follicles, while inhibiting Pak3 abrogated this activating effect. These results were recapitulated in letrozole-induced PCOS mouse ovaries. Of note, inhibiting PAK3 antagonised the positive effect of miR-125b-5p siRNA on the expressions of androgen synthesis-related enzymes and testosterone secretion. Luteinizing hormone (LH) inhibited miR-125b-5p expression, and stimulated Pak3 expression. CONCLUSION: High serum LH concentrations in PCOS patients repress miR-125b-5p expression, which further increases Pak3 expression, leading to activation of ERK1/2 signalling, thus stimulating the expression of androgen synthesis-related enzymes and testosterone secretion in HA-PCOS.


Assuntos
MicroRNAs/genética , Folículo Ovariano/metabolismo , Esteroides/biossíntese , Androgênios/biossíntese , Androgênios/genética , Animais , Estradiol/metabolismo , Estrogênios/biossíntese , Estrogênios/genética , Feminino , Regulação da Expressão Gênica/genética , Hiperandrogenismo/induzido quimicamente , Hiperandrogenismo/metabolismo , Letrozol , Hormônio Luteinizante/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/genética , Camundongos , Camundongos Endogâmicos C57BL , Síndrome do Ovário Policístico/induzido quimicamente , Síndrome do Ovário Policístico/genética , Síndrome do Ovário Policístico/metabolismo , Quinases Ativadas por p21/genética , Quinases Ativadas por p21/metabolismo
8.
Obesity (Silver Spring) ; 28(6): 1117-1128, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32347662

RESUMO

OBJECTIVES: The purpose of this study was to determine changes in the expression levels of kisspeptin-1 (Kiss1) in the hypothalamus during the development of polycystic ovary syndrome (PCOS) and after treatment with sleeve gastrectomy (SG). METHODS: This study used chronic dehydroepiandrosterone (DHEA) alone and DHEA plus a high-fat diet (HFD) to generate a PCOS rat model. Subsequently, SG was performed in the animals with PCOS and the effects on glucose tolerance, insulin sensitivity, sex hormones, estrous cyclicity, adiponectin, and Kiss1 expression in the hypothalamus were investigated. RESULTS: Impaired glucose tolerance, decreased insulin sensitivity, reduced adiponectin levels, disrupted estrous cyclicity, and elevated sex hormone levels associated with PCOS models were restored to normal following SG. In addition, SG was able to restore the increase in the expression of Kiss1 mRNA and Kiss1-positive neurons in the arcuate nucleus of rats with PCOS. Interestingly, although SG did not result in a significant loss of body weight in rats administered DHEA under a chow diet, it resulted in comparable metabolic improvements and Kiss1 expression in rats that had been administered DHEA along with an HFD. CONCLUSIONS: The recovery of normal levels of Kiss1 expression in the hypothalamus after SG in this study suggests that Kiss1 might play an important role in the development of PCOS and its improvement by SG.


Assuntos
Gastrectomia/métodos , Hipotálamo/metabolismo , Kisspeptinas/metabolismo , Síndrome do Ovário Policístico/genética , Síndrome do Ovário Policístico/cirurgia , Animais , Feminino , Humanos , Síndrome do Ovário Policístico/metabolismo , Ratos , Ratos Sprague-Dawley
9.
Gene ; 744: 144591, 2020 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-32220601

RESUMO

Polycystic ovary syndrome (PCOS) is a kind of endocrine disease among women across the global. Recently, many researches have reported circular RNAs can act as significant molecular biomarkers for diseases, especially in tumors. Several Circular RNAs are reported to be aberrantly expressed in PCOS patients. Here, we investigated the biological effects of hsa_circ_0118530 on human granulosa cells, KGN. We observed that hsa_circ_0118530 was greatly elevated in PCOS patients and granulosa cells (including KGN and COV434 cells) compared to normal IOSE80 cells. hsa_circ_0118530 siRNA was transfected into KGN cells. We found that KGN cell viability was repressed, cell apoptosis was induced while cell migration was greatly inhibited. TGF-ß1 was utilized to induce EMT process. As shown, loss of hsa_circ_0118530 significantly enhanced E-cadherin mRNA and protein levels while depressed N-cadherin expression. Furthermore, we indicated that decrease of hsa_circ_0118530 was able to inhibit ROS accumulation, MDA levels while induced SOD activity. Next, it was demonstrated that releases of inflammatory cytokine were suppressed by hsa_circ_0118530 down-regulation. Additionally, miR-136 was predicted and confirmed as the target of hsa_circ_0118530. For another, the functions of hsa_circ_0118530 on KGN cell progression, oxidative stress and inflammation releases were obviously reversed by miR-136 suppression. In conclusion, knockdown of hsa_circ_0118530 repressed PCOS progression via sponging miR-136.


Assuntos
Células da Granulosa/metabolismo , MicroRNAs/metabolismo , Síndrome do Ovário Policístico/genética , RNA Circular/metabolismo , Apoptose/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Transição Epitelial-Mesenquimal/genética , Feminino , Células da Granulosa/citologia , Humanos , Mediadores da Inflamação/metabolismo , Estresse Oxidativo/genética , Síndrome do Ovário Policístico/metabolismo , RNA Circular/biossíntese
10.
Gene ; 741: 144560, 2020 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-32169631

RESUMO

SNV (single nucleotide variation) in estrogen receptor (ESR1 and ESR2) genes are susceptibility markers for complex diseases, such as cancer, metabolic disorders and women infertility. We explored six widely used SNVs in ESR1 (rs2234693, rs9340799, rs3798577, rs3020314) and ESR2 (rs1256049, rs4986938) in polycystic ovary syndrome (PCOS) in women from Tunisia (n = 254) compared to controls (n = 170). Genotyping was performed by RFLP-PCR or real-time PCR and analyzed in GoldenHelix statistical package. Logistic regression revealed association of rs2234693, rs3798577 and rs3020314 (ESR1) and rs1256049 (ESR2), the association of rs2234693 (C/T) being the strongest with P < 4.81 × 10-6, 2.88 × 10-5 after Bonferroni correction, OR 0.31, 95%CI (0.18-0.53)). Correlations were found with LH, LH/FSH or hyperandrogenism and even more significant with metabolic syndrome (rs9340799) and hyperglycemia (rs3798577). Among 14 haplotypes reconstructed in ESR1gene, four haplotypes (H1 to H4) were associated with PCOS the strongest being that of H1 (P < 0.002) supported by Bonferroni (P < 0.033) and permutation tests (P < 4 x10-4). In haplotype trend regression, concordant correlations were found with insulin resistance (P < 0.033) for H2 and with high blood pressure for H3 (P < 0.048). While these data revealed influential role on metabolic rather and hormonal features of PCOS, the association of rs2234693 was the strongest among all ethnic populations studied thus far giving a new insight on estrogen receptor gene variation in distant North African populations and their role in metabolic alteration of PCOS.


Assuntos
Receptor alfa de Estrogênio/genética , Receptor beta de Estrogênio/genética , Predisposição Genética para Doença , Síndrome do Ovário Policístico/genética , Adulto , Estrogênios/genética , Estrogênios/metabolismo , Feminino , Estudos de Associação Genética , Genótipo , Humanos , Infertilidade Feminina/genética , Infertilidade Feminina/patologia , Modelos Logísticos , Pessoa de Meia-Idade , Síndrome do Ovário Policístico/patologia , Polimorfismo de Fragmento de Restrição/genética , Polimorfismo de Nucleotídeo Único/genética , Tunísia
11.
Arch Gynecol Obstet ; 301(4): 963-971, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32193602

RESUMO

PURPOSE: Circular RNAs (circRNAs) are widely expressed noncoding RNAs which play important roles in various processes. The present study aimed to explore the effect of maternal PCOS on the expression of circRNAs in fetus and assessed the potential role of circRNA in human ovarian granulosa cell proliferation. METHODS: Total RNA was extracted from the fetal side of placental tissues from maternal PCOS (n = 3) and healthy puerpera (n = 3) for circRNA microarray. Real-time reverse transcriptase quantitative PCR (RT-qPCR) was used to validate the microarray data in fetal side of placental tissues from puerpera with (n = 18) and without (n = 30) PCOS. Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were applied to predict the functions and pathways of circ_0023942 host genes. The circRNA-miRNA-mRNA network was constructed through bioinformatics prediction. Circ_0023942 overexpression vector was transiently transfected into human ovarian granulosa cell lines KGN and COV434. Cell proliferation was detected by cell counting kit-8. The protein expression level was determined by western blot. RESULTS: Compared with healthy puerpera, 14 circRNAs were significantly upregulated and 101 circRNAs were significantly downregulated in the fetal side of placenta from maternal PCOS according to the microarray data. Six differentially expressed circRNAs were selected for validation by RT-qPCR, and the expression patterns of circ_0023942, circ_0002151, circ_0001274, and circ_0008514 were consistent with the microarray data. Circ_0023942 was chosen for further investigation. GO and KEGG analysis predicted that circ_0023942 participated in the regulation of developmental process and the MAPK signaling pathway. Seven miRNAs were predicted to be the targets of circ_0023942. Overexpression of circ_0023942 inhibited human ovarian granulosa cell proliferation and suppressed the expression of CDK-4. CONCLUSION: Maternal PCOS impairs circ_0023942 expression in fetus. Overexpression of circ_0023942 inhibits human ovarian granulosa cell proliferation possibly via regulating CDK-4.


Assuntos
Células da Granulosa/metabolismo , Síndrome do Ovário Policístico/genética , RNA Circular/metabolismo , Proliferação de Células , Feminino , Humanos , Gravidez , Transfecção
12.
Fertil Steril ; 113(3): 661-669.e2, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32192599

RESUMO

OBJECTIVE: To investigate the clinical diagnostic value and role of micro-RNAs (miRNAs) in the pathogenesis of polycystic ovary syndrome (PCOS). DESIGN: Systematic review and meta-analysis. SETTING: Not applicable. PATIENT(S): Patients were women of reproductive age with PCOS and controls. INTERVENTION(S): Summary odds ratio was calculated using a random effects model. MAIN OUTCOME MEASURE(S): Association of micro-RNAs with PCOS. METHOD(S): An electronic literature search was conducted using PubMed, Scopus, and Google Scholar databases to identify all relevant studies up to May 2019. A random effects model was used to conduct a meta-analysis. Fold change and P values were used to pool effect size. A funnel plot was used to assess publication bias. Quality score was calculated using the QUADAS scale. Subgroup analysis was based on tissue type. Odds ratios, 95% confidence intervals, and P values were estimated using meta-analysis. Metaregression was performed for correlating covariates with effect size. Area under the curve and receiver operating characteristic analysis was done to assess diagnostic performance accuracy of miRNAs in PCOS. RESULT(S): Twenty-one studies with a total of 79 miRNAs were included initially. Only three miRNAs (miR-29a-5p, miR-320, miR-93) are reported in more than three studies as of December 2018, so 12 studies were finally included in the quantitative analysis of meta-analysis and 21 studies were involved in the systematic review. The micro-RNAs miR-29a-5p and miR-320 were found to be significantly associated with PCOS. Funnel plot revealed an absence of publication bias for miR-29a-5p and miR-320. Receiver operating characteristic analysis with an area under the curve value of 0.95 proved miR-29a-5p to be the better diagnostic marker of PCOS. CONCLUSION(S): Aberrant expression of various miRNAs plays an important role in PCOS pathogenesis. Micro-RNAs hold potential diagnostic value for PCOS. These findings may offer new insights for PCOS pathogenesis research. PROSPERO REGISTRATION NUMBER: CRD42018106198.


Assuntos
Biomarcadores/análise , MicroRNAs/análise , MicroRNAs/fisiologia , Síndrome do Ovário Policístico/diagnóstico , Adulto , Estudos de Casos e Controles , Técnicas de Diagnóstico Endócrino , Técnicas de Diagnóstico Obstétrico e Ginecológico , Feminino , Humanos , MicroRNAs/genética , Síndrome do Ovário Policístico/genética
13.
Gynecol Obstet Invest ; 85(2): 167-177, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32114577

RESUMO

INTRODUCTION: The goal of this study was to review relevant case-control trials in order to determine the association of paraoxonase 1 (PON1) gene polymorphisms (-108C/T, 55L/M, 192Q/R) and polycystic ovarian syndrome (PCOS) susceptibility. METHODS: Using appropriate keywords, we identified relevant studies using PubMed, Cochrane, Embase, CNKI, VANFUN, and VIP. Key pertinent sources in the literature were also reviewed, and all articles published through April 2019 were considered for inclusion. Based on the qualified studies, we performed a meta-analysis of associations between -108C/T, 55L/M and 192Q/R polymorphisms in PON1 and risk of PCOS. RESULTS: We included 13 case-control studies with 3,660 total patients in the PCOS group and 2,835 in the control group. These studies found that the population with -108C/T locus T were associated with lower PCOS susceptibility by heterozygote model (OR 0.442, 95% CI 0.259-0.754); the Caucasian population with -108C/T locus T were associated with higher PCOS susceptibility by regressive model (OR 2.087, 95% CI 1.242-3.504). The population with 55L/M locus M were associated with higher PCOS susceptibility by regressive model (OR 1.518, 95% CI 1.067-2.160); the Asian population with 55L/M locus M were associated with lower PCOS susceptibility by dominant model and heterozygote model. The population with 192Q/R locus R were associated with higher PCOS susceptibility by the 5 gene models. The Asian population with 192Q/R locus R were associated with higher PCOS susceptibility: allelic model (OR 1.271, 95% CI 1.139-1.417); homozygote model (OR 1.575, 95% CI 1.244-1.995); dominant model (OR 1.299, 95% CI 1.069-1.580); regressive model (OR 1.421, 95% CI 1.207-1.673). The Caucasian population with 192Q/R locus R were associated with higher PCOS susceptibility: heterozygote model (OR 2.113, 95% CI 1.266-3.526). CONCLUSION: Our meta-analysis suggested that 192Q/R locus R were associated with higher PCOS susceptibility in both the Asian and Caucasian population.


Assuntos
Arildialquilfosfatase/genética , Grupo com Ancestrais do Continente Asiático/genética , Grupo com Ancestrais do Continente Europeu/genética , Predisposição Genética para Doença/genética , Síndrome do Ovário Policístico/genética , Alelos , Estudos de Casos e Controles , Feminino , Predisposição Genética para Doença/etnologia , Heterozigoto , Humanos , Síndrome do Ovário Policístico/etnologia , Polimorfismo Genético
14.
Ann Endocrinol (Paris) ; 81(1): 18-27, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32127169

RESUMO

BACKGROUND: We aimed to identify key genes and microRNAs (miRNAs) associated with the development of polycystic ovary syndrome (PCOS). METHODS: GSE84376 mRNA microarray data (15 PCOS granulosa cells and 13 control granulosa cells) and GSE34526 mRNA microarray data (7 PCOS granulosa cells and 3 control granulosa cells) were downloaded from the Gene Expression Omnibus (GEO) database. First, differentially expressed gene (DEG) analysis, gene set enrichment analysis (GSEA) for differentially expressed mRNAs, and protein-protein interaction (PPI) network analysis were conducted. Next, miRNA-target genes were analyzed and functions predicted, and a competing endogenous RNA (ceRNA) network was constructed. Finally, the relationship between miR-486-5p and PRELID2 was experimentally validated. RESULTS: Spleen tyrosine kinase (SYK), major histocompatibility complex, class II, DR alpha (HLA-DRA), and interleukin 10 (IL-10) were important nodes in the PPI network. Interestingly, HLA-DRA was significantly enriched in phagosomes mediated by Staphylococcus aureus infection, and in IL-10 enriched during S. aureus infection. One miRNA (miR-486-5p) and a single target gene (PRELID2) were obtained from the ceRNA network. Further experiments showed that miR-486-5p is upregulated and PRELID2 is downregulated in PCOS patient granulosa cells, and that miR-486-5p targets the PRELID2 3'UTR. Topological property analysis showed that hsa-miR-4687-5p downregulation and hsa-miR-4651 upregulation determined the levels of most mRNAs. Levels of the hsa-miR-4651 target gene were significantly enriched in the leukocyte transendothelial migration pathway. CONCLUSIONS: Our results suggest that HLA-DRA and IL-10 may contribute to PCOS progression via phagosome enriched by S. aureus infection, while miR-486-5p may be implicated in follicular development in PCOS by targeting PRELID2. Besides, miR-4651 may be involved in inflammation via leukocyte transendothelial migration, by regulating its target gene. These findings may indicate new directions and constitute a breakthrough in studying the pathophysiology of PCOS.


Assuntos
MicroRNAs/genética , Síndrome do Ovário Policístico/genética , RNA Mensageiro/genética , Adulto , Estudos de Casos e Controles , Células Cultivadas , Feminino , Perfilação da Expressão Gênica , Redes Reguladoras de Genes , Estudos de Associação Genética , Predisposição Genética para Doença , Células da Granulosa/metabolismo , Humanos , MicroRNAs/metabolismo , Análise em Microsséries , Síndrome do Ovário Policístico/patologia , RNA Mensageiro/metabolismo
15.
BMC Med Genet ; 21(1): 30, 2020 02 12.
Artigo em Inglês | MEDLINE | ID: mdl-32050935

RESUMO

BACKGROUND: PCOS is a common disorder of women due to genetic, endocrine and environmental effects that manifests from puberty. The rs9939609 variant of fat mass and obesity associated (FTO) gene is linked to metabolic derangement in PCOS. We previously identified FTO (rs9939609) as a susceptibility locus for PCOS among Sri Lankan women and also explored the role of kisspeptin. Associated factors of the FTO candidate gene among South Asians with PCOS are unknown. METHODS: This study aimed to determine the association between FTO (rs9939609) polymorphism with clinical (BMI, acanthosis nigricans, hirsutism) and biochemical (serum kisspeptin and testosterone levels) characteristics of PCOS in a cohort of Sri Lankan women. Genetic and clinical data including serum kisspeptin and testosterone concentrations of our previously reported cases (n = 55) and controls (n = 110) were re-analyzed, specifically for an association with rs9939609 variant of FTO gene. RESULTS: Logistic regression analysis (AA - OR = 5.7, 95% CI = 2.41-13.63, p < 0.05) and genetic inheritance analysis (AA - OR = 5.49, 95%CI = 2.34-12.88, p < 0.05) showed that FTO (rs9939609) polymorphism is significantly associated with PCOS and its metabolic manifestations. Serum testosterone was significantly higher in affected women with mutant genotypes (AA+AT) than with the normal allele (TT) (p < 0.05). Although serum kisspeptin was higher in subjects with PCOS and mutant alleles than controls, this difference was not significant (p > 0.05). CONCLUSION: FTO gene variant rs9939609 is associated with hyperandrogenemia and metabolic manifestations of PCOS among women of Sri Lankan descent with the well-characterized phenotype. Serum kisspeptin and the FTO genotypes lack a significant association when adjusted for confounders.


Assuntos
Dioxigenase FTO Dependente de alfa-Cetoglutarato/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Síndrome do Ovário Policístico/genética , Adolescente , Adulto , Alelos , Grupo com Ancestrais do Continente Asiático/genética , Índice de Massa Corporal , Feminino , Regulação da Expressão Gênica/genética , Genótipo , Humanos , Pessoa de Meia-Idade , Fenótipo , Síndrome do Ovário Policístico/patologia , Polimorfismo de Nucleotídeo Único/genética , Sri Lanka
16.
PLoS One ; 15(2): e0229351, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32078641

RESUMO

Polycystic ovary syndrome (PCOS) affects around 10% of young women, with adverse consequences on fertility and cardiometabolic outcomes. PCOS appears to result from a genetic predisposition interacting with developmental events during fetal or perinatal life. We hypothesised that PCOS candidate genes might be expressed in the fetal ovary when the stroma develops; mechanistically linking the genetics, fetal origins and adult ovarian phenotype of PCOS. In bovine fetal ovaries (n = 37) of 18 PCOS candidate genes only SUMO1P1 was not expressed. Three patterns of expression were observed: early gestation (FBN3, GATA4, HMGA2, TOX3, DENND1A, LHCGR and FSHB), late gestation (INSR, FSHR, and LHCGR) and throughout gestation (THADA, ERBB4, RAD50, C8H9orf3, YAP1, RAB5B, SUOX and KRR1). A splice variant of FSHB exon 3 was also detected early in the bovine ovaries, but exon 2 was not detected. Three other genes, likely to be related to the PCOS aetiology (AMH, AR and TGFB1I1), were also expressed late in gestation. Significantly within each of the three gene groups, the mRNA levels of many genes were highly correlated with each other, despite, in some instances, being expressed in different cell types. TGFß is a well-known stimulator of stromal cell replication and collagen synthesis and TGFß treatment of cultured fetal ovarian stromal cells inhibited the expression of INSR, AR, C8H9orf3 and RAD50 and stimulated the expression of TGFB1I1. In human ovaries (n = 15, < 150 days gestation) many of the same genes as in bovine (FBN3, GATA4, HMGA2, FSHR, DENND1A and LHCGR but not TOX3 or FSHB) were expressed and correlated with each other. With so many relationships between PCOS candidate genes during development of the fetal ovary, including TGFß and androgen signalling, we suggest that future studies should determine if perturbations of these genes in the fetal ovary can lead to PCOS in later life.


Assuntos
Biomarcadores/análise , Desenvolvimento Fetal/genética , Regulação da Expressão Gênica no Desenvolvimento , Ovário/patologia , Síndrome do Ovário Policístico/patologia , Polimorfismo de Nucleotídeo Único , Adulto , Animais , Bovinos , Feminino , Genes Reguladores , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Ovário/metabolismo , Síndrome do Ovário Policístico/genética , Gravidez , Células Estromais/metabolismo , Células Estromais/patologia
17.
Arch. endocrinol. metab. (Online) ; 64(1): 11-16, Jan.-Feb. 2020. tab
Artigo em Inglês | LILACS | ID: biblio-1088769

RESUMO

ABSTRACT Objective The aim of this study was to assess the serum vitamin D level in a retrospective study in women with polycystic ovary syndrome (PCOS), according to the different phenotypes of the disease. Subjects and methods In this retrospective study, the records of 351 infertile women who were diagnosed with PCOS were examined, and 200 of them were enrolled in the study randomly in 4 PCOS phenotypes. Fifty normal ovulatory women with the history of male factor were selected as the control group. Parameters, including age, infertility duration, body mass index (BMI), hormone profile, as well as the serum vitamin D level were compared among the 4 phenotypes, with the P-value ≤ 0.05 considered statistically significant. Results The findings showed a higher serum vitamin D level in the control group than in PCOS patients, which was statistically significant (P < 0.001). In addition, there was no significant difference in the serum vitamin D level among the four phenotypes of PCOS. Conclusions No significant difference was found in the serum vitamin D level of the different phenotypes of PCOS. Further studies with larger sample sizes are recommended to be done to establish the role of the serum vitamin D level in PCOS patients.


Assuntos
Humanos , Feminino , Adolescente , Adulto , Adulto Jovem , Síndrome do Ovário Policístico/sangue , Vitamina D/sangue , Infertilidade Feminina/sangue , Fenótipo , Síndrome do Ovário Policístico/genética , Índice de Massa Corporal , Estudos de Casos e Controles , Estudos Retrospectivos
18.
DNA Cell Biol ; 39(8): 1401-1409, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32077751

RESUMO

Polycystic ovary syndrome (PCOS) is one of the most common female reproductive metabolisms. It is an endocrine disease that affects reproductive women and often exhibits with hyperandrogenemia, insulin resistance (IR), low inflammation, and an increased risk of type 2 diabetes mellitus, metabolic syndrome, and cardiovascular events such as hypertension and dyslipidemia in patients. However, the molecular mechanism of PCOS is still unclear. Recently, an increasing number of studies have shown that the oxidative stress induced by mitochondrial dysfunction has negative effects on IR, lipid metabolism, and follicular development, suggesting that mitochondrial dysfunction plays an essential role in the development of PCOS. Abnormal mitochondrial DNA copy number in patients with PCOS, and mitochondrial gene mutations, has been the focus of research in recent years, and functional mitochondrial diseases have been gradually accepted as a related factor in PCOS. This review is intended to summarize and discuss previous and recent studies and findings on the connections between mitochondrial dysfunction and PCOS.


Assuntos
Variações do Número de Cópias de DNA/genética , Predisposição Genética para Doença , Mitocôndrias/genética , Síndrome do Ovário Policístico/genética , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/patologia , Dislipidemias/genética , Dislipidemias/patologia , Feminino , Humanos , Hiperandrogenismo/genética , Hiperandrogenismo/patologia , Hipertensão/genética , Hipertensão/patologia , Resistência à Insulina/genética , Mitocôndrias/patologia , Mutação/genética , Síndrome do Ovário Policístico/patologia
19.
Nat Med ; 26(2): 252-258, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-32042192

RESUMO

Testosterone supplementation is commonly used for its effects on sexual function, bone health and body composition, yet its effects on disease outcomes are unknown. To better understand this, we identified genetic determinants of testosterone levels and related sex hormone traits in 425,097 UK Biobank study participants. Using 2,571 genome-wide significant associations, we demonstrate that the genetic determinants of testosterone levels are substantially different between sexes and that genetically higher testosterone is harmful for metabolic diseases in women but beneficial in men. For example, a genetically determined 1 s.d. higher testosterone increases the risks of type 2 diabetes (odds ratio (OR) = 1.37 (95% confidence interval (95% CI): 1.22-1.53)) and polycystic ovary syndrome (OR = 1.51 (95% CI: 1.33-1.72)) in women, but reduces type 2 diabetes risk in men (OR = 0.86 (95% CI: 0.76-0.98)). We also show adverse effects of higher testosterone on breast and endometrial cancers in women and prostate cancer in men. Our findings provide insights into the disease impacts of testosterone and highlight the importance of sex-specific genetic analyses.


Assuntos
Diabetes Mellitus Tipo 2/sangue , Síndrome do Ovário Policístico/sangue , Testosterona/sangue , Testosterona/farmacologia , Bancos de Espécimes Biológicos , Biomarcadores/sangue , Composição Corporal , Neoplasias da Mama/sangue , Neoplasias da Mama/genética , Análise por Conglomerados , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/genética , Neoplasias do Endométrio/sangue , Neoplasias do Endométrio/genética , Estradiol/sangue , Feminino , Estudo de Associação Genômica Ampla , Genótipo , Haplótipos , Humanos , Masculino , Análise da Randomização Mendeliana , Razão de Chances , Fenótipo , Síndrome do Ovário Policístico/etiologia , Síndrome do Ovário Policístico/genética , Polimorfismo de Nucleotídeo Único , Neoplasias da Próstata/sangue , Neoplasias da Próstata/genética , Fatores Sexuais , Software , Reino Unido
20.
Medicine (Baltimore) ; 99(4): e18720, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31977861

RESUMO

The methylenetetrahydrofolate reductase (MTHFR) may play a pathological role in polycystic ovary syndrome (PCOS). However, the conclusions of published reports on the relationship between the MTHFR C677T polymorphism and PCOS risk remain controversial.To derive a more precise estimation we performed a metaanalysis based on 22 studies that together included 2405 cases and 2419 controls. PubMed, EMBASE, WanFang and the Chinese National Knowledge Infrastructure databases were used to retrieve articles up to up to October 28, 2019. The crude odds ratios (ORs) with 95% confidence intervals (95% CI) were calculated to evaluate the association.Metaanalysis results showed a significant association between the MTHFR C677T polymorphism and PCOS risk in 3 genetic models (allele model: OR = 1.40, 95% CI = 1.27-1.53; dominant model: OR = 1.47, 95% CI = 1.17-1.85); homozygous model: OR = 1.90, 95% CI = 1.55-2.32). Moreover, significant associations were observed when stratified by ethnicity, source of controls, etiology, and genotype methods.This metaanalysis suggests that the T-allele of the MTHFR C677T polymorphism is associated with an increased risk of PCOS, especially in Asians further studies with larger population sizes are needed to confirm these results.


Assuntos
Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Síndrome do Ovário Policístico/genética , Grupos de Populações Continentais , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Polimorfismo de Nucleotídeo Único
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