Recent genome-wide association studies and replication analyses reported an association between variants of DENND1A gene and polycystic ovary syndrome (PCOS), mostly in Asians. We therefore examined whether the common DENND1A SNPs rs10818854, rs2479106, and rs10986105 are associated with PCOS in Bahraini Arab population. This case-control study involved 191 women with PCOS diagnosed according to the Rotterdam criteria, and 202 control women. SNP genotyping was performed by the allelic discrimination in real-time PCR. The outcome was that the minor allele frequencies of SNPs rs10818854, rs2479106, and rs10986105 were similar between women with PCOS and control women (P>0.05), even before correcting for multiple testing, and none of the tested DENND1A SNPs were associated with PCOS under co-dominant, dominant, or recessive genetic models. None of the tested DENND1A variants were associated with PCOS features (hirsutism, insulin sensitivity, menses pattern, free testosterone, and free androgen index). Taking common GTA haplotype as reference (OR=1.00), [rs10818854/rs2479106/rs10986105] 3-locus haplotype analysis demonstrated lack of association of any of the DENND1A haplotypes with PCOS, even before correcting for multiple testing. To conclude we demonstrated lack of association of DENND1A SNPs rs10818854, rs2479106, and rs10986105, previously associated with PCOS in Asians, with PCOS in Bahraini Arab women.

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.

Dyslipidemia is one of the common metabolic disorders in Polycystic Ovary Syndrome (PCOS). Proprotein convertase subtilisin kexin type 9 (PCSK9) is a new component of lipid metabolism and correlated to the development of dyslipidemia and atherosclerosis. This protein acts by preventing the recycling of LDL receptors (LDL-r) back to the cell surface and thus generates higher levels of LDLc. The objective of this study was to evaluate the PCSK9 polymorphisms rs505151 (c.2009A>G), rs562556 (c.1420A>G) and rs11206510 (T>C) and plasma PCSK9 levels in PCOS. A group of women with PCOS (n=97), and a group of healthy women (control, n=99) were selected. Biochemical parameters were determined by using Vitros system and polymorphisms were assessed by TaqMan SNP Genotyping Assays. Plasma PCSK9 levels or PCSK9 polymorphisms were not associated with PCOS. The genotype rs11206510TT was associated with higher levels of PCSK9 in both groups. The population investigated (PCOS+control groups) with the rs505151AA genotype presented higher HDLc levels. The GG genotype regarding rs562556 polymorphism was associated with higher HDLc in PCOS group, while the AA genotype carriers had higher plasma testosterone levels when evaluated all women in a same group. The results were the same by comparing recessive and dominant model despite PCOS or both groups altogether. Our results suggest that PCSK9 is not altered specifically in PCOS, but it could be associated with in lipid and androgen metabolism in Brazilian women.

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.

Polycystic ovary syndrome (PCOS) is a common endocrine disorder, presenting polygenic traits as well as determined by environmental factors. Given the overlap between PCOS and obesity, we assessed the frequencies of SNPs rs9939609 and rs8050136 in intron 1 of the FTO gene and their haplotypes in women with PCOS and healthy controls with regular cycles from Southern Brazil and investigated their relationship with metabolic traits and endocrine parameters.

Polycystic ovary syndrome (PCOS) shows not only hyperandrogenemia, hirsutism and fertility problems, but also metabolic disturbances including obesity, cardiovascular events and type-2 diabetes. Accumulating evidence suggests some degree of inflammation associated with prominent aspects of PCOS. We aimed to investigate the association of genetic variants 3'UTR rs17468190 (G/T) of the inflammation-associated gene MEP1A (GenBank ID: NM_005588.2) with metabolic disturbances in PCOS and healthy control women. Genetic variants rs17468190 (G/T) of MEP1A gene were analyzed in 576 PCOS women and 206 controls by using the Taqman fluorogenic 5'-exonuclease assay. This polymorphism was tested for association with anthropometric, metabolic, hormonal, and functional parameters of PCOS. There was a borderline significant difference in genotype distribution between PCOS and control women (p=0.046). In overweight/obese PCOS patients, the variants rs17468190 (G/T) in the MEP1A gene are associated with glucose and insulin metabolism. In a dominant model, the GG genotype of the MEP1A gene was more strongly associated with insulin metabolism in overweight/obese PCOS women (body mass index, BMI>25 kg/m(2)), than in GT+TT genotypes. The MEP1A GG-carriers showed a significantly increased homeostatic model assessment - insulin resistance (HOMA-IR) (p=0.003), elevation of fasting insulin (p=0.004) and stimulated insulin (30 min, p<0.001; 60 min, p=0.009; 120 min, p=0.009) as well as triglyceride (p=0.032) levels. MEP1A is a possible target gene for disease modification in PCOS. It might contribute to the abnormalities of glucose metabolism and insulin sensitivity and serve as a diagnostic or therapeutic target gene for PCOS.

Polycystic ovary syndrome (PCOS) is a common endocrine disorder, and results from interaction between modifiable and non-modifiable factors, including genetic predisposition. Previous genome-wide association studies and meta-analysis identified DENND1A as PCOS susceptibility locus in some, but not all populations. We investigated whether the association of DENND1A gene variants with PCOS was similar between Tunisian and Bahraini Arab women.

Polycystic ovary syndrome (PCOS) is a common endocrine disorder that affects women in their child-bearing age, and is often associated with insulin resistance and type 2 diabetes (T2DM). Given the overlap between PCOS and T2DM, we investigated the association of transcription factor-7-like 2 (TCF7L2) variants rs4506565, rs7903146, rs12243326, and rs12255372 with the susceptibility to PCOS.

The FTO (fat mass and obesity associated) gene was associated with different metabolic disorders in populations from different origins but with great difference between African and non-African populations. North-African populations combine many genetic backgrounds, among which African, Berber and Caucasian components, which makes North-Africans a good model for studying the genetic association of FTO. In the present investigation we explored the association of FTO gene with polycystic ovary syndrome (PCOS) in a population from Tunisia (n=278). Single nucleotide polymorphisms (SNPs) used in this study were previously associated in non-African populations: rs8050136 (A/C), rs9939609 (A/T), rs9930506 (G/A), or in both African and non-African populations: rs8057044 (A/G). Genotyping was performed by allelic discrimination method on StepOne real-time PCR system or KASPar technology. Linkage disequilibrium (LD) pattern was assessed by HAPLOVIEW and reconstruction of haplotypes was performed by PHASE, while statistical analyses were performed using StatView and GoldenHelix programs. Among the 13 haplotypes in the population, three (h1, h7 and h13) were strongly associated with PCOS notably h13 (P<0.0001, OR95%CI=0.040 [0.005-0.294]) while SNPs display weaker association. Moreover the LD pattern in FTO in the Tunisian population (r(2) index) was intermediary between those of Caucasian and Africans. This highlights the need for studying the genetics of complex disorders in the North-African populations taking into-account the haplotype structure of candidate loci more than SNPs taken alone.

Epidemiological studies suggested that ethnic/racial background influences the associations of altered leptin secretion and leptin gene (LEP) polymorphisms with polycystic ovary syndrome (PCOS). We investigated the association between LEP variants and plasma leptin levels with PCOS in Tunisian and Bahraini Arab women.

This study aimed to screen key genes and pathways involved in obese polycystic ovary syndrome (PCOS), and predict drugs for treatment of obese PCOS via bioinformatics approaches.

Polycystic ovary syndrome (PCOS) is an endocrine and metabolic heterogeneous disorder. The incidence of which reaches 5% to 10% among reproductive-age women. Abnormal folliculogenesis is considered to be a common characteristic of PCOS, but the cause of this disorder and its pathogenesis still remain uncertain. Previous studies had proved that dysregulation of microRNAs is related to the pathogenesis of PCOS. In this study, we investigated the effect of miR-323-3p on the human cumulus cells (CCs). We also investigated the underlying mechanisms of miR-323-3p on human granulosa-like tumor cell line (KGN) or primary human CCs by stimulating with Dihydrotestosterone (DHT). Our findings suggested that the level of miR-323-3p in human CCs of women with PCOS was down-regulated, compared with that of the control group. Moreover, the inhibition of the level of miR-323-3p could up-regulate of the steroidogenesis and promote the apoptosis in KGN cells. In addition, our data confirmed that the Insulin-like growth factor 1 (IGF-1) gene was the direct target of miR-323-3p. Furthermore, the mimic of miR-323-3p inhibited the expression of IGF-1, which down-regulated the levels of AR, AMHR-II, CYP19A, EGFR, and GATA-4. In conclusion, miR-323-3p targeting IGF-1 regulates the steroidogenesis and the activity of CCs, which plays an important role in the occurrence and development of PCOS. Our results have shown that miR-323-3p is a novel and promising molecular target for the improvement of the dysfunction of CCs in PCOS.

We investigated the link between polymorphisms in genes involved in mitochondrial biogenesis, mitochondrial transcription factor A (TFAM) and Peroxisome proliferator activated receptor gamma coactivator-1 alpha (PGC-1α) and further studied the role of these genes on the pathophysiology of polycystic ovary syndrome (PCOS). This case-control study was carried out in 118 PCOS cases and 110 controls. In the present study we genotyped three polymorphisms of PGC1-α gene (rs8192678-Gly482Ser, rs13131226 and rs2970856) and polymorphism of TFAM gene (rs1937-+35G/C) by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis. In addition, to better understand genetic contributions to the pathophysiology of PCOS, mtDNA copy number (MCN) was quantified using a qRT-PCR assay in the subjects. The results revealed that the distribution of genotypes and allele frequency of the PGC-1α Gly482Ser polymorphism in PCOS patients was statistically significant from those of the control group respectively (OR-2.488; 95% CI-1.0673 to 5.7998; P=0.047), (OR-1.6091; 95% CI-1.0955 to 2.3634; P=0.015) indicating that the presence of 'A' allele might confer risk to PCOS. Patients with the 'AA' genotype showed significantly lower levels of MCN compared with patients with other genotypes. In addition, patients carrying CT genotype of PGC1-α rs2970856 demonstrated significantly higher levels of LH (P=0.030) than TT and CC genotypes. In conclusion, our study indicates that carriers of the PGC-1α rs8192678 'Ser' allele have increased risk of developing PCOS.

Polycystic ovary syndrome (PCOS) is a complex endocrine disorder that involves multiple factors. Although the etiology of PCOS is unknown, there is an involvement of sex steroid hormones in the pathophysiology of this syndrome. Therefore, polymorphisms in genes involved in the action of estrogen may contribute to a woman's susceptibility to PCOS.

Insulin-like factor 3 (INSL3), secreted by the ovarian theca cells is involved in androgen production, follicular growth and oocyte maturation. Both androgens and INSL3 levels are reported to be elevated in women with polycystic ovary syndrome (PCOS), indicating that INSL3 could contribute to PCOS etiology. This case-control association study explored the impact of INSL3 polymorphisms on PCOS susceptibility and its related traits.

Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders in reproductive-aged women. However, the exact pathophysiology of PCOS remains largely unclear. We performed deep sequencing to investigate the mRNA and long noncoding RNA (lncRNA) expression profiles in the ovarian tissues of letrozole-induced PCOS rat model and control rats. A total of 2147 mRNAs and 158 lncRNAs were differentially expressed between the PCOS models and control. Gene ontology analysis indicated that differentially expressed mRNAs were associated with biological adhesion, reproduction, and metabolic process. Pathway analysis results indicated that these aberrantly expressed mRNAs were related to several specific signaling pathways, including insulin resistance, steroid hormone biosynthesis, PPAR signaling pathway, cell adhesion molecules, autoimmune thyroid disease, and AMPK signaling pathway. The relative expression levels of mRNAs and lncRNAs were validated through qRT-PCR. LncRNA-miRNA-mRNA network was constructed to explore ceRNAs involved in the PCOS model and were also verified by qRTPCR experiment. These findings may provide insight into the pathogenesis of PCOS and clues to find key diagnostic and therapeutic roles of lncRNA in PCOS.

We explored genetic susceptibility profile of the South Indian women with a large set of SNPs and tested if the lack of association of type 2 diabetes genes with PCOS, recently observed in a number of studies, holds true for this Indian population and suggest probable universality of this phenomenon. A prioritized set of 92 SNPs that belong to important reproductive and metabolic pathway genes were genotyped on 250 PCOS cases and 299 ethnically matched controls, representing the southern Indian population of Hyderabad, using SEQUENOM MassARRAY iPLEX™ platform. These data were analyzed both for individual SNP association patterns as well as for gene-gene interactions, besides obtaining cumulative risk score and the ROC curve with the help of appropriate statistical packages such as PLINK, SNPAssoc of R-program, Haploview, GMDR and SPSS. The analysis of 72 of the 92 SNPs, after excluding 20 of those that showed either minor allele frequency < 1% and/or deviated from Hardy Weinberg Equilibrium (p < .001), suggested that only 13 were associated with PCOS at p ≤ .05, but none after correction for multiple testing. Further, neither any of the diabetic genes nor the interactions between diabetic and reproductive pathway genes were found to be significant even at p ≤ .05.The lack of association of any of the SNPs with PCOS and/or the gene-gene interactions among them may be because of the minor effects of each of them on the phenotype(OR < 2). Further, that none of the type 2 diabetes genes were associated with PCOS in the present study as well as in the earlier studies from different ethnic groups may indicate probable universality of this pattern. It is possible that there are still other genetic variants, novel as well as already known, which may confer greater risk than the ones considered in this study and further studies are warranted to ascertain this both in the present population as well as in other ethnic and/or geographic groups of the Indian subcontinent.

Polycystic ovary syndrome (PCOS) is a very prevalent endocrine disease affecting reproductive women. Clinically, patients with this disorder are more vulnerable to develop type 2 diabetes mellitus (T2DM), cardiovascular events, as well as metabolic syndrome (MetS). To date, the molecular mechanism underlying PCOS remains largely unknown. Previously, we showed that mitochondrial dysfunction caused by mitochondrial DNA (mtDNA) mutation was an important cause for PCOS. In the current study, we described the clinical and biochemical features of a three-generation pedigree with maternally transmitted MetS, combined with PCOS. A total of three matrilineal relatives exhibited MetS including obesity, high triglyceride (TG) and Hemoglobin A1c (HbA1c) levels, and hypertension. Whereas one patient from the third generation manifestated PCOS. Mutational analysis of the whole mitochondrial genes from the affected individuals identified a set of genetic variations belonging to East Asia haplogroup B4b1c. Among these variants, the homoplasmic C3275T mutation disrupted a highly evolutionary conserved base-pairing (28A-46C) on the variable region of tRNALeu(UUR), whereas the T4363C mutation created a new base-pairing (31T-37A) in the anticodon stem of tRNAGln, furthermore, the A8343G mutation occurred at the very conserved position of tRNALys and may result the failure in mitochondrial tRNAs (mt-tRNAs) metabolism. Biochemical analysis revealed the deficiency in mitochondrial functions including lower levels of mitochondrial membrane potential (MMP), ATP production and mtDNA copy number, while a significantly increased reactive oxygen species (ROS) generation was observed in polymononuclear leukocytes (PMNs) from the individuals carrying these mt-tRNA mutations, suggesting that these mutations may cause mitochondrial dysfunction that was responsible for the clinical phenotypes. Taken together, our data indicated that mt-tRNA mutations were associated with MetS and PCOS in this family, which shaded additional light into the pathophysiology of PCOS that were manifestated by mitochondrial dysfunction.

Polycystic ovary syndrome is a common endocrinopathy characterized by anovulatory infertility, hyperandrogenism, insulin resistance and oxidative stress, which predisposes affected women to reproductive and cardiometabolic complications in later life. We have investigated the association of PON1 promoter polymorphisms with PCOS susceptibility, PON1 activity and its related traits in Indian women. The genotypic and allelic frequency distribution of only -907G/C polymorphism in PON1 promoter showed significant difference between non-hyperandrogenic control and PCOS women, and was significantly associated with reduced susceptibility to PCOS, considering the recessive model. PON1 lactonase and arylesterase activities were also significantly decreased in women with PCOS compared to controls. Further, PON1 promoter polymorphisms were linked to altered insulin and testosterone levels in hyperandrogenic and non-hyperandrogenic women with PCOS. This study highlights PON1 as an important candidate gene influencing genetic pathophysiology of PCOS.

The modified prolonged gonadotropin-releasing hormone agonist (GnRH-a) protocol lessens the ovarian hyperstimulation syndrome (OHSS) effect and improves the clinical pregnancy rate of women with polycystic ovary syndrome (PCOS) compared with the standard long GnRH-a protocol. However, the molecular basis of this process needs to be elucidated. Sprague Dawley (SD) female rats with letrozole-induced PCOS were divided into GnRH-a and blank groups. Rats in the GnRH-a group were given triptorelin for 11 days, whereas those in blank group were given an equal volume of 0.9% NaCl. Meanwhile, the changes in estrus cycle, hormonal profile, ovary index, ovarian histopathology and body weight were measured. The expressions of anti-mullerian hormone (AMH), type II receptor of AMH (AMHRII), and FSH receptor (FSHR) were taken as the indicators of follicular sensitivity. Changes of follicular counting and differences in antral follicle diameter at each stage were evaluated. The number of follicles from primordial to antral stages increased during downregulation and the differences in antral follicle diameter were reduced in the GnRH-a group, whereas no significant difference was found in the blank group. The results of Western blotting and ELISA indicated that the level of AMH in ovarian total protein and serum had a similar dynamic change in the GnRH-a group. The results of immunohistochemistry showed that follicular AMH, AMHRII, and FSHR significantly decreased in the GnRH-a group. Prolonged GnRH-a protocol can improve synchronization and sensitivity of follicular development by balancing the expressions of AMH, AMHRII, and FSHR among follicles at all levels, thereby achieving better therapeutic effect.