| BackgroundPolycystic ovary syndrome (PCOS) is a complex and heterogeneous disorder that is characterized by oligomenorrhea or amenorrhea, hyperandrogenism, multiple small subcapsular cystic follicles in the ovary on ultrasonography. The disorder has also been reported to be associated with metabolic syndromes, such as type 2 diabetes mellitus(T2DM), dyslipidemia, and hypertension. PCOS displays evident familial aggregation indicate that genetic factors are strongly associated with the etiology of PCOS. The strong clinical, phenotypic and pathophysiology overlap between T2DM and PCOS promotes a powerful argument for overlapping etiological determinants underlying the two conditions.The melatonin receptor 1B (MTNR1B) gene is a novel candidate gene for T2DM. It is located on human chromosome 11q21-q22 and encodes 1 of the 2 high-affinity G-protein-coupled receptors for the pineal gland hormone, melatonin. Melatonin plays an important role in regulation of the circadian clock. Studies have suggested that disturbances in circadian rhythmicity may affect metabolic control and increase the risk of diabetes.The function of melatonin is mediated by the melatonin receptor. The link between MTNR1B gene polymorphisms and T2DM has been confirmed. Among the SNPs of MTNR1B, rs1 0830963 and rs10830962 appears to be important functional MTNR1B polymorphisms have been reported to be strongly associated with glucose metabolism and impact onβ-cell function as well as increase the type 2 diabetes risk in human.ObjectiveThe purpose of this study was to determine the relationship between the SNPs rs10830963 and rs10830962 of MTNR1B the pathogenesis of PCOS. In addition, whether or not the MTNR1B gene plays a role in endocrine and clinical traits in PCOS patients, which may provide evidence for a better understanding of the susceptibility of the MTNR1B gene variation in the development of PCOS.MethodsA total of 1073 Chinese Han ethnic women, who were residents of Shandong province, were recruited consecutively from Center for Reprouctive Medicine, Provincial Hospital Affiliated to Shandong University.526 of the participants were patients with PCOS, which was diagnosed according to the Rotterdam PCOS consensus criteria. The control group included 547 age-matched women.Serum hormone levels were detected include Follicle-stimulating hormone (FSH), luteinizing hormone (LH), prolactin (PRL), testosterone (T), and estradiol (E2). Total cholesterol (TC), triglycerides (TG), and low-density lipoprotein (LDL) concentrations were measured. All PCOS patients underwent a 75-g oral glucose tolerance test (OGTT). Genomic DNA was extracted from the peripheral blood samples.The single nucleotide polymorphisms (SNPs) were detected through polymerase chain reaction Tm-shift genotyping method. To validate the SNP genotyping assays,5% of the genotyped samples were randomly selected for duplication accuracy with a direct sequencing protocol.Statistic MethodsThe analysis was performed using the Statistical Package for the Social Sciences software (version 13.0; SPSS, Chicago, IL, USA). A p<0.05 were accepted as statistically significant. The Hardy-Weinberg distribution of genotypes in the PCOS and control groups was assessed. Linkage disequilibrium between the two SNPs was analyzed using Haploview 4.0. Categorical data were expressed as frequencies and percentages.The results of serum hormone levels were reported as the mean±SD. Statistical analysis of allele and genotype frequencies between women with PCOS and controls was compared using Pearson'sχ2-test. The differences among PCOS patients and controls in clinical and biochemical variables were evaluated by an independent individuals were assessed using the Mann-Whitney U-test or one-way analysis of covariance in the PCOS group.ResultsThe frequencies of three genotypes and two allelotypes of the SNP, rs10830963, did significantly differ between women with PCOS and healthy controls (p<0.001 and p<0.001, respectively). The SNP, rs10830963, was significantly associated with higher fasting plasma glucose concentrations and increased the area under the curve (AUC) of plasma glucose levels during the OGTT, as well as increased homeostasis model assessment of insulin resistance (all p<0.05). No significant differences were observed in the genotypes and allele distributions of rs10830962 polymorphisms between the PCOS and control groups (p=0.311 and p=0.178, respectively). There was no significant difference in the Clinical and metabolic characteristics in women with PCOS with different genotypes in the SNP, rs10830962 (All p>0.05).ConclusionThe present study suggest that the SNP, rs10830963, in the MTNR1B gene is not only associated with susceptibility to PCOS among Han Chinese women, but also contributes to the PCOS phenotype. BackgroundMelatonin, the principal hormone of the pineal gland, is most widely recognized for its role in regulating mammalian circadian rhythms, sleep, and reproductive alterations. There is increasing evidence that disturbances in circadian rhythmicity are closely linked to metabolic conditions, including diabetes and obesity, in humans. In addition to controlling circadian rhythms, melatonin neutralizes reactive oxygen and nitrogen, and activates the immune system. Reactive oxygen species and apoptosis are involved in a number of reproductive events, including folliculogenesis, follicular atresia, oocyte maturation, ovulation, and corpus luteum formation. Thus, melatonin has direct effect on ovarian function. The function of melatonin is mainly mediated by melatonin receptor 1A (MTNR1A) and 1B (MTNR1B), both of which belong to the G protein-coupled receptor superfamily. MTNRIA is mainly expressed in alpha cells, while MTNR1B is predominantly expressed in beta cells. These findings suggest an important role of the MTNRIA and MTNR1B genes in the etiology and pathophysiology of polycystic ovary syndrome (PCOS). However, there is no study on the relationship between the MTNRIA gene polymorphisms and PCOS.The MTNRIA gene is located at chromosome 4q35.1, and is composed of two exons that encode a protein of 350 amino acids.The promoter of the MTNRIA is a functional region and associated with MTNR1A expression. SNP rs2119882 is located in the promoter region (-369 bp) of the MTNRIA gene. Rs2119882 could capture the other two SNPs (rs 11721818 and rs7687823) in the promoter region of the MTNRIA gene. The three SNPs covered 6.3 kb in the promoter region of the MTNR1A gene. Therefore, the SNP rs2119882 was the main functional SNP in MTNRIA.ObjectiveThe purpose of this study was to determine the relationship between the rs2119882 of MTNR1A and the pathogenesis of PCOS. In addition, whether or not the MTNR1A gene plays a role in endocrine and clinical traits in PCOS patients, which may provide evidence for a better understanding of the susceptibility of the MTNR1A gene variation in the development of PCOS.MethodsFour hundred eighty-one PCOS patients and 522 healthy residents of Shandong province were included in our study. All participants were northern Han ethnic women with complete clinical and biochemical data. PCOS was diagnosed by the Rotterdam PCOS consensus criteria.Genomic DNA was extracted from the peripheral blood samples. The single nucleotide polymorphisms (SNPs) were detected through polymerase chain reaction Tm-shift genotyping method. To validate the SNP genotyping assays,5% of genotyped samples were randomly selected for duplication accuracy with a direct sequencing protocol.Serum hormone levels were detected include Follicle-stimulating hormone (FSH), luteinizing hormone (LH), prolactin (PRL), testosterone (T), and estradiol (E2). Total cholesterol (TC), triglycerides (TG), and low-density lipoprotein (LDL) concentrations were measured. All PCOS patients underwent a 75-g oral glucose tolerance test (OGTT).Statistic MethodsThe analysis was performed using the Statistical Package for the Social Sciences software (version 13.0; SPSS, Chicago, IL, USA). A p<0.05 were accepted as statistically significant. The Hardy-Weinberg distribution of genotypes in the PCOS and control groups was assessed. The results of serum hormone levels were reported as the mean±SD. Categorical data were expressed as frequencies and percentages. Statistical analysis of allele and genotype frequencies between women with PCOS and controls was compared using Pearson'sχ2-test. The differences among PCOS patients and controls in clinical and biochemical variables were evaluated by an independent samples t-test. Differences in serum hormone levels among different genotypic individuals were assessed using the Mann-Whitney U-test or one-way analysis of covariance in the PCOS group. ResultsThe rs2119882 genotype frequencies of CC, CT, and TT were 13.60%(71/522), 45.21%(236/522), and 41.19%(215/522) in the healthy controls, and 20.58%(99/481), 44.70%(215/481), and 34.72%(167/481) in the PCOS patients, respectively. The frequencies of the three genotypes did significantly differ between the PCOS patients and healthy controls (p< 0.001). There were more carriers of the C allele in the PCOS group (42.93% [413/962]) than the controls (36.08% [376/1042],p=0.002). Furthermore, the PCOS patients with CC and CT genotypes had higher fasting plasma glucose and insulin levels at 0,30,60, and 120 min during the OGTT compared with the patients with the TT genotype (p<0.05). Carriers of the CC and CT genotypes at rs2119882 also had increased HOMA-IR compared with the patients with the TT genotype in the PCOS patients (p=0.005).There was no significant difference in age, BMI, and the levels of TC, TG, LDL, T, E2, LH, FSH, and PRL in the different genotypes in PCOS patients(All p>0.05).ConclusionThe present study suggest that the SNP rs2119882 is associated with insulin resistance in patients with PCOS, and it is one of the key factors responsible for the etiopathogenisis of PCOS among Han Chinese women. |
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