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Cui L.,Shandong University | Cui L.,National Research Center for Assisted Reproductive Technology and Reproductive Genetics | Cui L.,Key Laboratory for Reproductive Endocrinology | Cui L.,Shandong Provincial Key Laboratory of Reproductive Medicine | And 27 more authors.
Human Reproduction | Year: 2013

Study Question Are there any correlations between the phenotypes of polycystic ovary syndrome (PCOS) and the genotypes of the PCOS susceptibility single nucleotide polymorphisms (SNPs) in THADA, DENND1A and LHCGR? Summary Answer The PCOS susceptibility genes, THADA and DENND1A, carry risk alleles that are associated with endocrine and metabolic disturbances in patients with PCOS. What is Known AlreadyPCOS is a heterogeneous endocrinopathy characterized by oligo-anovulation, hyperandrogenism and polycystic ovaries. In a previous genome-wide association study, the SNP variants rs13429458, rs12478601, rs2479106, rs10818854 and rs13405728 in the THADA, DENND1A and LHCGR genes were identified as being independently associated with PCOS. The aim of this study was to identify any additional correlations between the phenotypes of PCOS and genotypes of the five SNPs described in the previous study. Study Design , Size, DurationIn the present cross-sectional study, a total of 1731 PCOS patients and 4964 controls were enrolled. Participants/Materials, Setting , Method SPatients were diagnosed according to Rotterdam criteria. Clinical information was collected from the patients and controls. Endocrine and metabolic parameters were evaluated for phenotype-genotype correlation analyses. Main Results and the Role of Chance Using a recessive model, the AA group for rs13429458 in THADA was associated with increased luteinizing hormone (LH) (P < 0.01) and testosterone (T) (P = 0.02) levels in subjects with PCOS; the LH/follicle-stimulating hormone ratio was also higher in the AA group (P < 0.01). Also using a recessive model, the CC genotype of rs12478601, also in THADA, was associated with increased levels of low-density lipoprotein (P = 0.02). Using a dominant model, the GG + AG group for rs2479106 in DENND1A was associated with elevated serum insulin levels 2 h after a glucose load in the patients with PCOS (P = 0.02). All of the comparisons were adjusted for age and BMI. Limitations , Reasons for Caution The relatively younger age of the participants may represent a considerable bias when evaluating metabolic alterations as a function of different genotypes, as significant metabolic disturbances may emerge later in life. Furthermore, the sample sizes of several sub-genotype groups were relatively small; to some extent this limited the statistical power of the analysis. Wider Implications of the FindingsThe PCOS susceptibility genes, THADA and DENND1A, carry risk alleles that are associated with endocrine and metabolic disturbances in PCOS patients of Han Chinese descent. The findings have shown genuine heterogeneity, stratified on the basis of both clinical findings and genotypes. Replication of these results is expected in other ethnic groups. Study Funding/Competing Interest (S)This research was supported by the National Basic Research Program of China (973 program) (2010CB945002, 2012CB944700), the National Natural Science Foundation of China (81000238, 81070461, 81000236, 30973170), the Graduate Independent Innovation Foundation of Shandong University (GIIFSDU) (21300070613242, 21300070613246), the Science Research Foundation item of no-earnings health vocation (201002013) and the National Key Technology Research and Development Program (2011BAI17B00). There are no competing interests. © 2012 The Author.


Cui L.,Shandong University | Cui L.,Key Laboratory for Reproductive Endocrinology | Cui L.,Shandong Provincial Key Laboratory of Reproductive Medicine | Cui L.,National Research Center for Assisted Reproductive Technology and Reproductive Genetics | And 25 more authors.
Human Reproduction | Year: 2015

study question: What is the direct genetic contribution of the polycystic ovary syndrome (PCOS) susceptibility single nucleotide polymorphisms (SNPs), identified by previous genome-wide association studies (GWAS) to the definitive clinical features of the syndrome? summaryanswer: Each single PCOS clinical feature had a specific genetic association, and rs4385527 in the chromosome 9 open reading frame 3 (C9orf3) conferred a particular risk to the three defined PCOS clinical features in this study, which suggested its fundamental role in the etiology of PCOS. what is known already: PCOS is a heterogeneous disorder characterized by anovulation (OA), hyperandrogenism (HA) and polycystic ovary morphology (PCOM). Two previous GWAS in China have identified 15 independent susceptibility SNPs related to PCOS (PCOS-SNPs). However, little is known about the candidate gene of each clinical feature. study design, size, duration: Case-control study. Three independent groups of women were recruited from 2010 to 2012: 746 subjects with OA only, 278 subjects with HA only and 536 subjects with PCOM only. A total of 1790 healthy women with none of the above pathological characteristics were also enrolled as control subjects during the same time period. participants/materials, setting, methods: All participants were women of reproductive age. Genotype and allelic frequencies of 15 PCOS-SNPs were determined in all subjects using direct sequencing and Sequenom Arrays. The allelic frequencies of each case group were compared with the controls. main results and the role of chance: After adjustment for age and BMI, variants in luteinizing hormone/choriogonadotropin receptor (LHCGR) (rs13405728), C9orf3 (rs4385527) and insulin receptor gene (INSR) (rs2059807) were strongly associated with OA (Padjust < 0.01,0.001 and,0.05, respectively); rs4385527 inC9orf3was strongly associatedwithHA(Padjust< 0.001); variants in the thyroid adenomaassociated gene (THADA) (rs13429458 and rs12478601), DENN/MADD domain containing 1A (DENND1A)(rs10818854), and C9orf3 (rs4385527) were significantly associated with PCOM (Padjust < 0.01,0.001,0.05 and,0.001, respectively). limitations, reasons for caution: The sample size of some case groups was relatively small, which therefore limited the statistical power of the analysis to a certain extent. wider implications of the findings: The present study indicates a potential common genetic basis of three PCOS clinical features. Other specific associated genes may play a synergistic role, leading to heterogeneous pathophysiological changes. Additionally, the increased frequency of PCOS-risk alleles in women with single PCOS clinical features suggests that these subjects have an elevated risk of developing the syndrome, although they cannot be currently diagnosed. study funding/competing interest(s): This research was supported by the National Basic Research Program of China (973 Program) (2012CB944700, 2011CB944502), the National Key Technology Research and Development Program(2011BAI17B00), the National Natural Science Foundation of China (81430029, 81201441, 81490743, 31371453), the Scientific Research Foundation of Shandong Province of Outstanding Young Scientist (2012BSE27089) and the Fundamental Research Funds of Shandong University(2014GN025). There were no competing interests. © 2015 The Author.


Zhao H.,Shandong University | Zhao H.,National Research Center for Assisted Reproductive Technology and Reproductive Genetics | Zhao H.,Shandong Provincial Key Laboratory of Reproductive Medicine | Xu X.,Shandong University | And 21 more authors.
Human Reproduction | Year: 2012

BACKGROUND: Polycystic ovary syndrome (PCOS) is a complex endocrine-metabolic disorder. A previous genome-wide association study (GWAS) identified five single nucleotide polymorphisms (SNPs) which were independently associated with PCOS in Han Chinese. To overcome population stratication, a family-based analysis was conducted to validate whether these five SNPs are associated with PCOS. METHODS: A total of 276 family trios (828 participants) having a proband with PCOS were included in the family-based study. The transmission disequilibrium test (TDT) was used to analyze the association between PCOS and five SNPs rs13429458, rs12478601, rs13405728, rs10818854 and rs2479106 in three susceptible loci 2p16.3, 2p21 and 9q33.3. RESULTS: A positive association was observed for the SNP rs13429458 (P 3.74 × 10 5). CONCLUSIONS: TDT confirms that SNP rs13429458, in the THADA gene, is significantly associated with risk of PCOS. This family-based analysis enhances our previous casecontrol GWAS and provides further support for the role of susceptibility loci in PCOS. © The Author 2011.


Shi Y.,Shanghai JiaoTong University | Shi Y.,Shanghai GenomePilot Institutes for Genomics and Human Health | Shi Y.,Changning Mental Health Center | Zhao H.,Shandong University | And 90 more authors.
Nature Genetics | Year: 2012

Following a previous genome-wide association study (GWAS 1) including 744 cases and 895 controls, we analyzed genome-wide association data from a new cohort of Han Chinese (GWAS 2) with 1,510 polycystic ovary syndrome (PCOS) cases and 2,016 controls. We followed up significantly associated signals identified in the combined results of GWAS 1 and 2 in a total of 8,226 cases and 7,578 controls. In addition to confirming the three loci we previously reported, we identify eight new PCOS association signals at P < 5 × 10-8: 9q22.32, 11q22.1, 12q13.2, 12q14.3, 16q12.1, 19p13.3, 20q13.2 and a second independent signal at 2p16.3 (the FSHR gene). These PCOS association signals show evidence of enrichment for candidate genes related to insulin signaling, sexual hormone function and type 2 diabetes (T2D). Other candidate genes were related to calcium signaling and endocytosis. Our findings provide new insight and direction for discovering the biological mechanisms of PCOS. © 2012 Nature America, Inc. All rights reserved.


Wang P.,Shandong University | Wang P.,National Research Center for Assisted Reproductive Technology and Reproductive Genetics | Wang P.,Key Laboratory for Reproductive Endocrinology of Ministry of Education | Wang P.,Shandong Provincial Key Laboratory of Reproductive Medicine | And 35 more authors.
Endocrinology | Year: 2014

Our previous genome-wide association study identified LH/choriogonadotropin receptor (LHCGR) as a susceptibility gene for polycystic ovary syndrome (PCOS). The objective of this study was to determine whether the genetic or epigenetic components associated with LHCGR participate in the pathogenesis of PCOS. The exons and flanking regions of LHCGR were sequenced from 192 women with PCOS, and no novel somatic mutations were identified. In addition, the methylation statuses of 6 cytosine-phosphate-guanine (CpG) sites in the promoter region of LHCGR were measured by pyrosequencing using peripheral blood cells from 85 women with PCOS and 88 control women. We identified 2 hypomethylated sites, CpG -174 (corrected P = .018) and -111 (corrected P = .006). Bisulfite sequencing then was performed to replicate these findings and detect additional CpG sites in the promoter. CpG +17 was significantly hypomethylated in women with PCOS (corrected P = .02). Methylation statuses were further evaluated using granulosa cells (GCs), and the region described was hypomethylated as a whole (P = .004) with 8 significantly hypomethylated sites (CpG -174, -148, -61, -43, -8, +10, +17, and +20). Transcription of LHCGR was elevated in women with PCOS compared with that in control women (P = .01). These findings were consistent with the decreased LHCGR methylation status associated with PCOS. The tendency of LHCGR to be hypomethylated across different tissues and its corresponding expression level suggest that hypomethylation of LHCGR is a potential mechanism underlying susceptibility to PCOS. Further studies are needed to evaluate whether a causal relationship exists between LHCGR methylation status and PCOS. Copyright © 2014 by the Endocrine Society.


Pang L.,Shandong University | Wei Z.,Guangxi Medical University | Li O.,Guangxi Medical University | Huang R.,Guangxi Medical University | And 7 more authors.
PLoS ONE | Year: 2013

Recurrent spontaneous abortion (RSA) is a health problem that affects approximately 1% to 5% reproductive age woman. Yet, in around half of these patients, the mechanism for RSA is unexplained. Recent studies have indicated that placental ischemia/hypoxia and endothelial dysfunction are important factors in miscarriage. Other studies have indicated that the level and expression of soluble FMS-like tyrosine kinase-1 (sFlt1) is increased under a hypoxic environment. However, decreased sFlt-1 in the maternal circulation during the first trimester has recently been proposed as a potential marker for identifying risk of pregnancy loss. In this prospective study clinical samples were obtained within a short time after the fetal death, protein expression and maternal serum levels of sFlt1 were assessed and compared to samples taken from those with normal pregnancies. Our results indicate that levels of VEGF and sFlt-1 are both increased in women during early pregnancy compared women that are not pregnant (p<0.05) indicating that VEGF and sFlt-1 are both associated with pregnancy. More importantly, we detected a significant (p<0.05) increase in sFlt1 and VEGF levels and expression in the RSA patients who suffered subsequent miscarriages compare to controls. These results demonstrate that there is likely a relationship between VEGF, sFlt-1 and RSA suggesting that the high levels and over expression of sFlt-1 and VEGF might be associated with the pathogenesis of RSA. © 2013 Pang et al.


Yan L.,Shandong University | Yan L.,National Research Center for Assisted Reproductive Technology and Reproductive Genetics | Yan L.,Key Laboratory for Reproductive Endocrinology of Ministry of Education | Yan L.,Shandong Provincial Key Laboratory of Reproductive Medicine | And 14 more authors.
Fertility and Sterility | Year: 2014

Objective To investigate the effect of fibroids that do not distort the endometrial cavity on IVF/intracytoplasmic sperm injection (ICSI) outcomes and to identify certain fibroid subgroups that may be deleterious to fertility outcomes. Design Retrospective cohort study. Setting University-based reproductive medicine center. Patient(s) A total of 10,268 patients undergoing IVF/ICSI between 2009 and 2011 in our unit. Intervention(s) Transvaginal ultrasound and hysteroscopy; controlled ovarian hyperstimulation and IVF/ICSI; strict matching criteria. Main Outcome Measure(s) Cycle cancellation, clinical pregnancy, miscarriage, and delivery rates. Result(s) We included 249 patients with fibroids who underwent IVF/ICSI. Higher day 3 FSH levels were found in women with fibroids compared with in control subjects. No significant differences were found in IVF/ICSI outcomes between the two groups. Patients with intramural fibroids with the largest diameter <2.85 cm or the sum of reported diameters <2.95 cm had a significantly higher delivery rate than patients with larger fibroids. A significant negative effect on delivery rate was noted when intramural fibroids with the largest diameter greater than 2.85 cm were considered, compared with matched controls without fibroids. Conclusion(s) Our results suggest that although non-cavity-distorting fibroids do not affect IVF/ICSI outcomes, intramural fibroids greater than 2.85 cm in size significantly impair the delivery rate of patients undergoing IVF/ICSI. © 2014 American Society for Reproductive Medicine, Published by Elsevier Inc.


Chen H.,Shenzhen University | Chen H.,Chinese University of Hong Kong | Wang C.,Chinese University of Hong Kong | Gao Y.,National Research Center for Assisted Reproductive Technology and Reproductive Genetics | And 6 more authors.
Protein Engineering, Design and Selection | Year: 2015

In our previous study, we have produced a neutralizing mAb of vascular endothelial growth factor receptor 3 (VEGFR-3), specifically BDD073, which could inhibit angiogenesis in the CAM model. However, the clinical application of BDD073 is restricted due to its mouse origin, which might cause human anti-mouse antibody reactions. Herein, we generated functional recombinant singlechain variable fragments (scFv) from mAb BDD073 producing mouse hybridoma cells. The scFv gene containing variable regions of heavy and light chains of BDD073 was cloned into an expression vector with trx tag and expressed in Escherichia coli BL21 (DE3). The recombinant scFv was purified and refolded with Ni-NTA agarose metal affinity column. The bacterially expressed scFv showed moderate potency and specificity to the human VEGFR-3. It may serve as a potential candidate of anti-VEGFR3 treatment for biotechnological and therapeutic applications. © The Author 2014. Published by Oxford University Press. All rights reserved.


Zhang N.,Shandong University | Zhang N.,Yantai Yuhuangding Hospital | Hao C.-F.,Yantai Yuhuangding Hospital | Zhuang L.-L.,Shandong University | And 11 more authors.
Reproductive BioMedicine Online | Year: 2013

This study assessed the true accuracy of follicular output rate (FORT) as a prognostic indicator of response to FSH and reproductive competence after IVF/intracytoplasmic sperm injection. A total of 1643 cycles, including 140 polycystic ovary syndrome (PCOS) patients who underwent ovarian stimulation, were studied. FORT was calculated as the ratio of preovulatory follicle count on the day of stimulation × 100/small antral follicle count (3-10 mm in diameter) at baseline. Low, medium and high FORT groups were defined according to tertile values. Among 1503 non-PCOS cycles, numbers of retrieved oocytes and of all embryos that could be transferred, as well as rates of good-quality embryos, embryo implantations and clinical pregnancies, progressively increased with FORT. In PCOS patients, FORT were significantly lower in patients who achieved clinical pregnancy compared with those who did not (0.56 ± 0.21 versus 0.66 ± 0.29, P = 0.031). Fertilization and good-quality embryo rates were significantly higher with medium FORT than low and high FORT (P = 0.001 and P = 0.047, respectively). Medium FORT in PCOS patients and high FORT in non-PCOS patients may predict better outcomes for IVF/ICSI. In the present study, we aimed to assess the true accuracy of the follicular output rate (FORT) as a prognostic indicator of the response to FSH and reproductive competence after IVF/intracytoplasmic sperm injection (ICSI). A total of 1643 IVF/ICSI cycles, including 140 polycystic ovary syndrome (PCOS) patients who underwent ovarian stimulation, were studied. FORT was calculated as the ratio of the preovulatory follicle count (PFC) on the day of human chorionic gonadotrophin stimulation × 100/small antral follicle count (AFC; 3-10 mm in diameter) at baseline. Low, medium and high FORT groups were defined according to the tertile values. Among 1503 non-PCOS cycles, the numbers of retrieved oocytes and of all embryos that could be transferred, as well as the rates of good-quality embryos, embryo implantations and clinical pregnancies, progressively increased from the lower to higher FORT groups. In PCOS patients, FORT was significantly lower in the patients who achieved clinical pregnancy compared with those who did not (0.56 ± 0.21 versus 0.66 ± 0.29, P < 0.05). Fertilization and good-quality embryo rates were significantly higher in the medium FORT group compared with the low and high FORT groups. The data from the present study suggest that medium FORT values in PCOS patients and high FORT values in non-PCOS patients may predict better outcomes for IVF/ICSI. © 2013, Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.

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