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Song G.,Shandong University | Yan J.,Shandong University | Yan J.,National Research Center for Assisted Reproductive Technology and Reproductive Genetics | Yan J.,Key Laboratory for Reproductive Endocrinology | And 6 more authors.
Reproductive BioMedicine Online | Year: 2015

KIAA0319L, PXK and JAZF1 gene polymorphisms were investigated to determine whether they conferred susceptibility to unexplained recurrent pregnancy loss (URPL) in a group of Chinese Han patients. Genotyping and sequencing of the single nucleotide polymorphisms (SNP) rs2275247(A/G) in KIAA0319L, rs2176082(C/T) and rs6445975(G/T) in PXK and the rs1635852(C/T) in JAZF1 were carried out in 84 couples with URPL and 102 healthy couples with at least one live birth. Frequencies of the SNP rs2176082(C/T) in PXK gene were significantly different between women with URPL and control women: P < 0.05; OR 95% CI 0.530 (0.287 to 0.979); OR 95% CI 0.482 (0.254 to 0.911) but were not significantly different after Bonferroni correction. The frequencies of the SNP rs2176082(C/T) in PXK gene showed no difference between the husband of a woman with URPL and a control husband: OR 95% CI 1.494 (0.821 to 2.721); OR 95% CI 1.567 (0.841 to 2.921). No statistically significant differences were observed in the distribution of any genotype or allele frequency or any genetic model of the other three SNPs between couples with URPL and control couples. Therefore, the rs2176082(C/T) polymorphism of PXK might play a possible role in the development of URPL in Chinese Han women. © 2014 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.


Song G.,Shandong University | Yan J.,Shandong University | Yan J.,National Research Center for Assisted Reproductive Technology and Reproductive Genetics | Yan J.,Key Laboratory for Reproductive Endocrinology | And 7 more authors.
European Journal of Obstetrics Gynecology and Reproductive Biology | Year: 2014

Study design: This is a case-control association study. Genomic DNA was extracted from peripheral blood samples from 84 couples with histories of three or more pregnancy losses and 69 age-matched healthy couples with at least one live birth and no histories of pregnancy loss. Polymerase chain reactions (PCRs) and sequencing with the fluorescent dye dideoxy-termination method were used to detect the rs4898 in TIMP-1, rs2277698 in TIMP-2, rs2234921 and rs5749511 in TIMP-3 and rs17035945 in TIMP-4 genotypes and allele frequencies.Objective: To investigate the association of tissue inhibitor of metalloproteinase (TIMP) gene polymorphisms with unexplained recurrent spontaneous abortions (URSA) in a well-defined group of Han Chinese couples.Results: Neither the allele frequencies nor any of the genetic model of the five TIMP gene SNPs (i.e., TIMP- 1-rs4898, TIMP-2-rs2277698, TIMP-3-rs5749511 and rs2234921, and TIMP-4-rs7035945) were significantly differences between the URSA couples and the control group.Conclusions: No evidence was found for any associations between the TIMP-1,-2,-3, or -4 genes SNPs with URSA in this Han Chinese Han. © 2014 Elsevier Ireland Ltd. All rights reserved.


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.


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.


Chen X.,Shandong University | Chen X.,National Research Center for Assisted Reproductive Technology and Reproductive Genetics | Chen X.,Key Laboratory for Reproductive Endocrinology | Chen X.,Shandong Provincial Key Laboratory of Reproductive Medicine | And 21 more authors.
Reproductive BioMedicine Online | Year: 2014

As a member of the homeobox (HOX) gene family, HOXA11 is expressed in the primordia of lower uterus and cervix during fetal life and is essential for endometrial development and embryo implantation in the adults. The aim of the present study was to investigate whether mutations in HOXA11 contribute to Müllerian duct anomalies (MDA) in Chinese. A cohort of 192 patients with MDA and 192 healthy controls was enrolled. Genomic DNA was extracted. All exons and exon-intron boundaries were amplified and sequenced. One novel synonymous variant (c.774G>A) and one known single-nucleotide polymorphism were identified, both of which were not found in the matched controls. The results suggest that mutations in the coding region of HOXA11 are not common in Chinese women with MDA. As a member of the homeobox gene family, HOXA11 is expressed in the primordia of lower uterus and cervix during fetal life and is essential for endometrial development and embryo implantation in the adults. The aim of the present study was to investigate whether mutations in HOXA11 contribute to Müllerian duct anomalies (MDA) in Chinese. A cohort of 192 patients with MDA and 192 healthy controls was enrolled. Genomic DNA was extracted. All exons and exon-intron boundaries were amplified and sequenced. One novel synonymous variant (c.774G>A) and one known single-nucleotide polymorphism were identified, both of which were not found in the matched controls. The results suggest that mutations in the coding region of HOXA11 are not common in Chinese women with MDA. © 2014, Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.


Chang X.,Shandong University of Technology | Chang X.,Key Laboratory for Reproductive Endocrinology | Qin Y.,Shandong University of Technology | Qin Y.,Key Laboratory for Reproductive Endocrinology | And 7 more authors.
Reproductive BioMedicine Online | Year: 2012

The WNT4 gene plays a crucial role in sexual differentiation and female genital tract development. This study screened WNT4 for mutation in 189 Chinese women with Müllerian duct abnormalities (10 Mayer-Rokitansky-Küster- Hauser syndrome, five Müllerian aplasia and 174 incomplete Müllerian fusion) and detected no perturbation that would indicate a major role for WNT4. Only one novel synonymous mutation (c.1091G > A) in exon 5 and one known single-nucleotide polymorphism (rs16826648) in exon 2 were found. The results suggest that WNT4 might not contribute to the aetiology of Müllerian duct abnormalities in Chinese women. © 2012, Reproductive Healthcare Ltd.


Zhao Z.,Shandong University | Zhao Z.,National Research Center for Assisted Reproductive Technology and Reproductive Genetics | Zhao Z.,Key Laboratory for Reproductive Endocrinology | Zhao Z.,Shandong Provincial Key Laboratory of Reproductive Medicine | And 18 more authors.
Reproductive BioMedicine Online | Year: 2013

P27 and SKP2, a major regulator of P27, play a crucial role in ovarian function in mice. Both P27-deficient and SKP2-deficient female mice develop premature ovarian failure (POF). The coding regions of SKP2 and P27 were examined in 200 Chinese women with POF and 200 control volunteers. This study is the first to investigate SKP2 in POF. No plausible pathogenic mutations were detected. The results suggest that mutations in SKP2 and P27 are not common in Chinese Han women with POF. P27 and Skp2, a major regulator of P27, play a crucial role in ovarian function in mice. Both P27-deficient and Skp2-deficient female mice develop premature ovarian failure (POF). The coding region of SKP2 and P27 were examined in 200 Chinese women with POF and 200 control volunteers. One known single-nucleotide polymorphism (SNP), rs6175530 in exon 7 of SKP2, and one known SNP, rs1690837 in exon 1 of P27, were identified. The present study is the first to discover variants occurring in SKP2 in association with POF. The results suggest that mutations in SKP2 and P27 are not common in Chinese Han women with POF. © 2013, Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.


Dang Y.,Shandong University of Technology | Dang Y.,Key Laboratory for Reproductive Endocrinology | Qin Y.,Shandong University of Technology | Qin Y.,Key Laboratory for Reproductive Endocrinology | And 9 more authors.
Fertility and Sterility | Year: 2012

Objective: To search for WNT7A gene mutations in a cohort of 191 Chinese Han patients with müllerian duct abnormalities (MDAs). Design: Phenotypic and mutational study. Setting: University hospital. Patient(s): A total of 191 Chinese Han patients with MDAs and 192 healthy control individuals. Intervention(s): Genomic DNA extracted from blood samples, all coding regions amplified by polymerase chain reaction (PCR) then directly sequenced to screen variants. Main Outcome Measure(s): Not applicable. Result(s): The sequence analysis revealed one novel synonymous variant and three known single-nucleotide polymorphisms (SNPs). Conclusion(s): The results indicate that mutations in the coding sequence of WNT7A are not responsible for müllerian duct abnormalities in the Chinese population. © 2012 American Society for Reproductive Medicine, Published by Elsevier Inc.


Xia M.,Shandong University | Xia M.,National Research Center for Assisted Reproductive Technology and Reproductive Genetics | Xia M.,Key Laboratory for Reproductive Endocrinology | Xia M.,Shandong Provincial Key Laboratory of Reproductive Medicine | And 25 more authors.
Fertility and Sterility | Year: 2012

Objective: To investigate whether LHX1 gene mutations exist in Han Chinese patients with müllerian duct abnormalities (MDAs). Design: Mutation screening. Setting: University hospital. Patient(s): Ninety-six MDA patients and 105 control subjects from a Han Chinese population. The parents of the patients carrying the genetic variation were also screened. Intervention(s): Gene sequencing. Main Outcome Measure(s): Karyotype, LHX1 gene sequencing. Result(s): We found no significant mutation in coding regions of LHX1. However, there is a new rare polymorphism of LHX1 gene, c.1070-1081del, found in 1 out of 77 incomplete müllerian fusion patients and 1 out of 105 control individuals in the Han Chinese population (thus affecting ∼1% of Han Chinese). Conclusion(s): No causative perturbation was identified in the LHX1 gene. Mutations in the coding regions of LHX1 may not be a common genetic etiologic factor involved in Han Chinese MDA patients. © 2012 American Society for Reproductive Medicine, Published by Elsevier Inc.

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