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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. Source

Zhao H.,Shandong University | Zhao H.,National Research Center for Assisted Reproductive Technology | Zhao H.,The Key Laboratory for Reproductive Endocrinology of Ministry of Education | Zhao H.,Shandong Provincial Key Laboratory of Reproductive Medicine | And 5 more authors.
Molecular Human Reproduction | Year: 2013

Many genetic association studies have been performed to investigate disorders of female reproduction, such as polycystic ovary syndrome, premature ovarian failure and endometriosis. These disorders typically manifest heterogeneously, and their pathogeneses are influenced by polygenic and environmental factors. Researchers evaluating these genetic associations have chosen candidate genes related to hormone action, steroid biosynthesis, inflammatory cytokines and autoimmune factors. Several of these genes have yielded statistically significant associations with female reproductive disorders; however, few associations have been robust and reproducible. Whole-genome association studies generate more reliable and unbiased results and represent a breakthrough in genetic studies of female reproduction. Nevertheless, to date only a very small fraction of the overall heritability has been identified and so further studies are needed. © The Author 2013. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. Source

Wang Z.,Shandong University | Wang Z.,Qingdao University | Li T.,Shandong University | Zhang W.,Shandong University | And 9 more authors.
Gynecologic Oncology | Year: 2012

Objective: The aim of this study was to explore the polycystic ovary syndrome (PCOS) related single nucleotide polymorphisms (SNPs) rs13405728 (in gene LHCGR), rs13429458 (in gene THADA) and rs2479106 (in gene DENND1A) in women with endometrial carcinoma. Methods: We conducted a case-control study comprising 96 Han Chinese women with endometrial carcinoma, and 192 healthy controls. SNPs rs13405728, rs13429458 and rs2479106 were genotyped by polymerase chain reaction (PCR) and direct sequencing. The effects of body mass index (BMI) and age were evaluated using an unconditional logistic regression model adjusted for potential confounders. Results: The allele frequencies of SNPs rs2479106 and rs13405728 were significantly different (P < 0.05) between endometrial carcinoma group and control group, and the difference was especially significant in the subgroup of endometrioid adenocarcinoma. Genotyping analysis showed that allele G in rs2479106 and allele A in rs13405728 could confer risk to endometrioid adenocarcinoma. Conclusions: Our results suggest that SNPs rs2479106 in gene DENND1A and rs13405728 in gene LHCGR are associated with endometrioid adenocarcinoma. © 2012 Elsevier Inc. Source

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. Source

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. Source

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