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Kung A.W.C.,University of Hong Kong | Xiao S.-M.,University of Hong Kong | Cherny S.,University of Hong Kong | Li G.H.Y.,University of Hong Kong | And 35 more authors.
American Journal of Human Genetics | Year: 2010

Bone mineral density (BMD), a diagnostic parameter for osteoporosis and a clinical predictor of fracture, is a polygenic trait with high heritability. To identify genetic variants that influence BMD in different ethnic groups, we performed a genome-wide association study (GWAS) on 800 unrelated Southern Chinese women with extreme BMD and carried out follow-up replication studies in six independent study populations of European descent and Asian populations including 18,098 subjects. In the meta-analysis, rs2273061 of the Jagged1 (JAG1) gene was associated with high BMD (p = 5.27 × 10-8 for lumbar spine [LS] and p = 4.15 × 10-5 for femoral neck [FN], n = 18,898). This SNP was further found to be associated with the low risk of osteoporotic fracture (p = 0.009, OR = 0.7, 95% CI 0.57-0.93, n = 1881). Region-wide and haplotype analysis showed that the strongest association evidence was from the linkage disequilibrium block 5, which included rs2273061 of the JAG1 gene (p = 8.52 × 10-9 for LS and 3.47 × 10-5 at FN). To assess the function of identified variants, an electrophoretic mobility shift assay demonstrated the binding of c-Myc to the "G" but not "A" allele of rs2273061. A mRNA expression study in both human bone-derived cells and peripheral blood mononuclear cells confirmed association of the high BMD-related allele G of rs2273061 with higher JAG1 expression. Our results identify the JAG1 gene as a candidate for BMD regulation in different ethnic groups, and it is a potential key factor for fracture pathogenesis. © 2010 The American Society of Human Genetics.

Liu B.,Chinese Academy of Sciences | Tang L.H.,Sloan Kettering Cancer Center | Liu Z.,Peking University | Mei M.,Chinese Academy of Sciences | And 17 more authors.
Journal of Clinical Endocrinology and Metabolism | Year: 2014

Purpose: We aimed to test whether -internexin could be a molecular biomarker of tumor aggressiveness and prognosis in pancreatic neuroendocrine tumors (PNETs). Patients and Methods: Using immunohistochemical staining and Western blot, we detected the expression of α-internexin in 350 tumors from 343 patients, of whom 257 were followed up. Methylation ofα-internexin promoter was examined by bisulfite sequencing to identify the crucial region that determines gene expression. Methylation of gene promoter in tumors was quantitatively measured by denaturing high performance liquid chromatography (DHPLC). We correlated -internexin expression with clinicopathological characteristics. Results: α-Internexin was expressed in 53% of 350 PNETs. The reduced expression of α-internexin wassignificantly associated with advanced stage (P<.0001), metastases (P<.0001),andrecurrence (P = .003). -Internexin expression was found in 57.1% of 212 surviving patients and in 17.1% of 35 deceased patients (P < .0001). Reduced expression of α-internexin was associated with shorter overall survival in PNET patients (log rank P<.0001) as well as in patients with noninsulinoma and nonfunctional (NF)-PNETs (log rank P = 0.0073 and P = 0.010, respectively). The crucial region of -internexin promoter (-149 to+96 nucleotides [nt]) was identified, and the hypomethylation of this area in PNETs was significantly associated with gene expression (P = .015). Conclusion: -Internexin can be a useful prognostic biomarker for PNETs. © 2014 by the Endocrine Society.

Liu Y.,Key Laboratory of Endocrinology | Liu H.J.,Peoples Hospital of Liaocheng | Li M.,Key Laboratory of Endocrinology | Zhou P.R.,Key Laboratory of Endocrinology | And 9 more authors.
Chinese Medical Journal | Year: 2014

Background Genetic factors are important in the pathogenesis of osteoporosis, but less is known about the genetic determinants of osteoporosis treatment. We aimed to explore the association between the gene polymorphisms of key enzyme farnesyl diphosphate synthase (FDPS) in mevalonate signaling pathway of osteoclast and response to alendronate therapy in osteoporotic postmenopausal women in China. Methods The study group comprised 639 postmenopausal women aged (62.2±7.0) years with osteoporosis or osteopenia who had been randomly assigned to low dose group (70 mg/2w) or standard dose group (70 mg/w) of alendronate in this 1-year study. We identified allelic variant of the FDPS gene using the polymerase chain reaction and restriction enzyme Faul. Before and after treatment, serum levels of calcium, phosphate, alkaline phosphatase (ALP), cross linked C-telopeptide of type I collagen (β-CTX) were detected. Bone mineral density (BMD) at lumbar spine and proximal femur was measured. The association was analyzed between the polymorphisms of FDPS gene and the changes of BMD, bone turnover biomarkers after the treatment. Results The FDPS rs2297480 polymorphisms were associated with baseline BMD at femoral neck, and patients with CC genotype had significantly higher baseline femoral neck BMD ((733.6±84.1) mg/cm2) than those with AC genotypes ((703.0±86.9) mg/cm2) and AA genotypes ((649.8±62.4) mg/cm2) (P <0.01). No significant difference in BMD at lumbar spine was observed among different genotypes of FDPS. The percentage change of serum ALP level was significantly lower in patients with CC genotype (-22.9%) than that in those with AC genotype (-24.1%) and AA genotype (-29.8%) of FDPS after 12 months of alendronate treatment (P <0.05). Neither percentage change of BMD nor β-CTX level after alendronate treatment had association with FDPS genotype. Conclusions FDPS gene was probably a candidate gene to predict femoral neck BMD at baseline. FDPS gene alleles could predict change percentage of ALP after treatment of alendronate, but possibly had no significant relationship with the responsiveness of BMD to alendronate therapy.

Zhang Z.,Shanghai JiaoTong University | Xia W.,Key Laboratory of Endocrinology | He J.,Shanghai JiaoTong University | Ke Y.,Shanghai JiaoTong University | And 9 more authors.
American Journal of Human Genetics | Year: 2012

By using whole-exome sequencing, we identified a homozygous guanine-to-adenine transition at the invariant -1 position of the acceptor site of intron 1 (c.97-1G>A) in solute carrier organic anion transporter family member 2A1 (SLCO2A1), which encodes a prostaglandin transporter protein, as the causative mutation in a single individual with primary hypertrophic osteoarthropathy (PHO) from a consanguineous family. In two other affected individuals with PHO from two unrelated nonconsanguineous families, we identified two different compound heterozygous mutations by using Sanger sequencing. These findings confirm that SLCO2A1 mutations inactivate prostaglandin E2 (PGE2) transport, and they indicate that mutations in SLCO2A1 are the pathogenic cause of PHO. Moreover, this study might also help to explain the cause of secondary hypertrophic osteoarthropathy. © 2012 The American Society of Human Genetics.

Wang Y.,Peking Union Medical College | Wang Y.,Key Laboratory of Endocrinology | Wang Y.,Peoples Hospital of Longkou City | Wang O.,Peking Union Medical College | And 9 more authors.
Medicine (United States) | Year: 2015

To investigate whether single nucleotide polymorphisms (SNPs) within 4 representative genes (VDR, GC, CYP2R1, and CYP24A1) encoding the core proteins involved in vitamin D production, degradation, and ligand-dependent signaling pathway are associated with gestational diabetes mellitus (GDM) in a Chinese population. A total of 1494 pregnant Han Chinese women (692 women with GDM and 802 women with normal glucose served as controls) were recruited through a 2-step approach. Participants were further divided into 2 groups according to body mass index before gestation (pre-BMI) (25 kg/m2). Nine SNPs (rs3733359, rs2282679, and rs16847024 in GC, rs2060793 and rs10741657 in CYP2R1, rs2248359 and rs6013897 in CYP24A1, rs11574143 and rs739837 in VDR) were genotyped using TaqMan allelic discrimination assays. The relationships between genotypes/alleles of a single locus as well as haplotypes of each gene and GDM were analyzed. We did not observe a significant difference in genotype frequency of each SNP between cases and controls. However, in the obese subgroup (pre-BMI ≥ 25 kg/m2), the risk allele-A of rs3733359 showed an association with increased risk of GDM (OR=1.739, 95% CI=1.066-2.837, P=0.027). The GG-haplotype frequency of rs3733359 and rs2282679 in GC was modestly lower in the GDM group (OR=0.848, 95% CI=0.719-0.999, P=0.048). Rs2060793 and rs10741657 were associated with insulin area under the curve (P=0.028, P=0.042, respectively), while rs739837 and rs6013897 demonstrated a correlation with fasting glucose (P=0.019, P=0.049, respectively). Additionally, rs2248359 displayed an association with leukocyte counts (B=0.063 P=0.033) and rs16847024 was related to high-sensitivity C-reactive protein levels (B=0.086, P=0.005). Our results indicate an association between GC variants and GDM, as well as a relation between a subset of loci in CYP2R1, CYP24A1, and VDR and clinical parameters related to GDM. Our findings may provide information for identifying biomarkers for early risk prediction of GDM and the pathways involved in disease progression. © 2015 Wolters Kluwer Health, Inc. All rights reserved.

Li N.S.,Peking Union Medical College | Li N.S.,Key Laboratory of Endocrinology
Science China Life Sciences | Year: 2011

Editorial comment Translational medicine is a new discipline which aims to eliminate the barrier between preclinical and clinical medicine. Here, Dr. Li discusses the application of translational medicine in the research, teaching and clinical work of Prof. Liu Shih-Hao, the founder of endocrinology in China, who was particularly renowned for his early work in calcium and phosphorus metabolism. This well-known success story can be traced back to an early appreciation of translational medicine by Prof. Liu Shih-Hao, and serves as an important and revelatory lesson for us all. © 2011 Science China Press and Springer-Verlag Berlin Heidelberg.

Wang O.,Key laboratory of Endocrinology | Wang C.,Key laboratory of Endocrinology | Nie M.,Key laboratory of Endocrinology | Cui Q.,Peking Union Medical College | And 6 more authors.
PLoS ONE | Year: 2012

Objective: It is widely recognized that the diagnosis of parathyroid carcinoma (PC) is often difficult because of the overlap of characteristics between malignant and benign parathyroid tumors, especially at an early stage. Based on the identification of tumor suppressor gene HRPT2/CDC73 and its association with hereditary and sporadic PC, screening of gene mutations and detection of parafibromin immunoreactivity have been suggested as diagnostic instruments of PC in Whites. There is little information about HRPT2/CDC73 mutations and its corresponding protein expression in patients with sporadic PC in Chinese population, and the long-term follow-up data is scarce. Methods: Paraffin-embedded tissues were obtained from 13 patients with PC, 13 patients with parathyroid adenoma (PA) and 7 patients with parathyroid hyperplasia(PH), and 6 normal parathyroid (NP) tissues as controls. Peripheral blood from 11 patients with PC was collected. PCR products using Genomic DNA extracted from tumor tissues or blood as template was sequenced for HRPT2/CDC73 gene. Expression of parafibromin in tumor tissues was evaluated by immunohistochemical analysis. Results: Six mutations in 6 of 13 patients with PC were identified, with three being novel. Four of them were germ-line mutations. Patients with mutations were susceptible to recurrence of the PC. Complete (8/13, 61.5%) or partial (5/13, 38.5%) loss of parafibromin expression was observed in PC tissues. All of tissue samples from normal parathyroid or benign parathyroid tumors displayed positive immunostaining of parafibromin except one adenoma. Conclusions: The present study supplies information on the mutations and protein expression of HRPT2/CDC73 gene and phenotypes of parathyroid carcinoma in Chinese population. And the expanded mutation database of this gene may benefit patients in the diagnosis and treatment of this disease. © 2012 Wang et al.

Wu X.,Key Laboratory of Endocrinology | Zhou Q.,Key Laboratory of Endocrinology | Mao J.,Key Laboratory of Endocrinology | Lu S.,Key Laboratory of Endocrinology | Nie M.,Key Laboratory of Endocrinology
Fertility and Sterility | Year: 2010

Objective: To show mutational analysis for androgen insensitivity syndrome (AIS)-associated male pseudohermaphroditism (MPH). Design: Case report. Setting: Key laboratory of endocrinology at a university hospital. Patient(s): Four unrelated Chinese patients with MPH referred to our clinic were investigated in this study. Intervention(s): Genomic DNA was extracted from peripheral blood leukocytes, and coding sequence abnormalities of androgen receptor (AR) gene were assessed by polymerase chain reaction and direct sequencing analysis. Main Outcome Measure(s): Molecular characterization of the AR gene. Result(s): Four mutations (p.P913R, p.D732 N, p.N848 K, fs879X, and p.R608 K) in the AR gene were identified in our study. The p.P913R mutation in the AR gene has not been described previously. Conclusion(s): Our study identified a novel mutation in the AR gene that may provide us new insights into the molecular mechanisms of AIS. The expanded database of these mutations should benefit patients in the diagnosis and treatment of this syndrome. © 2010 American Society for Reproductive Medicine.

Wang X.,Key Laboratory of Endocrinology | Nie M.,Key Laboratory of Endocrinology | Lu L.,Key Laboratory of Endocrinology | Tong A.,Key Laboratory of Endocrinology | And 2 more authors.
Steroids | Year: 2015

Steroid 11β-hydroxylase deficiency (11β-OHD), one of common cause of congenital adrenal hyperplasia (CAH), is an autosomal recessive disorder characterized by virilization, precocious pseudo-puberty, and hypertension. It is caused by CYP11B1 gene mutation. We performed molecular genetic analysis of the CYP11B1 gene in six patients with preliminary clinical diagnosis of 11β-OHD and four patients identified as potential 11β-OHD from a CAH cohort in which CYP21A2 gene mutations consecutively screened. Seven novel CYP11B1 mutations, including p.R454H, p.Q472P, p.Q155X, p.K173X, IVS2-1G>A, R454A fs 573X, and g.2704-g.3154del, and six previously described mutations (p.P94L, p.G267S, p.G379V, p.R448H, p.R454C and p.R141X) were identified. These mutations mainly clustered in exons 3 and 8. Eight of twenty alleles carried mutations occurring at the Arg454 position, which is a mutational hot spot for Han Chinese. The pathogenic nature of novel p.R454H mutation was predicted by protein sequence alignment and in silico analysis. All the identified mutations were responsible for the clinical features observed in these ten unrelated Chinese patients. This study expands the CYP11B1 mutation spectrum and provides evidence for prenatal diagnosis and genetic counseling. Genetic analysis is an alternative approach to help clinicians confirm uncertain 11β-OHD diagnosis, facilitating reasonable steroid replacement. © 2015 Elsevier Inc.

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