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Medicine Jun 2017To identify variants of the genes in fibroblast growth factors/fibroblast growth factor receptors (FGF/FGFR) signal pathway that predispose to mandibular prognathism... (Observational Study)
Observational Study
To identify variants of the genes in fibroblast growth factors/fibroblast growth factor receptors (FGF/FGFR) signal pathway that predispose to mandibular prognathism (MP) in the general Chinese population systematically.Targeted sequencing of the FGF/FGFR genes was conducted in 176 MP individuals and 155 class I malocclusion controls. The associations of common and rare variants with MP as a categorical phenotype and also continuous malocclusion phenotypes generated by principal component (PC) analysis were analyzed.One common variant, rs372127537, located in the 3'-untranslated region of FGF7 gene, was significantly related to PC1 (P = 4.22 × 10), which explained 23.23% of the overall phenotypic variation observed and corresponded to vertical discrepancies ranging from short anterior face height to long anterior face height, after Bonferroni correction. Also, 15 other variants were associated with PC1-4, although not significant after multiple corrections (P < .05). We also identified 3 variants: rs13317 in FGFR1, rs149242678 in FGF20, and rs79176051 FGF12 associated with MP (P < .05). With respect to rare variant analysis, variants within the FGF12 gene showed significant association with MP (P = .001).Association between FGF/FGFR signaling pathway and MP has been identified. We found a previously unreported SNP in FGF7 significantly related to increased facial height. Also, rare variants within the FGF12 were associated with MP. Our results provide new clues for genetic mechanisms of MP and shed light on strategies for evaluating rare variants that underlie complex traits. Future studies with larger sample sizes and more comprehensive genome coverage, and also in other population are required to replicate these findings.
Topics: Asian People; Cephalometry; China; Female; Fibroblast Growth Factor 7; Fibroblast Growth Factors; Gene Frequency; Genetic Association Studies; Genetic Predisposition to Disease; Genetic Variation; Genotyping Techniques; Humans; Male; Principal Component Analysis; Prognathism; Receptor, Fibroblast Growth Factor, Type 1; Young Adult
PubMed: 28640125
DOI: 10.1097/MD.0000000000007240 -
Genetics and Molecular Research : GMR Oct 2015Genome-wide association studies have reported numerous susceptibility loci for Parkinson's disease (PD). However, there have been few replication studies examining these...
Genome-wide association studies have reported numerous susceptibility loci for Parkinson's disease (PD). However, there have been few replication studies examining these loci in northern Chinese populations. To evaluate the relationships among 3 polymorphic markers located in the fibroblast growth factor 20 and transmembrane protein 175 genes and the genetic susceptibility to PD in northern Chinese subjects, 2 single nucleotide polymorphisms, and 1 insertion/deletion marker (rs591323 in FGF20; rs6599388 and rs142821586 in transmembrane protein 175 near the G-associated kinase/diacylglycerol kinase theta region) were investigated in 313 PD patients and 318 matched controls. Mismatched multiplex polymerase chain reaction-restriction fragment length polymorphism analysis as well as sequence-specific primer polymerase chain reaction and restriction fragment length polymorphism assays were performed. The genotypic frequency of rs591323 differed significantly between the patient and control groups; however, neither rs6599388 nor rs142821586 was associated with PD. We corrected the Hardy-Weinberg disequilibrium for rs6599388, which was previously reported to be common in 4 Asian descent populations into equilibrium status by simultaneously genotyping rs6599388 and rs142821586. In summary, we found that rs591323 was associated with PD but rs6599388 and rs142821586 were not associated with PD in a northern Chinese population.
Topics: Aged; Alleles; Asian People; Case-Control Studies; China; Female; Fibroblast Growth Factors; Genetic Association Studies; Genetic Markers; Genetic Predisposition to Disease; Genotype; Humans; INDEL Mutation; Male; Middle Aged; Odds Ratio; Parkinson Disease; Polymorphism, Single Nucleotide; Potassium Channels
PubMed: 26535683
DOI: 10.4238/2015.October.28.30 -
Journal of Colloid and Interface Science Jan 2016Dental bleaching with H2O2 is a common daily practice in dentistry to correct discoloration of anterior teeth. The aim of this study has been to determine whether this...
HYPOTHESIS
Dental bleaching with H2O2 is a common daily practice in dentistry to correct discoloration of anterior teeth. The aim of this study has been to determine whether this treatment of human teeth affects growth, differentiation and activity of osteoclast-like cells, as well as the putative modulatory action of osteostatin and fibroblast growth factor 2 (FGF-2).
EXPERIMENTS
Previously to the in vitro assays, structural, physical-chemical and morphological features of teeth after bleaching were studied. Osteoclast-like cells were cultured on human dentin disks, pre-treated or not with 38% H2O2 bleaching gel, in the presence or absence of osteostatin (100 nM) or FGF-2 (1 ng/ml). Cell proliferation and viability, intracellular content of reactive oxygen species (ROS), pro-inflammatory cytokine (IL-6 and TNFα) secretion and resorption activity were evaluated.
FINDINGS
Bleaching treatment failed to affect either the structural or the chemical features of both enamel and dentin, except for slight morphological changes, increased porosity in the most superficial parts (enamel), and a moderate increase in the wettability degree. In this scenario, bleaching produced an increased osteoclast-like cell proliferation but decreased cell viability and cytokine secretion, while it augmented resorption activity on dentin. The presence of either osteostatin or FGF-2 reduced the osteoclast-like cell proliferation induced by bleaching. FGF-2 enhanced ROS content, whereas osteostatin decreased ROS but increased TNFα secretion. The bleaching effect on resorption activity was increased by osteostatin, but this effect was less evident with FGF-2.
CONCLUSIONS
These findings further confirm the deleterious effects of tooth bleaching by affecting osteoclast growth and function as well as different modulatory actions of osteostatin and FGF-2.
Topics: Adolescent; Adsorption; Adult; Animals; Cell Survival; Cells, Cultured; Dentin; Fibroblast Growth Factors; Flow Cytometry; Humans; Hydrogen Peroxide; Macrophages; Mice; Osteoclasts; Parathyroid Hormone-Related Protein; Particle Size; Peptide Fragments; Reactive Oxygen Species; Surface Properties; Tooth Bleaching; Wettability; Young Adult
PubMed: 26407056
DOI: 10.1016/j.jcis.2015.09.035 -
PloS One 2015Nonalcoholic fatty liver disease (NAFLD) is a risk factor for Hepatocellular carcinoma (HCC), but he transition from NAFLD to HCC is poorly understood. Feature selection...
Nonalcoholic fatty liver disease (NAFLD) is a risk factor for Hepatocellular carcinoma (HCC), but he transition from NAFLD to HCC is poorly understood. Feature selection algorithms in human and genetically modified mice NAFLD and HCC microarray data were applied to generate signatures of NAFLD progression and HCC differential survival. These signatures were used to study the pathogenesis of NAFLD derived HCC and explore which subtypes of cancers that can be investigated using mouse models. Our findings show that: (I) HNF4 is a common potential transcription factor mediating the transcription of NAFLD progression genes (II) mice HCC derived from NAFLD co-cluster with a less aggressive human HCC subtype of differential prognosis and mixed etiology (III) the HCC survival signature is able to correctly classify 95% of the samples and gives Fgf20 and Tgfb1i1 as the most robust genes for prediction (IV) the expression values of genes composing the signature in an independent human HCC dataset revealed different HCC subtypes showing differences in survival time by a Logrank test. In summary, we present marker signatures for NAFLD derived HCC molecular pathogenesis both at the gene and pathway level.
Topics: Animals; Biomarkers; Carcinoma, Hepatocellular; Disease Progression; Fibroblast Growth Factors; Hepatocyte Nuclear Factor 4; Humans; Insulin Resistance; Intracellular Signaling Peptides and Proteins; LIM Domain Proteins; Liver; Liver Neoplasms; Mice; Mice, Knockout; Non-alcoholic Fatty Liver Disease; Risk Factors; p38 Mitogen-Activated Protein Kinases
PubMed: 25993042
DOI: 10.1371/journal.pone.0124544 -
Translational Psychiatry Feb 2015Pharmacogenetics may allow for a personalized treatment, but a combination with clinical variables may further enhance prediction. In particular, in the present paper,... (Randomized Controlled Trial)
Randomized Controlled Trial
Genetic variants in combination with early partial improvement as a clinical utility predictor of treatment outcome in major depressive disorder: the result of two pooled RCTs.
Pharmacogenetics may allow for a personalized treatment, but a combination with clinical variables may further enhance prediction. In particular, in the present paper, we investigated early partial improvement (EPI) defined as 20% or more improvement by rating scales 2 weeks after treatment, in combination with selected gene variants as a predictor of treatment outcome in patients with major depressive disorder. Two randomized controlled trials with 168 Japanese depressed patients were used. A stepwise multiple linear regression model with HAM-D score change at week 6 as the dependent variable and genotypes, EPI, baseline HAM-D score, age and sex as independent variables was performed in paroxetine, fluvoxamine and milnacipran, respectively, to estimate the prediction of HAM-D change at week 6. In the paroxetine sample, only EPI (P<0.001) was significantly associated with HAM-D change (n=81, R(2)=0.25, P<0.001). In the fluvoxamine sample, 5-HTTLPR La/Lg, S (P=0.029), FGF2 rs1449683C/T (P=0.013) and EPI (P=0.003) were associated with HAM-D change (n=42, R(2)=0.43, P<0.001). In the milnacipran sample, HTR-1A-1019C/G (P=0.001), ADRA2A-1297C/G (P=0.028) and EPI (P<0.001) were associated with outcome (n=45, R(2)=0.71, P<0.001). EPI in combination with genetic variants could be a useful predictor of treatment outcome and could strengthen the practical use of pharmacogenetic data in clinical practice.
Topics: Age Factors; Antidepressive Agents; Antidepressive Agents, Second-Generation; Cyclopropanes; Depressive Disorder, Major; Female; Fibroblast Growth Factors; Fluvoxamine; Humans; Japan; Male; Middle Aged; Milnacipran; Paroxetine; Psychiatric Status Rating Scales; Receptor, Serotonin, 5-HT1A; Receptors, Adrenergic, alpha-2; Serotonin Plasma Membrane Transport Proteins; Sex Factors; Treatment Outcome
PubMed: 25710119
DOI: 10.1038/tp.2015.6 -
Medecine Sciences : M/S Mar 2013
Topics: Animals; Cell Differentiation; Female; Fibroblast Growth Factor 9; Fibroblast Growth Factors; Humans; Kidney; Pregnancy; Renal Insufficiency; Stem Cells
PubMed: 23544377
DOI: 10.1051/medsci/2013293009 -
BMC Genomics Feb 2013The theoretical basis of genome-wide association studies (GWAS) is statistical inference of linkage disequilibrium (LD) between any polymorphic marker and a putative...
BACKGROUND
The theoretical basis of genome-wide association studies (GWAS) is statistical inference of linkage disequilibrium (LD) between any polymorphic marker and a putative disease locus. Most methods widely implemented for such analyses are vulnerable to several key demographic factors and deliver a poor statistical power for detecting genuine associations and also a high false positive rate. Here, we present a likelihood-based statistical approach that accounts properly for non-random nature of case-control samples in regard of genotypic distribution at the loci in populations under study and confers flexibility to test for genetic association in presence of different confounding factors such as population structure, non-randomness of samples etc.
RESULTS
We implemented this novel method together with several popular methods in the literature of GWAS, to re-analyze recently published Parkinson's disease (PD) case-control samples. The real data analysis and computer simulation show that the new method confers not only significantly improved statistical power for detecting the associations but also robustness to the difficulties stemmed from non-randomly sampling and genetic structures when compared to its rivals. In particular, the new method detected 44 significant SNPs within 25 chromosomal regions of size < 1 Mb but only 6 SNPs in two of these regions were previously detected by the trend test based methods. It discovered two SNPs located 1.18 Mb and 0.18 Mb from the PD candidates, FGF20 and PARK8, without invoking false positive risk.
CONCLUSIONS
We developed a novel likelihood-based method which provides adequate estimation of LD and other population model parameters by using case and control samples, the ease in integration of these samples from multiple genetically divergent populations and thus confers statistically robust and powerful analyses of GWAS. On basis of simulation studies and analysis of real datasets, we demonstrated significant improvement of the new method over the non-parametric trend test, which is the most popularly implemented in the literature of GWAS.
Topics: Algorithms; Case-Control Studies; Cohort Studies; Computer Simulation; Databases, Factual; Fibroblast Growth Factors; Genome-Wide Association Study; Genotype; Humans; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; Likelihood Functions; Linkage Disequilibrium; Models, Statistical; Parkinson Disease; Polymorphism, Single Nucleotide; Protein Serine-Threonine Kinases
PubMed: 23394771
DOI: 10.1186/1471-2164-14-88 -
Journal of Cellular Biochemistry Apr 2013Adult articular chondrocytes lack an effective repair response to correct damage from injury or osteoarthritis. Polypeptide growth factors that stimulate articular...
Adult articular chondrocytes lack an effective repair response to correct damage from injury or osteoarthritis. Polypeptide growth factors that stimulate articular chondrocyte proliferation and cartilage matrix synthesis may augment this response. Gene transfer is a promising approach to delivering such factors. Multiple growth factor genes regulate these cell functions, but multiple growth factor gene transfer remains unexplored. We tested the hypothesis that multiple growth factor gene transfer selectively modulates articular chondrocyte proliferation and matrix synthesis. We tested the hypothesis by delivering combinations of the transgenes encoding insulin-like growth factor I (IGF-I), fibroblast growth factor-2 (FGF-2), transforming growth factor beta1 (TGF-β1), bone morphogenetic protein-2 (BMP-2), and bone morphogenetic protien-7 (BMP-7) to articular chondrocytes and measured changes in the production of DNA, glycosaminoglycan, and collagen. The transgenes differentially regulated all these chondrocyte activities. In concert, the transgenes interacted to generate widely divergent responses from the cells. These interactions ranged from inhibitory to synergistic. The transgene pair encoding IGF-I and FGF-2 maximized cell proliferation. The three-transgene group encoding IGF-I, BMP-2, and BMP-7 maximized matrix production and also optimized the balance between cell proliferation and matrix production. These data demonstrate an approach to articular chondrocyte regulation that may be tailored to stimulate specific cell functions, and suggest that certain growth factor gene combinations have potential value for cell-based articular cartilage repair.
Topics: Animals; Bone Morphogenetic Protein 2; Bone Morphogenetic Protein 7; Cartilage, Articular; Cattle; Cell Differentiation; Cell Proliferation; Cells, Cultured; Chondrocytes; Collagen; Fibroblast Growth Factors; Gene Expression Regulation; Genetic Vectors; Humans; Insulin-Like Growth Factor I; Intercellular Signaling Peptides and Proteins; Proteoglycans; Time Factors; Transfection; Transforming Growth Factor beta1; Transgenes
PubMed: 23097312
DOI: 10.1002/jcb.24430 -
Developmental Cell Jun 2012The identity of niche signals necessary to maintain embryonic nephron progenitors is unclear. Here we provide evidence that Fgf20 and Fgf9, expressed in the niche, and...
The identity of niche signals necessary to maintain embryonic nephron progenitors is unclear. Here we provide evidence that Fgf20 and Fgf9, expressed in the niche, and Fgf9, secreted from the adjacent ureteric bud, are necessary and sufficient to maintain progenitor stemness. Reduction in the level of these redundant ligands in the mouse led to premature progenitor differentiation within the niche. Loss of FGF20 in humans, or of both ligands in mice, resulted in kidney agenesis. Sufficiency was shown in vitro where Fgf20 or Fgf9 (alone or together with Bmp7) maintained isolated metanephric mesenchyme or sorted nephron progenitors that remained competent to differentiate in response to Wnt signals after 5 or 2 days in culture, respectively. These findings identify a long-sought-after critical component of the nephron stem cell niche and hold promise for long-term culture and utilization of these progenitors in vitro.
Topics: Animals; Bone Morphogenetic Protein 7; Cell Differentiation; Congenital Abnormalities; Female; Fibroblast Growth Factor 9; Fibroblast Growth Factors; Humans; Kidney; Kidney Diseases; Male; Mesenchymal Stem Cells; Mice; Mutation; Nephrons; Organ Culture Techniques; Stem Cell Niche; Wnt Signaling Pathway
PubMed: 22698282
DOI: 10.1016/j.devcel.2012.04.018 -
Human Mutation Nov 2010MicroRNAs are short, approximately 22 nucleotide noncoding RNAs binding to partially complementary sites in the 3'UTR of target mRNAs. This process generally results in...
MicroRNAs are short, approximately 22 nucleotide noncoding RNAs binding to partially complementary sites in the 3'UTR of target mRNAs. This process generally results in repression of multiple targets by a particular microRNA. There is substantial interest in methods designed to predict the microRNA targets and effect of single nucleotide polymorphisms (SNPs) on microRNA binding, given the impact of microRNA on posttranscriptional regulation and its potential relation to complex diseases. We developed a web-based application, MicroSNiPer, which predicts the impact of a SNP on putative microRNA targets. This application interrogates the 3'-untranslated region and predicts if a SNP within the target site will disrupt/eliminate or enhance/create a microRNA binding site. MicroSNiPer computes these sites and examines the effects of SNPs in real time. MicroSNiPer is a user-friendly Web-based tool. Its advantages include ease of use, flexibility, and straightforward graphical representation of the results. It is freely accessible at http://cbdb.nimh.nih.gov/microsniper.
Topics: 3' Untranslated Regions; Algorithms; Animals; Base Sequence; Binding Sites; Computational Biology; Databases, Nucleic Acid; Fibroblast Growth Factors; Humans; Internet; Mice; MicroRNAs; Molecular Sequence Data; Polymorphism, Single Nucleotide; Software; User-Computer Interface
PubMed: 20809528
DOI: 10.1002/humu.21349