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Search Results: 1 - 10 of 469177 matches for " Ben A. Oostra "
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Association between Type 2 Diabetes Loci and Measures of Fatness
Slavica Pecioska,M. Carola Zillikens,Peter Henneman,Pieter J. Snijders,Ben A. Oostra,Cornelia M. van Duijn,Yurii S. Aulchenko
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0008541
Abstract: Type 2 diabetes (T2D) is a metabolic disorder characterized by disturbances of carbohydrate, fat and protein metabolism and insulin resistance. The majority of T2D patients are obese and obesity by itself may be a cause of insulin resistance. Our aim was to evaluate whether the recently identified T2D risk alleles are associated with human measures of fatness as characterized with Dual Energy X-ray Absorptiometry (DEXA).
Generation and Characterization of Fmr1 Knockout Zebrafish
Marjo J. den Broeder,Herma van der Linde,Judith R. Brouwer,Ben A. Oostra,Rob Willemsen,René F. Ketting
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0007910
Abstract: Fragile X syndrome (FXS) is one of the most common known causes of inherited mental retardation. The gene mutated in FXS is named FMR1, and is well conserved from human to Drosophila. In order to generate a genetic tool to study FMR1 function during vertebrate development, we generated two mutant alleles of the fmr1 gene in zebrafish. Both alleles produce no detectable Fmr protein, and produce viable and fertile progeny with lack of obvious phenotypic features. This is in sharp contrast to published results based on morpholino mediated knock-down of fmr1, reporting defects in craniofacial development and neuronal branching in embryos. These phenotypes we specifically addressed in our knock-out animals, revealing no significant deviations from wild-type animals, suggesting that the published morpholino based fmr1 phenotypes are potential experimental artifacts. Therefore, their relation to fmr1 biology is questionable and morpholino induced fmr1 phenotypes should be avoided in screens for potential drugs suitable for the treatment of FXS. Importantly, a true genetic zebrafish model is now available which can be used to study FXS and to derive potential drugs for FXS treatment.
Dopaminergic Neuronal Loss and Dopamine-Dependent Locomotor Defects in Fbxo7-Deficient Zebrafish
Tianna Zhao, Herma Zondervan-van der Linde, Lies-Anne Severijnen, Ben A. Oostra, Rob Willemsen, Vincenzo Bonifati
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0048911
Abstract: Recessive mutations in the F-box only protein 7 gene (FBXO7) cause PARK15, a Mendelian form of early-onset, levodopa-responsive parkinsonism with severe loss of nigrostriatal dopaminergic neurons. However, the function of the protein encoded by FBXO7, and the pathogenesis of PARK15 remain unknown. No animal models of this disease exist. Here, we report the generation of a vertebrate model of PARK15 in zebrafish. We first show that the zebrafish Fbxo7 homolog protein (zFbxo7) is expressed abundantly in the normal zebrafish brain. Next, we used two zFbxo7-specific morpholinos (targeting protein translation and mRNA splicing, respectively), to knock down the zFbxo7 expression. The injection of either of these zFbxo7-specific morpholinos in the fish embryos induced a marked decrease in the zFbxo7 protein expression, and a range of developmental defects. Furthermore, whole-mount in situ mRNA hybridization showed abnormal patterning and significant decrease in the number of diencephalic tyrosine hydroxylase-expressing neurons, corresponding to the human nigrostriatal or ventral tegmental dopaminergic neurons. Of note, the number of the dopamine transporter-expressing neurons was much more severely depleted, suggesting dopaminergic dysfunctions earlier and larger than those due to neuronal loss. Last, the zFbxo7 morphants displayed severe locomotor disturbances (bradykinesia), which were dramatically improved by the dopaminergic agonist apomorphine. The severity of these morphological and behavioral abnormalities correlated with the severity of zFbxo7 protein deficiency. Moreover, the effects of the co-injection of zFbxo7- and p53-specific morpholinos were similar to those obtained with zFbxo7-specific morpholinos alone, supporting further the contention that the observed phenotypes were specifically due to the knock down of zFbxo7. In conclusion, this novel vertebrate model reproduces pathologic and behavioral hallmarks of human parkinsonism (dopaminergic neuronal loss and dopamine-dependent bradykinesia), representing therefore a valid tool for investigating the mechanisms of selective dopaminergic neuronal death, and screening for modifier genes and therapeutic compounds.
Lack of association of two common polymorphisms on 9p21 with risk of coronary heart disease and myocardial infarction; results from a prospective cohort study
Abbas Dehghan, Mandy van Hoek, Eric JG Sijbrands, Ben A Oostra, Albert Hofman, Cornelia M van Duijn, Jacqueline CM Witteman
BMC Medicine , 2008, DOI: 10.1186/1741-7015-6-30
Abstract: The Rotterdam Study is a population-based, prospective cohort study among 7983 participants aged 55 years and older. Associations of the polymorphisms with CHD and MI were assessed by use of Cox proportional hazards analyses.In an additive model, the age and sex adjusted hazard ratios (HRs) (95% confidence interval) for CHD and MI were 1.03 (0.90, 1.18) and 0.94 (0.82, 1.08) per copy of the G allele of rs10757274. The corresponding HRs were 1.03 (0.90, 1.18) and 0.93 (0.81, 1.06) for the G allele of rs10757278. The association of the SNPs with CHD and MI was not significant in any of the subgroups of CHD risk factors.we were not able to show an association of the studied SNPs with risks of CHD and MI. This may be due to differences in genes involved in the occurrence of CHD in young and older people.It has been considered for long that genes play a substantial role in susceptibility to coronary heart disease (CHD) [1]. Up to now, a limited number of these genes have been identified through the candidate gene approach and genome wide linkage studies. Recently a number of genome wide association (GWA) studies have identified several genetic variants on chromosome 9p21 associated with the risk of CHD. McPherson et al. found a Single Nucleotide Polymorphism (SNP), rs10757274, on chromosome 9p21 associated with the risk of CHD [2]. Helgadottir et al. found a close-by SNP, rs10757278, in the same 9p21 region associated with the risk of myocardial infarction (MI) [3]. These findings were followed by another GWA study by Samani et al [4], which found rs1333049 to be associated with the risk of coronary artery disease [4]. All three SNPs are located within the same Linkage Disequilibrium (LD) block on chromosome 9 approximately 22 million base pairs from the 9p telomere, adjacent to two tumor suppressor genes, CDKN2A and CDKN2B. These genes are involved in regulation of cell proliferation. Abnormal proliferation is one of the characteristics of atherosclerosis, one of the pa
Congenital Dyserythropoietic Anemia Type II: molecular analysis and expression of the SEC23B Gene
Francesca Punzo, Aida M Bertoli-Avella, Saverio Scianguetta, Fulvio Della Ragione, Maddalena Casale, Luisa Ronzoni, Maria D Cappellini, Gianluca Forni, Ben A Oostra, Silverio Perrotta
Orphanet Journal of Rare Diseases , 2011, DOI: 10.1186/1750-1172-6-89
Abstract: SEC23B was sequenced in 16 patients, their relatives and 100 control participants. SEC23B transcript level were studied by quantitative PCR (qPCR) in peripheral erythroid precursors and lymphocytes from the patients and healthy control participants. Sec23B protein content was analyzed by immunoblotting in samples of erythroblast cells from CDAII patients and healthy controls.All of the investigated cases carried SEC23B mutations on both alleles, with the exception of two patients in which a single heterozygous mutation was found. We identified 15 different SEC23B mutations, of which four represent novel mutations: p.Gln214Stop, p.Thr485Ala, p.Val637Gly, and p.Ser727Phe. The CDAII patients exhibited a 40-60% decrease of SEC23B mRNA levels in erythroid precursors when compared with the corresponding cell type from healthy participants. The largest decrease was observed in compound heterozygote patients with missense/nonsense mutations. In three patients, Sec23B protein levels were evaluated in erythroid precursors and found to be strictly correlated with the reduction observed at the transcript level. We also demonstrate that Sec23B mRNA expression levels in lymphocytes and erythroblasts are similar.In this study, we identified four novel SEC23B mutations associated with CDAII disease. We also demonstrate that the genetic alteration results in a significant decrease of SEC23B transcript in erythroid precursors. Similar down-regulation was observed in peripheral lymphocytes, suggesting that the use of these cells might be sufficient in the identification of Sec23B gene alterations. Finally, we demonstrate that decreased Sec23B protein levels in erythroid precursors correlate with down-regulation of the SEC23B mRNA transcript.Congenital dyserythropoietic anemias (CDAs) are a group of rare hereditary disorders characterized by ineffective erythropoiesis and distinct morphological abnormalities of the erythroblasts in the bone marrow [1]. CDA type II (CDAII, OMIM 224100),
Genetic Factors Influence the Clustering of Depression among Individuals with Lower Socioeconomic Status
Sandra López-León, Wing Chi Choy, Yurii S. Aulchenko, Stephan J. Claes, Ben A. Oostra, Johan P. Mackenbach, Cornelia M. van Duijn, A. Cecile J. W. Janssens
PLOS ONE , 2009, DOI: 10.1371/journal.pone.0005069
Abstract: Objective To investigate the extent to which shared genetic factors can explain the clustering of depression among individuals with lower socioeconomic status, and to examine if neuroticism or intelligence are involved in these pathways. Methods In total 2,383 participants (1,028 men and 1,355 women) of the Erasmus Rucphen Family Study were assessed with the Center for Epidemiologic Studies Depression Scale (CES-D) and the Hospital Anxiety and Depression Scale (HADS-D). Socioeconomic status was assessed as the highest level of education obtained. The role of shared genetic factors was quantified by estimating genetic correlations (ρG) between symptoms of depression and education level, with and without adjustment for premorbid intelligence and neuroticism scores. Results Higher level of education was associated with lower depression scores (partial correlation coefficient ?0.09 for CES-D and ?0.17 for HADS-D). Significant genetic correlations were found between education and both CES-D (ρG = ?0.65) and HADS-D (ρG = ?0.50). The genetic correlations remained statistically significant after adjusting for premorbid intelligence and neuroticism scores. Conclusions Our study suggests that shared genetic factors play a role in the co-occurrence of lower socioeconomic status and symptoms of depression, which suggest that genetic factors play a role in health inequalities. Further research is needed to investigate the validity, causality and generalizability of our results.
Loss of Nuclear Activity of the FBXO7 Protein in Patients with Parkinsonian-Pyramidal Syndrome (PARK15)
Tianna Zhao,Esther De Graaff,Guido J. Breedveld,Agnese Loda,Lies-Anne Severijnen,Cokkie H. Wouters,Frans W. Verheijen,Marieke C. J. Dekker,Pasquale Montagna,Rob Willemsen,Ben A. Oostra,Vincenzo Bonifati
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0016983
Abstract: Mutations in the F-box only protein 7 gene (FBXO7) cause PARK15, an autosomal recessive neurodegenerative disease presenting with severe levodopa-responsive parkinsonism and pyramidal disturbances. Understanding the PARK15 pathogenesis might thus provide clues on the mechanisms of maintenance of brain dopaminergic neurons, the same which are lost in Parkinson's disease. The protein(s) encoded by FBXO7 remain very poorly characterized. Here, we show that two protein isoforms are expressed from the FBXO7 gene in normal human cells. The isoform 1 is more abundant, particularly in primary skin fibroblasts. Both isoforms are undetectable in cell lines from the PARK15 patient of an Italian family; the isoform 1 is undetectable and the isoform 2 is severely decreased in the patients from a Dutch PARK15 family. In human cell lines and mouse primary neurons, the endogenous or over-expressed, wild type FBXO7 isoform 1 displays mostly a diffuse nuclear localization. An intact N-terminus is needed for the nuclear FBXO7 localization, as N-terminal modification by PARK15-linked missense mutation, or N-terminus tag leads to cytoplasmic mislocalization. Furthermore, the N-terminus of wild type FBXO7 (but not of mutant FBXO7) is able to confer nuclear localization to profilin (a cytoplasmic protein). Our data also suggest that overexpressed mutant FBXO7 proteins (T22M, R378G and R498X) have decreased stability compared to their wild type counterpart. In human brain, FBXO7 immunoreactivity was highest in the nuclei of neurons throughout the cerebral cortex, intermediate in the globus pallidum and the substantia nigra, and lowest in the hippocampus and cerebellum. In conclusion, the common cellular abnormality found in the PARK15 patients from the Dutch and Italian families is the depletion of the FBXO7 isoform 1, which normally localizes in the cell nucleus. The activity of FBXO7 in the nucleus appears therefore crucial for the maintenance of brain neurons and the pathogenesis of PARK15.
Modeling of Environmental Effects in Genome-Wide Association Studies Identifies SLC2A2 and HP as Novel Loci Influencing Serum Cholesterol Levels
Wilmar Igl ,?sa Johansson,James F. Wilson,Sarah H. Wild,Ozren Pola?ek,Caroline Hayward,Veronique Vitart,Nicholas Hastie,Pavao Rudan,Carsten Gnewuch,Gerd Schmitz,Thomas Meitinger,Peter P. Pramstaller,Andrew A. Hicks,Ben A. Oostra,Cornelia M. van Duijn,Igor Rudan,Alan Wright,Harry Campbell,Ulf Gyllensten,EUROSPAN Consortium
PLOS Genetics , 2010, DOI: 10.1371/journal.pgen.1000798
Abstract: Genome-wide association studies (GWAS) have identified 38 larger genetic regions affecting classical blood lipid levels without adjusting for important environmental influences. We modeled diet and physical activity in a GWAS in order to identify novel loci affecting total cholesterol, LDL cholesterol, HDL cholesterol, and triglyceride levels. The Swedish (SE) EUROSPAN cohort (NSE = 656) was screened for candidate genes and the non-Swedish (NS) EUROSPAN cohorts (NNS = 3,282) were used for replication. In total, 3 SNPs were associated in the Swedish sample and were replicated in the non-Swedish cohorts. While SNP rs1532624 was a replication of the previously published association between CETP and HDL cholesterol, the other two were novel findings. For the latter SNPs, the p-value for association was substantially improved by inclusion of environmental covariates: SNP rs5400 (pSE,unadjusted = 3.6×10?5, pSE,adjusted = 2.2×10?6, pNS,unadjusted = 0.047) in the SLC2A2 (Glucose transporter type 2) and rs2000999 (pSE,unadjusted = 1.1×10?3, pSE,adjusted = 3.8×10?4, pNS,unadjusted = 0.035) in the HP gene (Haptoglobin-related protein precursor). Both showed evidence of association with total cholesterol. These results demonstrate that inclusion of important environmental factors in the analysis model can reveal new genetic susceptibility loci.
A Genome-Wide Association Study of Optic Disc Parameters
Wishal D. Ramdas equal contributor,Leonieke M. E. van Koolwijk equal contributor,M. Kamran Ikram equal contributor,Nomdo M. Jansonius,Paulus T. V. M. de Jong,Arthur A. B. Bergen,Aaron Isaacs,Najaf Amin,Yurii S. Aulchenko,Roger C. W. Wolfs,Albert Hofman,Fernando Rivadeneira,Ben A. Oostra,Andre G. Uitterlinden,Pirro Hysi,Christopher J. Hammond,Hans G. Lemij,Johannes R. Vingerling ,Caroline C. W. Klaver equal contributor,Cornelia M. van Duijn equal contributor
PLOS Genetics , 2010, DOI: 10.1371/journal.pgen.1000978
Abstract: The optic nerve head is involved in many ophthalmic disorders, including common diseases such as myopia and open-angle glaucoma. Two of the most important parameters are the size of the optic disc area and the vertical cup-disc ratio (VCDR). Both are highly heritable but genetically largely undetermined. We performed a meta-analysis of genome-wide association (GWA) data to identify genetic variants associated with optic disc area and VCDR. The gene discovery included 7,360 unrelated individuals from the population-based Rotterdam Study I and Rotterdam Study II cohorts. These cohorts revealed two genome-wide significant loci for optic disc area, rs1192415 on chromosome 1p22 (p = 6.72×10?19) within 117 kb of the CDC7 gene and rs1900004 on chromosome 10q21.3-q22.1 (p = 2.67×10?33) within 10 kb of the ATOH7 gene. They revealed two genome-wide significant loci for VCDR, rs1063192 on chromosome 9p21 (p = 6.15×10?11) in the CDKN2B gene and rs10483727 on chromosome 14q22.3-q23 (p = 2.93×10?10) within 40 kbp of the SIX1 gene. Findings were replicated in two independent Dutch cohorts (Rotterdam Study III and Erasmus Rucphen Family study; N = 3,612), and the TwinsUK cohort (N = 843). Meta-analysis with the replication cohorts confirmed the four loci and revealed a third locus at 16q12.1 associated with optic disc area, and four other loci at 11q13, 13q13, 17q23 (borderline significant), and 22q12.1 for VCDR. ATOH7 was also associated with VCDR independent of optic disc area. Three of the loci were marginally associated with open-angle glaucoma. The protein pathways in which the loci of optic disc area are involved overlap with those identified for VCDR, suggesting a common genetic origin.
A meta-analysis of genome-wide data from five European isolates reveals an association of COL22A1, SYT1, and GABRR2 with serum creatinine level
Cristian Pattaro, Alessandro De Grandi, Veronique Vitart, Caroline Hayward, Andre Franke, Yurii S Aulchenko, Asa Johansson, Sarah H Wild, Scott A Melville, Aaron Isaacs, Ozren Polasek, David Ellinghaus, Ivana Kolcic, Ute N?thlings, Lina Zgaga, Tatijana Zemunik, Carsten Gnewuch, Stefan Schreiber, Susan Campbell, Nick Hastie, Mladen Boban, Thomas Meitinger, Ben A Oostra, Peter Riegler, Cosetta Minelli, Alan F Wright, Harry Campbell, Cornelia M van Duijn, Ulf Gyllensten, James F Wilson, Michael Krawczak, Igor Rudan, Peter P Pramstaller, the EUROSPAN consortium
BMC Medical Genetics , 2010, DOI: 10.1186/1471-2350-11-41
Abstract: We performed a meta-analysis of genome-wide association studies of SCR undertaken in five population isolates ('discovery cohorts'), all of which are part of the European Special Population Network (EUROSPAN) project. Genes showing the strongest evidence for an association with SCR (candidate loci) were replicated in two additional population-based samples ('replication cohorts').After the discovery meta-analysis, 29 loci were selected for replication. Association between SCR level and polymorphisms in the collagen type XXII alpha 1 (COL22A1) gene, on chromosome 8, and in the synaptotagmin-1 (SYT1) gene, on chromosome 12, were successfully replicated in the replication cohorts (p value = 1.0 × 10-6 and 1.7 × 10-4, respectively). Evidence of association was also found for polymorphisms in a locus including the gamma-aminobutyric acid receptor rho-2 (GABRR2) gene and the ubiquitin-conjugating enzyme E2-J1 (UBE2J1) gene (replication p value = 3.6 × 10-3). Previously reported findings, associating glomerular filtration rate with SNPs in the uromodulin (UMOD) gene and in the schroom family member 3 (SCHROOM3) gene were also replicated.While confirming earlier results, our study provides new insights in the understanding of the genetic basis of serum creatinine regulatory processes. In particular, the association with the genes SYT1 and GABRR2 corroborate previous findings that highlighted a possible role of the neurotransmitters GABAA receptors in the regulation of the glomerular basement membrane and a possible interaction between GABAAreceptors and synaptotagmin-I at the podocyte level.In epidemiological population-based surveys, serum creatinine (SCR) represents the most important biomarker for a quick and non-invasive assessment of kidney function, allowing estimation of the glomerular filtration rate (GFR) [1]. At the same time, an increased SCR level has also been recognized as a risk factor for adverse outcomes in patients hospitalized for cardiac surgery or heart
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