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Find video protocols related to scientific articles indexed in Pubmed.
Ear2 deletion causes early memory and learning deficits in APP/PS1 mice.
J. Neurosci.
PUBLISHED: 06-27-2014
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To assess the consequences of locus ceruleus (LC) degeneration and subsequent noradrenaline (NA) deficiency in early Alzheimer's disease (AD), mice overexpressing mutant amyloid precursor protein and presenilin-1 (APP/PS1) were crossed with Ear2(-/-) mice that have a severe loss of LC neurons projecting to the hippocampus and neocortex. Testing spatial memory and hippocampal long-term potentiation revealed an impairment in APP/PS1 Ear2(-/-) mice, whereas APP/PS1 or Ear2(-/-) mice showed only minor changes. These deficits were associated with distinct synaptic changes including reduced expression of the NMDA 2A subunit and increased levels of NMDA receptor 2B in APP/PS1 Ear2(-/-) mice. Acute pharmacological replacement of NA by L-threo-DOPS partially restored phosphorylation of ?-CaMKII and spatial memory performance in APP/PS1 Ear2(-/-) mice. These changes were not accompanied by altered APP processing or amyloid ? peptide (A?) deposition. Thus, early LC degeneration and subsequent NA reduction may contribute to cognitive deficits via CaMKII and NMDA receptor dysfunction independent of A? and suggests that NA supplementation could be beneficial in treating AD.
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The contribution of genetic factors to phenotype and progression of drusen in early age-related macular degeneration.
Graefes Arch. Clin. Exp. Ophthalmol.
PUBLISHED: 05-28-2014
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Genetic factors contribute to the development and progression of age-related macular degeneration (AMD). We aimed to assess the association of drusen as phenotypic characteristics of early AMD and their progression with polymorphisms in the CFH, ABCA1, and ARMS2 genes.
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Systematic permutation testing in GWAS pathway analyses: identification of genetic networks in dilated cardiomyopathy and ulcerative colitis.
BMC Genomics
PUBLISHED: 03-10-2014
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Genome wide association studies (GWAS) are applied to identify genetic loci, which are associated with complex traits and human diseases. Analogous to the evolution of gene expression analyses, pathway analyses have emerged as important tools to uncover functional networks of genome-wide association data. Usually, pathway analyses combine statistical methods with a priori available biological knowledge. To determine significance thresholds for associated pathways, correction for multiple testing and over-representation permutation testing is applied.
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Paradoxical effects on force generation after efficient ?1-adrenoceptor knockdown in reconstituted heart tissue.
J. Pharmacol. Exp. Ther.
PUBLISHED: 01-15-2014
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Stimulation of myocardial ?(1)-adrenoceptors (AR) is a major mechanism that increases cardiac function. We investigated the functional consequences of genetic ?(1)-AR knockdown in three-dimensional engineered heart tissue (EHT). For ?(1)-AR knockdown, short interfering RNA (siRNA) sequences targeting specifically the ?(1)-AR (shB1) and a scrambled control (shCTR) were subcloned into a recombinant adeno-associated virus (AAV)-short hairpin RNA (shRNA) expression system. Transduction efficiency was ?100%, and radioligand binding revealed 70% lower ?(1)-AR density in AAV6-shB1-transduced EHTs. Force measurements, performed over the culture period of 14 days, showed paradoxically higher force generation in AAV6-shB1 compared with shCTR under basal (0.19 ± 0.01 versus 0.13 ± 0.01 mN) and after ?-AR-stimulated conditions with isoprenaline (?fractional shortening: 72 ± 5% versus 34 ± 4%). Large scale gene expression analysis revealed that AAV6-shCTR compared with nontransduced EHTs showed only few differentially regulated genes (<20), whereas AAV6-shB1 induced marked changes in gene expression (>250 genes), indicating that ?(1)-AR knockdown itself determines the outcome. None of the regulated genes pointed to obvious off-target effects to explain higher force generation. Moreover, compensational regulation of ?(2)-AR signaling or changes in prominent ?(1)-AR downstream targets could be ruled out. In summary, we show paradoxically higher force generation and isoprenaline responses after efficient ?(1)-AR knockdown in EHTs. Our findings 1) reveal an unexpected layer of complexity in gene regulation after specific ?(1)-AR knockdown rather than unspecific dysregulations through transcriptional interference, 2) challenge classic assumptions on the role of cardiac ?(1)-AR, and 3) may open up new avenues for ?-AR loss-of-function research in vivo.
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Specific gene expression responses to parasite genotypes reveal redundancy of innate immunity in vertebrates.
PLoS ONE
PUBLISHED: 01-01-2014
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Vertebrate innate immunity is the first line of defense against an invading pathogen and has long been assumed to be largely unspecific with respect to parasite/pathogen species. However, recent phenotypic evidence suggests that immunogenetic variation, i.e. allelic variability in genes associated with the immune system, results in host-parasite genotype-by-genotype interactions and thus specific innate immune responses. Immunogenetic variation is common in all vertebrate taxa and this reflects an effective immunological function in complex environments. However, the underlying variability in host gene expression patterns as response of innate immunity to within-species genetic diversity of macroparasites in vertebrates is unknown. We hypothesized that intra-specific variation among parasite genotypes must be reflected in host gene expression patterns. Here we used high-throughput RNA-sequencing to examine the effect of parasite genotypes on gene expression patterns of a vertebrate host, the three-spined stickleback (Gasterosteus aculeatus). By infecting naïve fish with distinct trematode genotypes of the species Diplostomum pseudospathaceum we show that gene activity of innate immunity in three-spined sticklebacks depended on the identity of an infecting macroparasite genotype. In addition to a suite of genes indicative for a general response against the trematode we also find parasite-strain specific gene expression, in particular in the complement system genes, despite similar infection rates of single clone treatments. The observed discrepancy between infection rates and gene expression indicates the presence of alternative pathways which execute similar functions. This suggests that the innate immune system can induce redundant responses specific to parasite genotypes.
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DNA Methyltransferase inhibition reverses epigenetically embedded phenotypes in lung cancer preferentially affecting Polycomb target genes.
Clin. Cancer Res.
PUBLISHED: 12-13-2013
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Cancer cell phenotypes are partially determined by epigenetic specifications such as DNA methylation. Metastasis development is a late event in cancerogenesis and might be associated with epigenetic alterations.
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Advances in understanding stroke risk in children - a geneticists view.
Br. J. Haematol.
PUBLISHED: 09-04-2013
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The advent of the genomic era has provided novel insights into the genetic architecture of common complex diseases, such as thrombophilia and stroke. Since 2006, a growing number of genome wide association studies (GWAS) for common complex diseases have revealed new candidate loci and genomic regions that play an important role in disease aetiology and progression. While GWAS on the above mentioned traits are abundant in adults, similar studies in paediatric study cohorts are lagging behind. However, genetic research in this important clinical area has gained momentum and starts to provide us with exciting insights into the genetic underpinnings of stroke with paediatric onset. Here we review recent advances in genetic association studies underlying stroke in children and aim to translate the results to clinical utility. These studies comprise candidate gene approaches and GWAS, and represent the current status on what we have learnt about the genetic architecture underlying paediatric stroke, and how this may affect medical practice in the years to come.
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A genome-wide association study identifies 6p21 as novel risk locus for dilated cardiomyopathy.
Eur. Heart J.
PUBLISHED: 07-12-2013
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Dilated cardiomyopathy (DCM) is one of the leading causes for cardiac transplantations and accounts for up to one-third of all heart failure cases. Since extrinsic and monogenic causes explain only a fraction of all cases, common genetic variants are suspected to contribute to the pathogenesis of DCM, its age of onset, and clinical progression. By a large-scale case-control genome-wide association study we aimed here to identify novel genetic risk loci for DCM.
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Postgwas: advanced GWAS interpretation in R.
PLoS ONE
PUBLISHED: 01-01-2013
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We present a comprehensive toolkit for post-processing, visualization and advanced analysis of GWAS results. In the spirit of comparable tools for gene-expression analysis, we attempt to unify and simplify several procedures that are essential for the interpretation of GWAS results. This includes the generation of advanced Manhattan and regional association plots including rare variant display as well as novel interaction network analysis tools for the investigation of systems-biology aspects. Our package supports virtually all model organisms and represents the first cohesive implementation of such tools for the popular language R. Previous software of that range is dispersed over a wide range of platforms and mostly not adaptable for custom work pipelines. We demonstrate the utility of this package by providing an example workflow on a publicly available dataset.
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Genome-Wide Association Identifies TBX5 as Candidate Gene for Osteochondrosis Providing a Functional Link to Cartilage Perfusion as Initial Factor.
Front Genet
PUBLISHED: 01-01-2013
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Osteochondrosis (OC) is an orthopedic syndrome of the joints that occurs in children and adolescents and domestic animals, particularly pigs, horses, and dogs. OC is the most frequent cause of leg weakness in rapidly growing pigs causing animal welfare issues and economic losses. In this study, a genome-wide association study (GWAS) was performed using the Porcine 60k SNPChip in animals of the breed Large White (n?=?298) to identify chromosome regions and candidate genes associated with OC lesion scores. A total of 19 SNPs on chromosomes (SSC) 3, 5, 8, 10, 14, and 18 were significantly associated with OC lesion scores (p-values???10(-5)). The SNPs MARC0098684, MARC00840086, MARC0093124, and ASGA0062794 at SSC14 36.1-38.2?Mb encompass a region of six linkage disequilibrium (LD) blocks. The most significant SNP ASGA0062794 is located in a LD block spanning 465?kb and covering the gene encoding T-box transcription factor 5 (TBX5). A SNP (c.54T?>?C) identified in TBX5 was significantly associated with OC lesion scores in a single-marker analysis. TBX5 c.54T?>?C showed highest LD with ASGA00627974 (r (2)?=?0.96) and superior association with OC lesion scores over other SNPs when included in the genome scan, whereas its treatment as an additional fixed effect in the GWAS statistical model led to a drop of significance of nearby markers. Moreover, real-time PCR showed different transcript abundance of TBX5 in healthy and defect cartilage. The results imply that the association signal obtained on SCC14 is largely attributable to TBX5 c.54T?>?C likely to be in LD with a regulatory polymorphism of TBX5. The transcription factor TBX5 interacts with GJA5 and MEF2C both being involved in vascularization. This study provides evidence for epistatic interaction of TBX5 and MEF2C, thus supporting deficiency of blood supply to growth cartilage as being fundamental for the initiation of OC.
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Inherited risk factors for thrombotic diseases in children: the genome-wide perspective.
Semin. Thromb. Hemost.
PUBLISHED: 12-20-2011
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As a result of technological advances in the field of high-throughput genomics, there has been a remarkable transition in studying the nature of complex genetic disorders. The genetic analysis of prothrombotic risk factors has shifted from candidate gene to genome-wide association studies (GWAS) in adults. GWAS established a framework in which up to 90% of common genetic variation can be analyzed in a single experiment. Given the ubiquity of the GWAS approach in the adult population, it will become essential for clinicians and researchers in the field of pediatrics to interpret results derived from genetic high-throughput studies. Here, we review the current knowledge regarding genetic factors affecting prothrombotic risk in children and adults. Advantages and pitfalls of the GWAS approach are discussed, including the use of intermediate phenotypes, deep resequencing, and the differences between family-based and association studies. Intelligently designed and well-powered studies incorporating stringent phenotype assessment will contribute to decipher the genetic basis of stroke and venous thrombosis in children.
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The identification of phosducin as a novel candidate gene for hypertension and its role in sympathetic activation.
Curr. Opin. Nephrol. Hypertens.
PUBLISHED: 05-27-2011
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The primary objective of this review is to familiarize readers with the recent identification of phosducin (Pdc) as a novel candidate gene for stress-induced hypertension using comparative genetics and the elucidation of its role in sympathetic activation.
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Gp130-dependent release of acute phase proteins is linked to the activation of innate immune signaling pathways.
PLoS ONE
PUBLISHED: 04-05-2011
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Elevated levels of acute phase proteins (APP) are often found in patients with cardiovascular diseases. In a previous study, we demonstrated the importance of the IL-6-gp130 axis -as a key regulator of inflammatory acute phase signaling in hepatocytes-for the development of atherosclerosis.
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Six sequence variants on chromosome 9p21.3 are associated with a positive family history of myocardial infarction: a multicenter registry.
BMC Cardiovasc Disord
PUBLISHED: 03-07-2011
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Recent genome-wide association studies have identified several genetic loci linked to coronary artery disease (CAD) and myocardial infarction (MI). The 9p21.3 locus was verified by numerous replication studies to be the first common locus for CAD and MI. In the present study, we investigated whether six single nucleotide polymorphisms (SNP) rs1333049, rs1333040, rs10757274, rs2383206, rs10757278, and rs2383207 representing the 9p21.3 locus were associated with the incidence of an acute MI in patients with the main focus on the familial aggregation of the disease.
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Large-scale association analysis identifies 13 new susceptibility loci for coronary artery disease.
Heribert Schunkert, Inke R König, Sekar Kathiresan, Muredach P Reilly, Themistocles L Assimes, Hilma Holm, Michael Preuss, Alexandre F R Stewart, Maja Barbalic, Christian Gieger, Devin Absher, Zouhair Aherrahrou, Hooman Allayee, David Altshuler, Sonia S Anand, Karl Andersen, Jeffrey L Anderson, Diego Ardissino, Stephen G Ball, Anthony J Balmforth, Timothy A Barnes, Diane M Becker, Lewis C Becker, Klaus Berger, Joshua C Bis, S Matthijs Boekholdt, Eric Boerwinkle, Peter S Braund, Morris J Brown, Mary Susan Burnett, Ian Buysschaert, , John F Carlquist, Li Chen, Sven Cichon, Veryan Codd, Robert W Davies, George Dedoussis, Abbas Dehghan, Serkalem Demissie, Joseph M Devaney, Patrick Diemert, Ron Do, Angela Doering, Sandra Eifert, Nour Eddine El Mokhtari, Stephen G Ellis, Roberto Elosua, James C Engert, Stephen E Epstein, Ulf de Faire, Marcus Fischer, Aaron R Folsom, Jennifer Freyer, Bruna Gigante, Domenico Girelli, Solveig Gretarsdottir, Vilmundur Gudnason, Jeffrey R Gulcher, Eran Halperin, Naomi Hammond, Stanley L Hazen, Albert Hofman, Benjamin D Horne, Thomas Illig, Carlos Iribarren, Gregory T Jones, J Wouter Jukema, Michael A Kaiser, Lee M Kaplan, John J P Kastelein, Kay-Tee Khaw, Joshua W Knowles, Genovefa Kolovou, Augustine Kong, Reijo Laaksonen, Diether Lambrechts, Karin Leander, Guillaume Lettre, Mingyao Li, Wolfgang Lieb, Christina Loley, Andrew J Lotery, Pier M Mannucci, Seraya Maouche, Nicola Martinelli, Pascal P McKeown, Christa Meisinger, Thomas Meitinger, Olle Melander, Pier Angelica Merlini, Vincent Mooser, Thomas Morgan, Thomas W Mühleisen, Joseph B Muhlestein, Thomas Münzel, Kiran Musunuru, Janja Nahrstaedt, Christopher P Nelson, Markus M Nöthen, Oliviero Olivieri, Riyaz S Patel, Chris C Patterson, Annette Peters, Flora Peyvandi, Liming Qu, Arshed A Quyyumi, Daniel J Rader, Loukianos S Rallidis, Catherine Rice, Frits R Rosendaal, Diana Rubin, Veikko Salomaa, M Lourdes Sampietro, Manj S Sandhu, Eric Schadt, Arne Schäfer, Arne Schillert, Stefan Schreiber, Jürgen Schrezenmeir, Stephen M Schwartz, David S Siscovick, Mohan Sivananthan, Suthesh Sivapalaratnam, Albert Smith, Tamara B Smith, Jaapjan D Snoep, Nicole Soranzo, John A Spertus, Klaus Stark, Kathy Stirrups, Monika Stoll, W H Wilson Tang, Stephanie Tennstedt, Gudmundur Thorgeirsson, Gudmar Thorleifsson, Maciej Tomaszewski, André G Uitterlinden, Andre M van Rij, Benjamin F Voight, Nick J Wareham, George A Wells, H-Erich Wichmann, Philipp S Wild, Christina Willenborg, Jaqueline C M Witteman, Benjamin J Wright, Shu Ye, Tanja Zeller, Andreas Ziegler, Francois Cambien, Alison H Goodall, L Adrienne Cupples, Thomas Quertermous, Winfried März, Christian Hengstenberg, Stefan Blankenberg, Willem H Ouwehand, Alistair S Hall, Panos Deloukas, John R Thompson, Kari Stefansson, Robert Roberts, Unnur Thorsteinsdottir, Christopher J O'Donnell, Ruth McPherson, Jeanette Erdmann, Nilesh J Samani.
Nat. Genet.
PUBLISHED: 02-10-2011
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We performed a meta-analysis of 14 genome-wide association studies of coronary artery disease (CAD) comprising 22,233 individuals with CAD (cases) and 64,762 controls of European descent followed by genotyping of top association signals in 56,682 additional individuals. This analysis identified 13 loci newly associated with CAD at P < 5 × 10?? and confirmed the association of 10 of 12 previously reported CAD loci. The 13 new loci showed risk allele frequencies ranging from 0.13 to 0.91 and were associated with a 6% to 17% increase in the risk of CAD per allele. Notably, only three of the new loci showed significant association with traditional CAD risk factors and the majority lie in gene regions not previously implicated in the pathogenesis of CAD. Finally, five of the new CAD risk loci appear to have pleiotropic effects, showing strong association with various other human diseases or traits.
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The functional -374T/A polymorphism of the receptor for advanced glycation end products may modulate Crohns disease.
Am. J. Physiol. Gastrointest. Liver Physiol.
PUBLISHED: 02-10-2011
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The receptor for advanced glycation end products (RAGE) is involved in innate immune mechanisms. Polymorphisms of the RAGE gene have been described as a factor amplifying inflammation in susceptible patients, but the association with Crohns disease (CD) is not known. The coding RAGE polymorphism G82S (rs2070600) and two promoter polymorphisms, -374T/A (rs1800624) and -429T/C (rs1800625), were studied in two samples from Germany and the United States consisting of 421 and 317 CD patients and 549 and 218 controls, respectively. To test the functional relevance, additional data on serum soluble RAGE (sRAGE), tissue RNA, and protein levels were collected and immunohistochemical stainings of bowel tissue of CD patients and healthy controls as well as models of experimental (dextran sodium sulfate-induced) colitis in RAGE knockout and wild-type mice were performed. The -374T/A RAGE promotor single nucleotide polymorphism (SNP) was negatively associated with CD (odds ratio = 0.708, 95% confidence interval = 0.535-0.938, P = 0.016) and with stenosis (OR = 0.627, P = 0.04) in the German sample. Transmission disequilibrium testing confirmed an undertransmission of the -374A allele. Serum sRAGE levels were higher in patients in complete remission of the -374AA/TA group (1,975 ± 299 pg/ml; -374TT group: 1,310 ± 153 pg/ml SE, P < 0.05) and showed a trend toward decreased levels in CD patients with active disease compared with CD patients in remission. Further in vitro and in vivo studies indicated that an increase of sRAGE ameliorates inflammation. The -429T/C and the G82S polymorphism were not associated with CD. The -374T/A RAGE polymorphism leading to facilitated RAGE gene transcription may to some degree protect from developing a stricturing subphenotype of CD, most likely by increasing levels of sRAGE, which neutralizes proinflammatory mediators.
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Lack of association between the Trp719Arg polymorphism in kinesin-like protein-6 and coronary artery disease in 19 case-control studies.
Themistocles L Assimes, Hilma Holm, Sekar Kathiresan, Muredach P Reilly, Gudmar Thorleifsson, Benjamin F Voight, Jeanette Erdmann, Christina Willenborg, Dhananjay Vaidya, Changchun Xie, Chris C Patterson, Thomas M Morgan, Mary Susan Burnett, Mingyao Li, Mark A Hlatky, Joshua W Knowles, John R Thompson, Devin Absher, Carlos Iribarren, Alan Go, Stephen P Fortmann, Stephen Sidney, Neil Risch, Hua Tang, Richard M Myers, Klaus Berger, Monika Stoll, Svati H Shah, Gudmundur Thorgeirsson, Karl Andersen, Aki S Havulinna, J Enrique Herrera, Nauder Faraday, Yoonhee Kim, Brian G Kral, Rasika A Mathias, Ingo Ruczinski, Bhoom Suktitipat, Alexander F Wilson, Lisa R Yanek, Lewis C Becker, Patrick Linsel-Nitschke, Wolfgang Lieb, Inke R König, Christian Hengstenberg, Marcus Fischer, Klaus Stark, Wibke Reinhard, Janina Winogradow, Martina Grassl, Anika Grosshennig, Michael Preuss, Stefan Schreiber, H-Erich Wichmann, Christa Meisinger, Jean Yee, Yechiel Friedlander, Ron Do, James B Meigs, Gordon Williams, David M Nathan, Calum A MacRae, Liming Qu, Robert L Wilensky, William H Matthai, Atif N Qasim, Hakon Hakonarson, Augusto D Pichard, Kenneth M Kent, Lowell Satler, Joseph M Lindsay, Ron Waksman, Christopher W Knouff, Dawn M Waterworth, Max C Walker, Vincent E Mooser, Jaume Marrugat, Gavin Lucas, Isaac Subirana, Joan Sala, Rafael Ramos, Nicola Martinelli, Oliviero Olivieri, Elisabetta Trabetti, Giovanni Malerba, Pier Franco Pignatti, Candace Guiducci, Daniel Mirel, Melissa Parkin, Joel N Hirschhorn, Rosanna Asselta, Stefano Duga, Kiran Musunuru, Mark J Daly, Shaun Purcell, Sandra Eifert, Peter S Braund, Benjamin J Wright, Anthony J Balmforth, Stephen G Ball, , Willem H Ouwehand, Panos Deloukas, Michael Scholz, Francois Cambien, Andreas Huge, Thomas Scheffold, Veikko Salomaa, Domenico Girelli, Christopher B Granger, Leena Peltonen, Pascal P McKeown, David Altshuler, Olle Melander, Joseph M Devaney, Stephen E Epstein, Daniel J Rader, Roberto Elosua, James C Engert, Sonia S Anand, Alistair S Hall, Andreas Ziegler, Christopher J O'Donnell, John A Spertus, David Siscovick, Stephen M Schwartz, Diane Becker, Unnur Thorsteinsdottir, Kari Stefansson, Heribert Schunkert, Nilesh J Samani, Thomas Quertermous.
J. Am. Coll. Cardiol.
PUBLISHED: 06-14-2010
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We sought to replicate the association between the kinesin-like protein 6 (KIF6) Trp719Arg polymorphism (rs20455), and clinical coronary artery disease (CAD).
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Genetic variants in the C-reactive protein gene are associated with microangiopathic ischemic stroke.
Cerebrovasc. Dis.
PUBLISHED: 02-23-2010
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C-reactive protein (CRP) is an independent risk factor for cardiovascular disease and ischemic stroke. CRP serum levels are influenced by genetic variation in the CRP gene. Studies investigating the relationship between ischemic stroke and polymorphisms in the CRP gene produced equivocal results. Here we investigate single-nucleotide polymorphisms (SNPs) in the CRP gene in a large German ischemic stroke sample.
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Susceptibility genes and progression in age-related maculopathy: a study of single eyes.
Invest. Ophthalmol. Vis. Sci.
PUBLISHED: 09-24-2009
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The specific role of single-nucleotide polymorphisms (SNPs) in the progression of age-related maculopathy (AMD) is not clearly understood. The present study was conducted to investigated whether variants in three susceptibility genes are differentially associated with progression to early and late AMD.
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Fibrinogen alpha and gamma genes and factor VLeiden in children with thromboembolism: results from 2 family-based association studies.
Blood
PUBLISHED: 06-10-2009
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Previous case-control studies showed that genetic variation in the fibrinogen gamma gene (FGG) increased the risk for deep vein thrombosis (VT) in adults. We investigated the association between the fibrinogen alpha (FGA) and FGG haplotypes, the factor V(Leiden)-mutation, and pediatric VT and thromboembolic stroke (TS) in 2 independent study samples. Association analysis revealed that the FGA-H1 and FGG-H2 haplotypes were significantly overtransmitted to VT patients (FGA-H1, P = .05; FGG: H2, P = .032). In contrast, the FGG-H3 haplotype was undertransmitted (P = .022). In an independent study sample, FGA-H1 (P = .008) and FGG-H2 (P = .05) were significantly associated with TS. The association of FGA and FGG haplotypes with VT was more pronounced in FV(Leiden)-negative families (FGA-H1, P = .001; FGG-H2, P = .001), indicating a genetic interaction between both risk factors. The risk-conferring FGG-H2 and the protective FGG-H3 haplotypes correlated with low (FGG-H2) and high (FGG-H3) levels of the gamma chain variant, respectively. These results provide independent and novel evidence that FGA-H1 and FGG-H2 variants are associated with an increased risk of VT and TS in children. The observed negative correlation of genetic VT risk with the plasma levels of the fibrinogen gamma variant suggests that FGG-H2 and -H3 haplotypes modify thrombosis risk by controlling the level of this FGG splice isoform.
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Nexilin mutations destabilize cardiac Z-disks and lead to dilated cardiomyopathy.
Nat. Med.
PUBLISHED: 06-02-2009
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Z-disks, the mechanical integration sites of heart and skeletal muscle cells, link anchorage of myofilaments to force reception and processing. The key molecules that enable the Z-disk to persistently withstand the extreme mechanical forces during muscle contraction have not yet been identified. Here we isolated nexilin (encoded by NEXN) as a novel Z-disk protein. Loss of nexilin in zebrafish led to perturbed Z-disk stability and heart failure. To evaluate the role of nexilin in human heart failure, we performed a genetic association study on individuals with dilated cardiomyopathy and found several mutations in NEXN associated with the disease. Nexilin mutation carriers showed the same cardiac Z-disk pathology as observed in nexilin-deficient zebrafish. Expression in zebrafish of nexilin proteins encoded by NEXN mutant alleles induced Z-disk damage and heart failure, demonstrating a dominant-negative effect and confirming the disease-causing nature of these mutations. Increasing mechanical strain aggravated Z-disk damage in nexilin-deficient skeletal muscle, implying a unique role of nexilin in protecting Z-disks from mechanical trauma.
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Phosducin influences sympathetic activity and prevents stress-induced hypertension in humans and mice.
J. Clin. Invest.
PUBLISHED: 05-19-2009
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Hypertension and its complications represent leading causes of morbidity and mortality. Although the cause of hypertension is unknown in most patients, genetic factors are recognized as contributing significantly to an individuals lifetime risk of developing the condition. Here, we investigated the role of the G protein regulator phosducin (Pdc) in hypertension. Mice with a targeted deletion of the gene encoding Pdc (Pdc-/- mice) had increased blood pressure despite normal cardiac function and vascular reactivity, and displayed elevated catecholamine turnover in the peripheral sympathetic system. Isolated postganglionic sympathetic neurons from Pdc-/- mice showed prolonged action potential firing after stimulation with acetylcholine and increased firing frequencies during membrane depolarization. Furthermore, Pdc-/- mice displayed exaggerated increases in blood pressure in response to post-operative stress. Candidate gene-based association studies in 2 different human populations revealed several SNPs in the PDC gene to be associated with stress-dependent blood pressure phenotypes. Individuals homozygous for the G allele of an intronic PDC SNP (rs12402521) had 12-15 mmHg higher blood pressure than those carrying the A allele. These findings demonstrate that PDC is an important modulator of sympathetic activity and blood pressure and may thus represent a promising target for treatment of stress-dependent hypertension.
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Platelet reactivity and clopidogrel resistance are associated with the H2 haplotype of the P2Y12-ADP receptor gene.
Int. J. Cardiol.
PUBLISHED: 05-08-2009
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Platelet hyperreactivity was reported in clopidogrel-naiotave carriers of the H2 haplotype of the P2Y(12) platelet ADP receptor. Here, we studied the influence of this genetic variant on clopidogrel responsiveness.
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Association of the protein Z ATG haplotype with symptomatic nonvascular stroke or thromboembolism in white children: a family-based cohort study.
Blood
PUBLISHED: 04-30-2009
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To clarify the role of protein Z (PZ) in children with stroke/thromboembolism (TE), the present haplotype (HT)-based family study was performed. We genotyped 365 pediatric stroke/TE families (stroke n = 216; TE n = 149) for 4 single nucleotide polymorphisms (SNPs; rs3024718, rs3024731, rs3024772, and rs3024778) to assess the association between genetic variation within a conserved block of linkage disequilibrium harboring the PZ gene and pediatric TE. Association was assessed with use of the transmission disequilibrium test (TDT), corrected for multiple testing (permutation testing: HAPLOVIEW). In addition, PZ antigen was determined and correlated with carriership of PZ haplotypes and the FV G1691A mutation. Rs3024718, rs3024731, and rs3024772 are in tight linkage disequilibrium (LD) and define 4 haplotypes, capturing 97% of the genetic variation for this LD block. HT1 (ATG) was significantly overtransmitted from parents to affected offspring (HT frequency 73.5%, T:U 122:80, chi(2) = 8.791, P = .003). The ATG risk haplotype was significantly correlated with greater PZ antigen levels. Multivariate analysis adjusted for age, sex, established thrombophilias, smoking, fibrinogen, and PZ levels revealed a significant association of the ATG haplotype and TE in children (odds ratio [OR] 1.4; 95% confidence interval [95% CI] 1.08-1.93). Our results suggest that the ATG haplotype of the PZ gene is a genetic marker for symptomatic TE in white German children.
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Genetic analysis of salt-sensitive hypertension in Dahl rats reveals a link between cardiac fibrosis and high cholesterol.
Cardiovasc. Res.
PUBLISHED: 03-27-2009
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Previously we confirmed an important role of rat chromosome 19 (RNO19) for salt-sensitive hypertension and target organ damage in male Dahl salt-sensitive rats (SS rats). The aim of this study was to further analyse the basis of left ventricular (LV) fibrosis development in both male and female rats in this model. To this end we utilized a consomic SS-19(SHR) rat strain in which RNO19 was transferred from spontaneously hypertensive rats (SHR) into the susceptible background of SS.
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HBEGF, SRA1, and IK: Three cosegregating genes as determinants of cardiomyopathy.
Genome Res.
PUBLISHED: 02-05-2009
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Human dilated cardiomyopathy (DCM), a disorder of the cardiac muscle, causes considerable morbidity and mortality and is one of the major causes of sudden cardiac death. Genetic factors play a role in the etiology and pathogenesis of DCM. Disease-associated genetic variations identified to date have been identified in single families or single sporadic patients and explain a minority of the etiology of DCM. We show that a 600-kb region of linkage disequilibrium (LD) on 5q31.2-3, harboring multiple genes, is associated with cardiomyopathy in three independent Caucasian populations (combined P-value = 0.00087). Functional assessment in zebrafish demonstrates that at least three genes, orthologous to loci in this LD block, HBEGF, IK, and SRA1, result independently in a phenotype of myocardial contractile dysfunction when their expression is reduced with morpholino antisense reagents. Evolutionary analysis across multiple vertebrate genomes suggests that this heart failure-associated LD block emerged by a series of genomic rearrangements across amphibian, avian, and mammalian genomes and is maintained as a cluster in mammals. Taken together, these observations challenge the simple notion that disease phenotypes can be traced to altered function of a single locus within a haplotype and suggest that a more detailed assessment of causality can be necessary.
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Osteopontin gene variation and cardio/cerebrovascular disease phenotypes.
Atherosclerosis
PUBLISHED: 01-22-2009
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We aimed at associating common osteopontin (OPN) gene variants with cardiovascular disease phenotypes.We scanned the OPN gene in 190 chromosomes from myocardial infarction (MI) patients and identified five variants in the promoter, three synonymous and one non-synonymous variant. All variants were investigated in case-control studies for MI (ECTIM: 990 cases, 900 controls) and brain infarction (BI) (GENIC: 466 cases, 444 controls). Promoter variants were functionally analyzed by bandshift assays, the coding D147D [T/C] by Western blot. Allele D147D C was independently and significantly associated with lower apoB levels (P=0.044 [ECTIM] P=0.03 [GENIC]), its allele frequency was significantly lower in patients with BI compared to controls (OR [95% CI] 0.39 [0.20-0.74], P=0.004), and C allele carriers had a significantly lower frequency of presence of carotid plaques (P=0.02). Bandshifts with HepG2 and Ea.hy926 nuclear proteins did not reveal any functionality of promoter variants, whereas the OPN-441C-containing construct resulted in reduced OPN protein expression in Western blots, complying with its potential protective effect on the phenotypes studied.We here provide evidence that a portion of the OPN locus is likely to associate with cardiovascular disease-related phenotypes. However, further experiments are warranted to clarify the functional role of OPN variants.
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Genome-wide association of early-onset myocardial infarction with single nucleotide polymorphisms and copy number variants.
, Sekar Kathiresan, Benjamin F Voight, Shaun Purcell, Kiran Musunuru, Diego Ardissino, Pier M Mannucci, Sonia Anand, James C Engert, Nilesh J Samani, Heribert Schunkert, Jeanette Erdmann, Muredach P Reilly, Daniel J Rader, Thomas Morgan, John A Spertus, Monika Stoll, Domenico Girelli, Pascal P McKeown, Chris C Patterson, David S Siscovick, Christopher J O'Donnell, Roberto Elosua, Leena Peltonen, Veikko Salomaa, Stephen M Schwartz, Olle Melander, David Altshuler, Pier Angelica Merlini, Carlo Berzuini, Luisa Bernardinelli, Flora Peyvandi, Marco Tubaro, Patrizia Celli, Maurizio Ferrario, Raffaela Fetiveau, Nicola Marziliano, Giorgio Casari, Michele Galli, Flavio Ribichini, Marco Rossi, Francesco Bernardi, Pietro Zonzin, Alberto Piazza, Jean Yee, Yechiel Friedlander, Jaume Marrugat, Gavin Lucas, Isaac Subirana, Joan Sala, Rafael Ramos, James B Meigs, Gordon Williams, David M Nathan, Calum A MacRae, Aki S Havulinna, Göran Berglund, Joel N Hirschhorn, Rosanna Asselta, Stefano Duga, Marta Spreafico, Mark J Daly, James Nemesh, Joshua M Korn, Steven A McCarroll, Aarti Surti, Candace Guiducci, Lauren Gianniny, Daniel Mirel, Melissa Parkin, Noel Burtt, Stacey B Gabriel, John R Thompson, Peter S Braund, Benjamin J Wright, Anthony J Balmforth, Stephen G Ball, Alistair S Hall, Patrick Linsel-Nitschke, Wolfgang Lieb, Andreas Ziegler, Inke König, Christian Hengstenberg, Marcus Fischer, Klaus Stark, Anika Grosshennig, Michael Preuss, H-Erich Wichmann, Stefan Schreiber, Willem Ouwehand, Panos Deloukas, Michael Scholz, Francois Cambien, Mingyao Li, Zhen Chen, Robert Wilensky, William Matthai, Atif Qasim, Hakon H Hakonarson, Joe Devaney, Mary-Susan Burnett, Augusto D Pichard, Kenneth M Kent, Lowell Satler, Joseph M Lindsay, Ron Waksman, Christopher W Knouff, Dawn M Waterworth, Max C Walker, Vincent Mooser, Stephen E Epstein, Thomas Scheffold, Klaus Berger, Andreas Huge, Nicola Martinelli, Oliviero Olivieri, Roberto Corrocher, Pascal McKeown, Erdmann Erdmann, Inke R König, Hilma Holm, Gudmar Thorleifsson, Unnur Thorsteinsdottir, Kari Stefansson, Ron Do, Changchun Xie, David Siscovick.
Nat. Genet.
PUBLISHED: 01-16-2009
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We conducted a genome-wide association study testing single nucleotide polymorphisms (SNPs) and copy number variants (CNVs) for association with early-onset myocardial infarction in 2,967 cases and 3,075 controls. We carried out replication in an independent sample with an effective sample size of up to 19,492. SNPs at nine loci reached genome-wide significance: three are newly identified (21q22 near MRPS6-SLC5A3-KCNE2, 6p24 in PHACTR1 and 2q33 in WDR12) and six replicated prior observations (9p21, 1p13 near CELSR2-PSRC1-SORT1, 10q11 near CXCL12, 1q41 in MIA3, 19p13 near LDLR and 1p32 near PCSK9). We tested 554 common copy number polymorphisms (>1% allele frequency) and none met the pre-specified threshold for replication (P < 10(-3)). We identified 8,065 rare CNVs but did not detect a greater CNV burden in cases compared to controls, in genes compared to the genome as a whole, or at any individual locus. SNPs at nine loci were reproducibly associated with myocardial infarction, but tests of common and rare CNVs failed to identify additional associations with myocardial infarction risk.
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Role of reduced ADAMTS13 in arterial ischemic stroke: a pediatric cohort study.
Ann. Neurol.
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Previous studies in adults and mice have implicated ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13), also known as von Willebrand factor (VWF)-cleaving protease, as a protective factor for stroke. Here we investigated ADAMTS13 in 208 pediatric patients with arterial ischemic stroke (AIS) and 125 population-based control children in a frequency-matched case-control study.
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DNA methylation changes are a late event in acute promyelocytic leukemia and coincide with loss of transcription factor binding.
Blood
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The origin of aberrant DNA methylation in cancer remains largely unknown. In the present study, we elucidated the DNA methylome in primary acute promyelocytic leukemia (APL) and the role of promyelocytic leukemia-retinoic acid receptor ? (PML-RAR?) in establishing these patterns. Cells from APL patients showed increased genome-wide DNA methylation with higher variability than healthy CD34(+) cells, promyelocytes, and remission BM cells. A core set of differentially methylated regions in APL was identified. Age at diagnosis, Sanz score, and Flt3-mutation status characterized methylation subtypes. Transcription factor-binding sites (eg, the c-myc-binding sites) were associated with low methylation. However, SUZ12- and REST-binding sites identified in embryonic stem cells were preferentially DNA hypermethylated in APL cells. Unexpectedly, PML-RAR?-binding sites were also protected from aberrant DNA methylation in APL cells. Consistent with this, myeloid cells from preleukemic PML-RAR? knock-in mice did not show altered DNA methylation and the expression of PML-RAR? in hematopoietic progenitor cells prevented differentiation without affecting DNA methylation. Treatment of APL blasts with all-trans retinoic acid also did not result in immediate DNA methylation changes. The results of the present study suggest that aberrant DNA methylation is associated with leukemia phenotype but is not required for PML-RAR?-mediated initiation of leukemogenesis.
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Increased afterload induces pathological cardiac hypertrophy: a new in vitro model.
Basic Res. Cardiol.
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Increased afterload results in pathological cardiac hypertrophy, the most important risk factor for the development of heart failure. Current in vitro models fall short in deciphering the mechanisms of hypertrophy induced by afterload enhancement. The aim of this study was to develop an experimental model that allows investigating the impact of afterload enhancement (AE) on work-performing heart muscles in vitro. Fibrin-based engineered heart tissue (EHT) was cast between two hollow elastic silicone posts in a 24-well cell culture format. After 2 weeks, the posts were reinforced with metal braces, which markedly increased afterload of the spontaneously beating EHTs. Serum-free, triiodothyronine-, and hydrocortisone-supplemented medium conditions were established to prevent undefined serum effects. Control EHTs were handled identically without reinforcement. Endothelin-1 (ET-1)- or phenylephrine (PE)-stimulated EHTs served as positive control for hypertrophy. Cardiomyocytes in EHTs enlarged by 28.4 % under AE and to a similar extent by ET-1- or PE-stimulation (40.6 or 23.6 %), as determined by dystrophin staining. Cardiomyocyte hypertrophy was accompanied by activation of the fetal gene program, increased glucose consumption, and increased mRNA levels and extracellular deposition of collagen-1. Importantly, afterload-enhanced EHTs exhibited reduced contractile force and impaired diastolic relaxation directly after release of the metal braces. These deleterious effects of afterload enhancement were preventable by endothelin-A, but not endothelin-B receptor blockade. Sustained afterload enhancement of EHTs alone is sufficient to induce pathological cardiac remodeling with reduced contractile function and increased glucose consumption. The model will be useful to investigate novel therapeutic approaches in a simple and fast manner.
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A genome-wide association study identifies a gene network of ADAMTS genes in the predisposition to pediatric stroke.
Blood
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Pediatric stroke is a rare but highly penetrant disease with a strong genetic background. Although there are an increasing number of genome-wide association studies (GWASs) for stroke in adults, such studies for stroke of pediatric onset are lacking. Here we report the results of the first GWAS on pediatric stroke using a large cohort of 270 family-based trios. GWAS was performed using the Illumina 370 CNV single nucleotide polymorphisms array and analyzed using the transmission disequilibrium test as implemented in PLINK. An enrichment analysis was performed to identify additional true association signals among lower P value signals and searched for cumulatively associated genes within protein interaction data using dmGWAS. We observed clustering of association signals in 4 genes belonging to one family of metalloproteinases at high (ADAMTS12, P = 2.9 × 10(-6); ADAMTS2, P = 8.0 × 10(-6)) and moderate (ADAMTS13, P = 9.3 × 10(-4); ADAMTS17, P = 8.5 × 10(-4)) significance levels. Over-representation and gene-network analyses highlight the importance of the extracellular matrix in conjunction with members of the phosphoinositide and calcium signaling pathways in the susceptibility for pediatric stroke. Associated extracellular matrix components, such as ADAMTS proteins, in combination with misbalanced coagulation signals as unveiled by gene network analysis suggest a major role of postnatal vascular injury with subsequent thrombus formation as the leading cause of pediatric stroke.
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Apolipoprotein(a) genetic sequence variants associated with systemic atherosclerosis and coronary atherosclerotic burden but not with venous thromboembolism.
J. Am. Coll. Cardiol.
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The purpose of this study is investigate the effects of variants in the apolipoprotein(a) gene (LPA) on vascular diseases with different atherosclerotic and thrombotic components.
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Selective loss of noradrenaline exacerbates early cognitive dysfunction and synaptic deficits in APP/PS1 mice.
Biol. Psychiatry
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Degeneration of the locus coeruleus (LC), the major noradrenergic nucleus in the brain, occurs early and is ubiquitous in Alzheimers disease (AD). Experimental lesions to the LC exacerbate AD-like neuropathology and cognitive deficits in several transgenic mouse models of AD. Because the LC contains multiple neuromodulators known to affect amyloid ? toxicity and cognitive function, the specific role of noradrenaline (NA) in AD is not well understood.
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Genome-wide patterns of standing genetic variation in a marine population of three-spined sticklebacks.
Mol. Ecol.
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Since the end of the Pleistocene, the three-spined stickleback (Gasterosteus aculeatus) has repeatedly colonized and adapted to various freshwater habitats probably originating from ancestral marine populations. Standing genetic variation and the underlying genomic architecture both have been speculated to contribute to recent adaptive radiations of sticklebacks. Here, we expand on the current genomic resources of this fish by providing extensive genome-wide variation data from six individuals from a marine (North Sea) stickleback population. Using next-generation sequencing and a combination of paired-end and mate-pair libraries, we detected a wide size range of genetic variation. Among the six individuals, we found more than 7% of the genome is polymorphic, consisting of 2599111 SNPs, 233464 indels and structural variation (SV) (>50 bp) such as 1054 copy-number variable regions (deletions and duplications) and 48 inversions. Many of these polymorphisms affect gene and coding sequences. Based on SNP diversity, we determined outlier regions concordant with signatures expected under adaptive evolution. As some of these outliers overlap with pronounced regions of copy-number variation, we propose the consideration of such SV when analysing SNP data from re-sequencing approaches. We further discuss the value of this resource on genome-wide variation for further investigation upon the relative contribution of standing variation on the parallel evolution of sticklebacks and the importance of the genomic architecture in adaptive radiation.
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Plasma HDL cholesterol and risk of myocardial infarction: a mendelian randomisation study.
Benjamin F Voight, Gina M Peloso, Marju Orho-Melander, Ruth Frikke-Schmidt, Maja Barbalic, Majken K Jensen, George Hindy, Hilma Holm, Eric L Ding, Toby Johnson, Heribert Schunkert, Nilesh J Samani, Robert Clarke, Jemma C Hopewell, John F Thompson, Mingyao Li, Gudmar Thorleifsson, Christopher Newton-Cheh, Kiran Musunuru, James P Pirruccello, Danish Saleheen, Li Chen, Alexandre F R Stewart, Arne Schillert, Unnur Thorsteinsdottir, Gudmundur Thorgeirsson, Sonia Anand, James C Engert, Thomas Morgan, John Spertus, Monika Stoll, Klaus Berger, Nicola Martinelli, Domenico Girelli, Pascal P McKeown, Christopher C Patterson, Stephen E Epstein, Joseph Devaney, Mary-Susan Burnett, Vincent Mooser, Samuli Ripatti, Ida Surakka, Markku S Nieminen, Juha Sinisalo, Marja-Liisa Lokki, Markus Perola, Aki Havulinna, Ulf de Faire, Bruna Gigante, Erik Ingelsson, Tanja Zeller, Philipp Wild, Paul I W de Bakker, Olaf H Klungel, Anke-Hilse Maitland-van der Zee, Bas J M Peters, Anthonius de Boer, Diederick E Grobbee, Pieter W Kamphuisen, Vera H M Deneer, Clara C Elbers, N Charlotte Onland-Moret, Marten H Hofker, Cisca Wijmenga, W M Monique Verschuren, Jolanda M A Boer, Yvonne T van der Schouw, Asif Rasheed, Philippe Frossard, Serkalem Demissie, Cristen Willer, Ron Do, José M Ordovás, Gonçalo R Abecasis, Michael Boehnke, Karen L Mohlke, Mark J Daly, Candace Guiducci, Noel P Burtt, Aarti Surti, Elena González, Shaun Purcell, Stacey Gabriel, Jaume Marrugat, John Peden, Jeanette Erdmann, Patrick Diemert, Christina Willenborg, Inke R König, Marcus Fischer, Christian Hengstenberg, Andreas Ziegler, Ian Buysschaert, Diether Lambrechts, Frans Van de Werf, Keith A Fox, Nour Eddine El Mokhtari, Diana Rubin, Jürgen Schrezenmeir, Stefan Schreiber, Arne Schäfer, John Danesh, Stefan Blankenberg, Robert Roberts, Ruth McPherson, Hugh Watkins, Alistair S Hall, Kim Overvad, Eric Rimm, Eric Boerwinkle, Anne Tybjaerg-Hansen, L Adrienne Cupples, Muredach P Reilly, Olle Melander, Pier M Mannucci, Diego Ardissino, David Siscovick, Roberto Elosua, Kari Stefansson, Christopher J O'Donnell, Veikko Salomaa, Daniel J Rader, Leena Peltonen, Stephen M Schwartz, David Altshuler, Sekar Kathiresan.
Lancet
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High plasma HDL cholesterol is associated with reduced risk of myocardial infarction, but whether this association is causal is unclear. Exploiting the fact that genotypes are randomly assigned at meiosis, are independent of non-genetic confounding, and are unmodified by disease processes, mendelian randomisation can be used to test the hypothesis that the association of a plasma biomarker with disease is causal.
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Evolutionary dynamics of co-segregating gene clusters associated with complex diseases.
PLoS ONE
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The distribution of human disease-associated mutations is not random across the human genome. Despite the fact that natural selection continually removes disease-associated mutations, an enrichment of these variants can be observed in regions of low recombination. There are a number of mechanisms by which such a clustering could occur, including genetic perturbations or demographic effects within different populations. Recent genome-wide association studies (GWAS) suggest that single nucleotide polymorphisms (SNPs) associated with complex disease traits are not randomly distributed throughout the genome, but tend to cluster in regions of low recombination.
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Inherited thrombophilia in children with venous thromboembolism and the familial risk of thromboembolism: an observational study.
Blood
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Screening for inherited thrombophilia (IT) is controversial; persons at high risk for venous thromboembolism (VTE) who benefit from screening need to be identified. We tested 533 first- and second-degree relatives of 206 pediatric VTE patients for IT (antithrombin, protein C, protein S, factor V G1691A, factor II G20210A) and determined the incidence of symptomatic VTE relative to their IT status. The risk for VTE was significantly increased among family members with, versus without, IT (hazard ratio = 7.6; 95% confidence interval [CI], 4.0-14.5; P < .001) and highest among carriers of antithrombin, protein C, or protein S deficiency (hazard ratio = 25.7; 95% CI, 12.2-54.2; P < .001). Annual incidences of VTE were 2.82% (95% CI, 1.63%-4.80%) among family members found to be carriers of antithrombin, protein C, or protein S deficiency, 0.42% (0.12%-0.53%) for factor II G202010A, 0.25% (0.12%-0.53%) for factor V G1691A, and 0.10% (0.06%-0.17%) in relatives with no IT. Given the high absolute risk of VTE in relatives with protein C, protein S, and antithrombin deficiency, we suggest screening for these forms of hereditary thrombophilia in children with VTE and their relatives. Interventional studies are required to assess whether thromboembolism can be prevented in this high-risk population.
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Promotor polymorphisms of plasminogen activator inhibitor-1 and other thrombophilic genotypes in cerebral venous thrombosis: a case-control study in adults.
J. Neurol.
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Plasminogen activator inhibitor 1 (PAI-1) is the main inhibitor of tissue-type and urokinase-type plasminogen activator. A 4G/5G polymorphism in the promoter region of the PAI-1 gene has been reported to enhance the plasma levels of PAI-1. In particular, the 4G allele (guanosine deletion) has been linked with increased plasma PAI-1 levels, which may lead to impaired activity of the fibrinolytic system, thus increasing the incidence of thrombotic events. The aim of this case-control study was to analyze whether variants of the PAI-1 promotor genotype 4G/4G, 4G/5G and 5G/5G, in particular the 4G/5G-variant, constitute an independent risk factor of cerebral venous thrombosis (CVT). A total of 136 consecutive patients with proven CVT were compared to 1,054 DNA specimens of healthy controls from a population-based cohort. PAI-1 promotor polymorphisms were evaluated using polymerase chain reaction. No significant association of CVT with PAI-1 4G/5G was found in either the additive (OR 1.04; 95 % CI 0.78-1.38) or in the dominant model (OR 1.24; 95 % CI 0.72-2.13). Also, the prevalence of the other genotypes (4G/4G and 5G/5G) in patients was not significantly different from controls. When considering the variants of the PAI-1 promoter genotype in combination with known genetical thrombophilias, no differences were found either. As was expected, the prothrombin (G20210A) genotype was confirmed as an independent risk factor for CVT. We conclude that the 4G allele of the PAI-1 polymorphism does not increase the risk of CVT in adults.
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Genetic variants implicated in telomere length associated with left ventricular function in patients with hypertension and cardiac organ damage.
J. Mol. Med.
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Telomere length has emerged as a biological correlate for ageing, which in turn is a risk factor for the manifestation of cardiovascular diseases. This study investigated the relation between leucocyte telomere length (LTL) and its genetic background to cardiac structure and function in patients with arterial hypertension. We analysed a cohort of 1,106 treated hypertensive patients (83.3% males; mean age, 57.9?±?9.8 years) with an ejection fraction (EF) over 40% and documented cardiovascular disease or target organ damage. LTL and genotypes of single nucleotide polymorphisms (SNPs), previously implicated in LTL, were determined by real-time PCR. The mean left ventricular mass index (LVMI) and EF were 51.8? ±? 21.0 g/H2.7 and 61.1 ?±? 9.6%, respectively. In multivariate adjusted analysis, a 1.5-fold LTL was positively related with a 2.2% increase of LVMI (CI?=?0.1% to 4.2%, p?=?0.044) and an absolute increase in EF of 0.6% (CI?=?0.1% to 1.1%, p?=?0.028). One SNP near TERC (rs16847897) showed a significant absolute difference in EF dependent on allele status (rs16847897, G allele 2.7%; CI?=?0.7% to 4.6%; p raw?=?0.008, p mt?=?0.048, after adjustment for multiple testing). This applied also for two SNPs in BICD1 (rs2630578, C allele ?1.8%; CI?=??2.8% to ?0.7%; p raw?=?0.002, p mt?=?0.018; rs1151026, G allele ?1.9%, CI?=??3.0% to ?0.8%; p raw?
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