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Featured researches published by Jan Haas.


Nature Communications | 2012

New insights into the Tyrolean Iceman's origin and phenotype as inferred by whole-genome sequencing

Andreas Keller; Angela Graefen; Markus Ball; Mark Matzas; Valesca Boisguerin; Frank Maixner; Petra Leidinger; Christina Backes; Rabab Khairat; Michael Forster; Björn Stade; Andre Franke; Jens Mayer; Jessica Spangler; Stephen F. McLaughlin; Minita Shah; Clarence Lee; Timothy T. Harkins; Alexander Sartori; Andres Moreno-Estrada; Brenna M. Henn; Martin Sikora; Ornella Semino; Jacques Chiaroni; Siiri Rootsi; Natalie M. Myres; Vicente M. Cabrera; Peter A. Underhill; Carlos Bustamante; Eduard Egarter Vigl

The Tyrolean Iceman, a 5,300-year-old Copper age individual, was discovered in 1991 on the Tisenjoch Pass in the Italian part of the Ötztal Alps. Here we report the complete genome sequence of the Iceman and show 100% concordance between the previously reported mitochondrial genome sequence and the consensus sequence generated from our genomic data. We present indications for recent common ancestry between the Iceman and present-day inhabitants of the Tyrrhenian Sea, that the Iceman probably had brown eyes, belonged to blood group O and was lactose intolerant. His genetic predisposition shows an increased risk for coronary heart disease and may have contributed to the development of previously reported vascular calcifications. Sequences corresponding to ~60% of the genome of Borrelia burgdorferi are indicative of the earliest human case of infection with the pathogen for Lyme borreliosis.


Genome Biology | 2013

A blood based 12-miRNA signature of Alzheimer disease patients.

Petra Leidinger; Christina Backes; Stephanie Deutscher; Katja Schmitt; Sabine C. Mueller; Karen Frese; Jan Haas; Klemens Ruprecht; Friedemann Paul; Cord F. Stähler; Christoph J. G. Lang; Benjamin Meder; Tamas Bartfai; Eckart Meese; Andreas Keller

BackgroundAlzheimer disease (AD) is the most common form of dementia but the identification of reliable, early and non-invasive biomarkers remains a major challenge. We present a novel miRNA-based signature for detecting AD from blood samples.ResultsWe apply next-generation sequencing to miRNAs from blood samples of 48 AD patients and 22 unaffected controls, yielding a total of 140 unique mature miRNAs with significantly changed expression levels. Of these, 82 have higher and 58 have lower abundance in AD patient samples. We selected a panel of 12 miRNAs for an RT-qPCR analysis on a larger cohort of 202 samples, comprising not only AD patients and healthy controls but also patients with other CNS illnesses. These included mild cognitive impairment, which is assumed to represent a transitional period before the development of AD, as well as multiple sclerosis, Parkinson disease, major depression, bipolar disorder and schizophrenia. miRNA target enrichment analysis of the selected 12 miRNAs indicates an involvement of miRNAs in nervous system development, neuron projection, neuron projection development and neuron projection morphogenesis. Using this 12-miRNA signature, we differentiate between AD and controls with an accuracy of 93%, a specificity of 95% and a sensitivity of 92%. The differentiation of AD from other neurological diseases is possible with accuracies between 74% and 78%. The differentiation of the other CNS disorders from controls yields even higher accuracies.ConclusionsThe data indicate that deregulated miRNAs in blood might be used as biomarkers in the diagnosis of AD or other neurological diseases.


European Heart Journal | 2015

Atlas of the clinical genetics of human dilated cardiomyopathy

Jan Haas; Karen Frese; Barbara Peil; Wanda Kloos; Andreas Keller; Rouven Nietsch; Zhu Feng; Sabine Müller; Elham Kayvanpour; Britta Vogel; Farbod Sedaghat-Hamedani; Wei Keat Lim; Xiaohong Zhao; Dmitriy Fradkin; Doreen Köhler; Simon Fischer; Jennifer Franke; Sabine Marquart; Ioana Barb; Daniel Tian Li; Ali Amr; Philipp Ehlermann; Derliz Mereles; Tanja Weis; Sarah Hassel; Andreas Kremer; Vanessa King; Emil Wirsz; Richard Isnard; Michel Komajda

AIM Numerous genes are known to cause dilated cardiomyopathy (DCM). However, until now technological limitations have hindered elucidation of the contribution of all clinically relevant disease genes to DCM phenotypes in larger cohorts. We now utilized next-generation sequencing to overcome these limitations and screened all DCM disease genes in a large cohort. METHODS AND RESULTS In this multi-centre, multi-national study, we have enrolled 639 patients with sporadic or familial DCM. To all samples, we applied a standardized protocol for ultra-high coverage next-generation sequencing of 84 genes, leading to 99.1% coverage of the target region with at least 50-fold and a mean read depth of 2415. In this well characterized cohort, we find the highest number of known cardiomyopathy mutations in plakophilin-2, myosin-binding protein C-3, and desmoplakin. When we include yet unknown but predicted disease variants, we find titin, plakophilin-2, myosin-binding protein-C 3, desmoplakin, ryanodine receptor 2, desmocollin-2, desmoglein-2, and SCN5A variants among the most commonly mutated genes. The overlap between DCM, hypertrophic cardiomyopathy (HCM), and channelopathy causing mutations is considerably high. Of note, we find that >38% of patients have compound or combined mutations and 12.8% have three or even more mutations. When comparing patients recruited in the eight participating European countries we find remarkably little differences in mutation frequencies and affected genes. CONCLUSION This is to our knowledge, the first study that comprehensively investigated the genetics of DCM in a large-scale cohort and across a broad gene panel of the known DCM genes. Our results underline the high analytical quality and feasibility of Next-Generation Sequencing in clinical genetic diagnostics and provide a sound database of the genetic causes of DCM.


Basic Research in Cardiology | 2011

MicroRNA signatures in total peripheral blood as novel biomarkers for acute myocardial infarction.

Benjamin Meder; Andreas Keller; Britta Vogel; Jan Haas; Farbod Sedaghat-Hamedani; Elham Kayvanpour; Steffen Just; Anne Borries; Jessica Rudloff; Petra Leidinger; Eckart Meese; Hugo A. Katus; Wolfgang Rottbauer

MicroRNAs (miRNAs) are important regulators of adaptive and maladaptive responses in cardiovascular diseases and hence are considered to be potential therapeutical targets. However, their role as novel biomarkers for the diagnosis of cardiovascular diseases still needs to be systematically evaluated. We assessed here for the first time whole-genome miRNA expression in peripheral total blood samples of patients with acute myocardial infarction (AMI). We identified 121 miRNAs, which are significantly dysregulated in AMI patients in comparison to healthy controls. Among these, miR-1291 and miR-663b show the highest sensitivity and specificity for the discrimination of cases from controls. Using a novel self-learning pattern recognition algorithm, we identified a unique signature of 20 miRNAs that predicts AMI with even higher power (specificity 96%, sensitivity 90%, and accuracy 93%). In addition, we show that miR-30c and miR-145 levels correlate with infarct sizes estimated by Troponin T release. The here presented study shows that single miRNAs and especially miRNA signatures derived from peripheral blood, could be valuable novel biomarkers for cardiovascular diseases.


Circulation-cardiovascular Genetics | 2011

Targeted Next-Generation Sequencing for the Molecular Genetic Diagnostics of Cardiomyopathies

Benjamin Meder; Jan Haas; Andreas Keller; Christiane Heid; Steffen Just; Anne Borries; Valesca Boisguerin; Maren Scharfenberger-Schmeer; Peer F. Stähler; Markus Beier; Dieter Weichenhan; Tim M. Strom; Arne Pfeufer; Bernhard Korn; Hugo A. Katus; Wolfgang Rottbauer

Background—Today, mutations in more than 30 different genes have been found to cause inherited cardiomyopathies, some associated with very poor prognosis. However, because of the genetic heterogeneity and limitations in throughput and scalability of current diagnostic tools up until now, it is hardly possible to genetically characterize patients with cardiomyopathy in a fast, comprehensive, and cost-efficient manner. Methods and Results—We established an array-based subgenomic enrichment followed by next-generation sequencing to detect mutations in patients with hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM). With this approach, we show that the genomic region of interest can be enriched by a mean factor of 2169 compared with the coverage of the whole genome, resulting in high sequence coverage of selected disease genes and allowing us to define the genetic pathogenesis of cardiomyopathies in a single sequencing run. In 6 patients, we detected disease-causing mutations, 2 microdeletions, and 4 point mutations. Furthermore, we identified several novel nonsynonymous variants, which are predicted to be harmful, and hence, might be potential disease mutations or modifiers for DCM or HCM. Conclusions—The approach presented here allows for the first time a comprehensive genetic screening in patients with hereditary DCM or HCM in a fast and cost-efficient manner.


Embo Molecular Medicine | 2013

Alterations in cardiac DNA methylation in human dilated cardiomyopathy.

Jan Haas; Karen Frese; Yoon Jung Park; Andreas Keller; Britta Vogel; Anders M. Lindroth; Dieter Weichenhan; Jennifer Franke; Simon Fischer; Andrea Bauer; Sabine Marquart; Farbod Sedaghat-Hamedani; Elham Kayvanpour; Doreen Köhler; Nadine M. Wolf; Sarah Hassel; Rouven Nietsch; Thomas Wieland; Philipp Ehlermann; Jobst Hendrik Schultz; Andreas Dösch; Derliz Mereles; Stefan E. Hardt; Johannes Backs; Jörg D. Hoheisel; Christoph Plass; Hugo A. Katus; Benjamin Meder

Dilated cardiomyopathies (DCM) show remarkable variability in their age of onset, phenotypic presentation, and clinical course. Hence, disease mechanisms must exist that modify the occurrence and progression of DCM, either by genetic or epigenetic factors that may interact with environmental stimuli. In the present study, we examined genome‐wide cardiac DNA methylation in patients with idiopathic DCM and controls. We detected methylation differences in pathways related to heart disease, but also in genes with yet unknown function in DCM or heart failure, namely Lymphocyte antigen 75 (LY75), Tyrosine kinase‐type cell surface receptor HER3 (ERBB3), Homeobox B13 (HOXB13) and Adenosine receptor A2A (ADORA2A). Mass‐spectrometric analysis and bisulphite‐sequencing enabled confirmation of the observed DNA methylation changes in independent cohorts. Aberrant DNA methylation in DCM patients was associated with significant changes in LY75 and ADORA2A mRNA expression, but not in ERBB3 and HOXB13. In vivo studies of orthologous ly75 and adora2a in zebrafish demonstrate a functional role of these genes in adaptive or maladaptive pathways in heart failure.


European Heart Journal | 2014

A genome-wide association study identifies 6p21 as novel risk locus for dilated cardiomyopathy

Benjamin Meder; Frank Rühle; Tanja Weis; Georg Homuth; Andreas Keller; Jennifer Franke; Barbara Peil; Justo Lorenzo Bermejo; Karen Frese; Andreas Huge; Anika Witten; Britta Vogel; Jan Haas; Uwe Völker; Florian Ernst; Alexander Teumer; Philipp Ehlermann; Christian Zugck; Frauke Friedrichs; Heyo K. Kroemer; Marcus Dörr; Wolfgang Hoffmann; Bernhard Maisch; Sabine Pankuweit; Volker Ruppert; Thomas Scheffold; Uwe Kühl; Hans Peter Schultheiss; Reinhold Kreutz; Georg Ertl

AIMS 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. METHODS AND RESULTS Applying a three-staged study design, we analysed more than 4100 DCM cases and 7600 controls. We identified and successfully replicated multiple single nucleotide polymorphism on chromosome 6p21. In the combined analysis, the most significant association signal was obtained for rs9262636 (P = 4.90 × 10(-9)) located in HCG22, which could again be replicated in an independent cohort. Taking advantage of expression quantitative trait loci (eQTL) as molecular phenotypes, we identified rs9262636 as an eQTL for several closely located genes encoding class I and class II major histocompatibility complex heavy chain receptors. CONCLUSION The present study reveals a novel genetic susceptibility locus that clearly underlines the role of genetically driven, inflammatory processes in the pathogenesis of idiopathic DCM.


Molecular and Cellular Probes | 2011

Next-generation sequencing entering the clinical arena.

Jan Haas; Hugo A. Katus; Benjamin Meder

Over the last decade the genetic etiology of many heritable diseases could be resolved. For heart muscle diseases, so called cardiomyopathies, mutations in more than 40 different genes have been identified. Due to this large genetic heterogeneity and missing of adequate gene-diagnostic tools, most patients are not genetically characterized, which would be important for individualized patient care. Currently, next-generation sequencing technologies are revolutionizing genetic and epigenetic research, since they are capable to produce billions of bases of sequence information in a single experiment. Accordingly, this powerful technology can now also open avenues for genetic diagnostics. The scope of this article is to illustrate technical approaches, clinical applications, and yet unsolved problems of next-generation sequencing entering the clinical arena.


Cardiovascular Research | 2016

A mutation in the glutamate-rich region of RNA-binding motif protein 20 causes dilated cardiomyopathy through missplicing of titin and impaired Frank–Starling mechanism

Abdelaziz Beqqali; Ilse A. E. Bollen; T.B. Rasmussen; Maarten M.G. van den Hoogenhof; Hanneke W. M. van Deutekom; Sebastian Schafer; Jan Haas; Benjamin Meder; Keld E. Sørensen; Ralph J. van Oort; Jens Mogensen; Norbert Hubner; Esther E. Creemers; Jolanda van der Velden; Yigal M. Pinto

AIM Mutations in the RS-domain of RNA-binding motif protein 20 (RBM20) have recently been identified to segregate with aggressive forms of familial dilated cardiomyopathy (DCM). Loss of RBM20 in rats results in missplicing of the sarcomeric gene titin (TTN). The functional and physiological consequences of RBM20 mutations outside the mutational hotspot of RBM20 have not been explored to date. In this study, we investigated the pathomechanism of DCM caused by a novel RBM20 mutation in human cardiomyocytes. METHODS AND RESULTS We identified a family with DCM carrying a mutation (RBM20(E913K/+)) in a glutamate-rich region of RBM20. Western blot analysis of endogenous RBM20 protein revealed strongly reduced protein levels in the heart of an RBM20(E913K/+ )carrier. RNA deep-sequencing demonstrated massive inclusion of exons coding for the spring region of titin in the RBM20(E913K/+ )carrier. Titin isoform analysis revealed a dramatic shift from the less compliant N2B towards the highly compliant N2BA isoforms in RBM20(E913K/+ )heart. Moreover, an increased sarcomere resting-length was observed in single cardiomyocytes and isometric force measurements revealed an attenuated Frank-Starling mechanism (FSM), which was rescued by protein kinase A treatment. CONCLUSION A mutation outside the mutational hotspot of RBM20 results in haploinsufficiency of RBM20. This leads to disturbed alternative splicing of TTN, resulting in a dramatic shift to highly compliant titin isoforms and an impaired FSM. These effects may contribute to the early onset, and malignant course of DCM caused by RBM20 mutations. Altogether, our results demonstrate that heterozygous loss of RBM20 suffices to profoundly impair myocyte biomechanics by its disturbance of TTN splicing.


Clinical Chemistry | 2014

Influence of the Confounding Factors Age and Sex on MicroRNA Profiles from Peripheral Blood

Benjamin Meder; Christina Backes; Jan Haas; Petra Leidinger; Cord F. Stähler; Thomas Großmann; Britta Vogel; Karen Frese; Evangelos Giannitsis; Hugo A. Katus; Eckart Meese; Andreas Keller

BACKGROUND MicroRNAs (miRNAs) measured from blood samples are promising minimally invasive biomarker candidates that have been extensively studied in several case-control studies. However, the influence of age and sex as confounding variables remains largely unknown. METHODS We systematically explored the impact of age and sex on miRNAs in a cohort of 109 physiologically unaffected individuals whose blood was characterized by microarray technology (stage 1). We also investigated an independent cohort from a different institution consisting of 58 physiologically unaffected individuals having a similar mean age but with a smaller age distribution. These samples were measured by use of high-throughput sequencing (stage 2). RESULTS We detected 318 miRNAs that were significantly correlated with age in stage 1 and, after adjustment for multiple testing of 35 miRNAs, remained statistically significant. Regarding sex, 144 miRNAs showed significant dysregulation. Here, no miRNA remained significant after adjustment for multiple testing. In the high-throughput datasets of stage 2, we generally observed a smaller number of significant associations, mainly as an effect of the smaller cohort size and age distribution. Nevertheless, we found 7 miRNAs that were correlated with age, of which 5 were concordant with stage 1. CONCLUSIONS The age distribution of individuals recruited for case-control studies needs to be carefully considered, whereas sex may be less confounding. To support the translation of miRNAs into clinical application, we offer a web-based application (http://www.ccb.uni-saarland.de/mirnacon) to test individual miRNAs or miRNA signatures for their likelihood of being influenced.

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Ali Amr

Heidelberg University

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