The Danish National Research Foundation Center for Cardiac Arrhythmia

Copenhagen, Denmark

The Danish National Research Foundation Center for Cardiac Arrhythmia

Copenhagen, Denmark

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PubMed | University Utrecht, Leiden University, The Danish National Research Foundation Center for Cardiac Arrhythmia, Erasmus Medical Center and 7 more.
Type: Journal Article | Journal: Nature methods | Year: 2014

Genome-wide association studies (GWAS) have identified thousands of loci associated with complex traits, but it is challenging to pinpoint causal genes in these loci and to exploit subtle association signals. We used tissue-specific quantitative interaction proteomics to map a network of five genes involved in the Mendelian disorder long QT syndrome (LQTS). We integrated the LQTS network with GWAS loci from the corresponding common complex trait, QT-interval variation, to identify candidate genes that were subsequently confirmed in Xenopus laevis oocytes and zebrafish. We used the LQTS protein network to filter weak GWAS signals by identifying single-nucleotide polymorphisms (SNPs) in proximity to genes in the network supported by strong proteomic evidence. Three SNPs passing this filter reached genome-wide significance after replication genotyping. Overall, we present a general strategy to propose candidates in GWAS loci for functional studies and to systematically filter subtle association signals using tissue-specific quantitative interaction proteomics.


Olesen M.S.,The Danish National Research Foundation Center for Cardiac Arrhythmia | Olesen M.S.,Copenhagen University | Bentzen B.H.,The Danish National Research Foundation Center for Cardiac Arrhythmia | Bentzen B.H.,Copenhagen University | And 15 more authors.
BMC Medical Genetics | Year: 2012

Background: Atrial fibrillation (AF) is the most common arrhythmia. The potassium current I Ksis essential for cardiac repolarization. Gain-of-function mutations in K V7.1, the pore-forming α-subunit of the I Kschannel, have been associated with AF. We hypothesized that early-onset lone AF is associated with mutations in the I Kschannel regulatory subunit KCNE1.Methods: In 209 unrelated early-onset lone AF patients (< 40 years) the entire coding sequence of KCNE1 was bidirectionally sequenced. We analyzed the identified KCNE1 mutants electrophysiologically in heterologous expression systems.Results: Two non-synonymous mutations G25V and G60D were found in KCNE1 that were not present in the control group (n = 432 alleles) and that have not previously been reported in any publicly available databases or in the exom variant server holding exom data from more than 10.000 alleles. Proband 1 (female, age 45, G25V) had onset of paroxysmal AF at the age of 39 years. Proband 2 (G60D) was diagnosed with lone AF at the age of 33 years. The patient has inherited the mutation from his mother, who also has AF. Both probands had no mutations in genes previously associated with AF. In heterologous expression systems, both mutants showed significant gain-of-function for I Ksboth with respect to steady-state current levels, kinetic parameters, and heart rate-dependent modulation.Conclusions: Mutations in K V7.1 leading to gain-of-function of I Kscurrent have previously been described in lone AF, yet this is the first time a mutation in the beta-subunit KCNE1 is associated with the disease. This finding further supports the hypothesis that increased potassium current enhances AF susceptibility. © 2012 Olesen et al; licensee BioMed Central Ltd.


Smajilovic S.,Copenhagen University | Chattopadhyay N.,Central Drug Research Institute | Tfelt-Hansen J.,Copenhagen University | Tfelt-Hansen J.,The Danish National Research Foundation Center for Cardiac Arrhythmia
Open Heart Failure Journal | Year: 2010

Calcium is a crucial signal molecule in the cardiovascular system. Calcium (Ca 2+) acts as a second messenger via changes in intracellular Ca 2+ levels through the actions of calcium channels and pumps. However, it is now well known that calcium may also be an extracellular first messenger through a G-protein-coupled receptor that senses extracellular Ca 2+ concentration, the calcium-sensing receptor (CaR). The CaR is one of the key players in extracellular calcium homeostasis, but besides being expressed in the major organs involved in calcium homeostasis, the parathyroid gland, kidney and intestine, the CaR has also been found to be functionally expressed in other tissues. Although several studies demonstrated the CaR in heart and blood vessels, exact roles of the receptor in the cardiovascular system still remain to be elucidated. This review will summarize the current knowledge on the expression and possible functions of the CaR in the cardiac tissue. © Smajilovic et al.; Licensee Bentham Open.


Lundby A.,Novo Nordisk AS | Lundby A.,The Danish National Research Foundation Center for Cardiac Arrhythmia | Lundby A.,The Broad Institute of MIT and Harvard | Lage K.,Novo Nordisk AS | And 12 more authors.
Cell Reports | Year: 2012

The local interaction of F-actin with myosin-II motor filaments and crosslinking proteins is crucial for the force generation, dynamics, and reorganization of the intracellular cytoskeleton. By using a bottom-up approach, we are able to show that the contractility of reconstituted active actin systems is tightly controlled by the local pH. The pH-dependent intrinsic crossbridge strength of myosin-II is identified to account for a sharp transition of the actin/myosin-II activity from noncontractile to contractile by a change in pH of only 0.1. This pH-dependent contractility is a generic feature, which is observed in all studied crosslinked actin/myosin-II systems. The specific type and concentration of crosslinking protein allows one to sensitively adjust the range of pH where contraction occurs, which can recover the behavior found in Xenopus laevis oocyte extracts. Small variations in pH provide a mechanism of controlling the contractility of cytoskeletal structures, which can be expected to have broad implications in our understanding of cytoskeletal regulation


Christensen A.,Copenhagen University | Christensen A.,The Danish National Research Foundation Center for Cardiac Arrhythmia | Andersen C.,Copenhagen University | Tybjaerg-Hansen A.,Copenhagen University | And 4 more authors.
Clinical Genetics | Year: 2011

A single report has associated mutations in TMEM43 (LUMA) with a distinctive form of arrhythmogenic right ventricular cardiomyopathy (ARVC). We aimed at performing mutational analysis of the gene and characterizing the associated immunohistochemical features. Sixty-five unrelated patients (55 fulfilling Task Force criteria and 10 borderline cases) were screened for mutations in TMEM43. Immunohistochemistry with anti-TMEM43, anti-plakoglobin, anti-plakophilin-2, anti-connexin-43, and anti-emerin antibodies was performed on myocardium from TMEM43-positive patients (n = 3) and healthy controls (n = 3). The genetic screening identified heterozygous variants in two families: one reported mutation (c.1073C> T; in two related patients) and one novel variant (c.705+ 7G> A; in one patient) of unknown significance. All three patients fulfilled Task Force criteria and did not carry mutations in any other ARVC-related gene. Immunostaining with TMEM43 antibody showed intense staining of the sarcolemma. The signal level was reduced in all the three TMEM43-positive patients. Immunostaining with plakoglobin-specific antibody also showed reduced signal levels in the three carriers. All patients displayed a similar immunoreactive signal for plakophilin-2, connexin-43, and emerin. In conclusion, two TMEM43 sequence variants were identified in this Danish ARVC cohort. Evaluation of the expression of TMEM43 showed a unique cardiac localization. The immunoreactive signal for the desmosomal protein plakoglobin was reduced in mutation carriers. The TMEM43 gene underlies a distinctive form of ARVC which may share a final common pathway with desmosome-associated ARVC. © 2011 John Wiley & Sons A/S.


Andreasen C.,The Danish National Research Foundation Center for Cardiac Arrhythmia | Andreasen C.,Copenhagen University | Refsgaard L.,The Danish National Research Foundation Center for Cardiac Arrhythmia | Refsgaard L.,Copenhagen University | And 15 more authors.
Canadian Journal of Cardiology | Year: 2013

Background: Sudden infant death syndrome (SIDS) is the leading cause of death in the first 6 months after birth in the industrialized world. The genetic contribution to SIDS has been investigated intensively and to date, 14 cardiac channelopathy genes have been associated with SIDS. Newly published data from National Heart, Lung, and Blood Institute Grand Opportunity (NHLBI GO) Exome Sequencing Project (ESP) provided important knowledge on genetic variation in the background population. Our aim was to identify all variants previously associated with SIDS in ESP to improve the discrimination between plausible disease-causing mutations and variants most likely to be false-positive. Methods: The PubMed database was searched to identify SIDS-associated channelopathy variants and the prevalence of these in the ESP population (6500 individuals) were obtained. In silico prediction tools were applied to variants present in ESP and 6 SIDS-associated variants (CAV3 p.C72W, p.T78M; KCNH2 p.R148W, and SCN5A p.S216L, p.V1951L, p.F2004L) were genotyped in our own control population. Results: Nineteen different missense variants previously associated with SIDS were identified in ESP affecting 225 of 6424 alleles. This corresponds to 1:29 individuals in the ESP population being carriers of a SIDS-associated variant. Genotyping of 6SIDS-associated variants in our own controls revealed frequencies comparable with those found in ESP. Conclusions: A very high prevalence of previously SIDS-associated variants was identified in exome data from population studies. Our findings indicate that the suggested disease-causing role of some of these variants is questionable. A cautious interpretation of these variants must be made when found in SIDS victims. © 2013 Canadian Cardiovascular Society.


Nielsen M.W.,The Danish National Research Foundation Center for Cardiac Arrhythmia | Nielsen M.W.,Copenhagen University | Holst A.G.,The Danish National Research Foundation Center for Cardiac Arrhythmia | Holst A.G.,Copenhagen University | And 3 more authors.
Frontiers in Physiology | Year: 2013

Brugada syndrome (BrS) is a clinical entity first described in 1992. BrS is characterized by ST-segment elevations in the right precordial leads and susceptibility to ventricular arrhythmias and sudden cardiac death. It affects young subjects, predominantly males, with structurally normal hearts. The prevalence varies with ethnicity ranging from 1:2,000 to 1:100,000 in different parts of the world. Today, hundreds of variants in 17 genes have been associated with BrS of which mutations in SCN5A, coding for the cardiac voltage-gated sodium channel, accounts for the vast majority. Despite this, approximately 70% of BrS cases cannot be explained genetically with the current knowledge. Moreover, the monogenic role of some of the variants previously described as being associated with BrS has been questioned by their occurrence in about 4% (1:23) of the general population as found in NHLBI GO Exome Sequencing Project (ESP) currently including approximately 6500 individuals. If we add the variants described in the five newest identified genes associated with BrS, they appear at an even higher prevalence in the ESP (1:21). The current standard treatment of BrS is an implantable cardioverter-defibrillator (ICD). The risk stratification and indications for ICD treatment are based on the ECG and on the clinical and family history. In this review we discuss the genetic basis of BrS. © 2013 Nielsen, Holst, Olesen and Olesen.


Olesen M.S.,The Danish National Research Foundation Center for Cardiac Arrhythmia | Olesen M.S.,Copenhagen University | Holst A.G.,The Danish National Research Foundation Center for Cardiac Arrhythmia | Holst A.G.,Copenhagen University | And 11 more authors.
Canadian Journal of Cardiology | Year: 2012

Background: Three distinct genetic loci on chromosomes 1q21, 4q25, and 16q22 have been associated with atrial fibrillation (AF) in genome-wide association studies (GWAS). Five additional loci have been associated primarily with the PR interval and subsequently with AF. We aimed to investigate if 8 single nucleotide polymorphisms (SNPs), representing the 8 genomic loci previously linked with AF in genome-wide association studies, were associated with early-onset lone AF. Methods: We included 209 patients with early-onset lone AF, and a control group consisting of 534 individuals free of AF. The 8 SNPs were genotyped using TaqMan assays (Applied Biosystems, Foster City, CA). Results: Three SNPs were found to be significantly associated with early-onset lone AF: rs2200733 closest to PITX2 (odds ratio [OR], 1.62; 95% confidence interval [CI], 1.16-2.27; P = 0.004), rs3807989 near to CAV1 (OR 1.35; 95% CI, 1.06-1.72; P = 0.015), and rs11047543 near to SOX5 (OR 1.70; 95% CI, 1.18-2.44; P = 0.004). When correcting for multiple testing, rs2200733 and rs11047543 were still significantly associated with AF. Conclusions: Three SNPs, rs2200733 (4q25), rs3807989 (7p31), and rs11047543 (12p12), were associated with early-onset lone AF. All 3 SNPs are positioned close to genes that in previous studies have been demonstrated to be important for cardiac morphology/development, thereby suggesting a link between these SNPs and structural heart disease. Our results however, indicate that variants in these 3 loci are associated with AF through mechanisms that do not involve major structural abnormalities in the heart. © 2012 Canadian Cardiovascular Society.

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