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Finding a Needle in a QT Interval Big Data Haystack: The Role for Orthogonal Datasets.
Roden DM, Mosley JD, Denny JC
(2016) J Am Coll Cardiol 68: 1765-1768
MeSH Terms: Ether-A-Go-Go Potassium Channels, Humans, Long QT Syndrome, Potassium Channels, Voltage-Gated, Torsades de Pointes
Added March 14, 2018
0 Communities
1 Members
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5 MeSH Terms
Long QT Syndrome and Potentially Pathogenic Genetic Variants--In Reply.
Van Driest SL, Wells QS, Roden DM
(2016) JAMA 315: 2467-8
MeSH Terms: Arrhythmias, Cardiac, Electronic Health Records, Ether-A-Go-Go Potassium Channels, Female, Genetic Variation, Humans, Laboratories, Male, NAV1.5 Voltage-Gated Sodium Channel, Phenotype
Added April 6, 2017
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1 Members
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10 MeSH Terms
Association of Arrhythmia-Related Genetic Variants With Phenotypes Documented in Electronic Medical Records.
Van Driest SL, Wells QS, Stallings S, Bush WS, Gordon A, Nickerson DA, Kim JH, Crosslin DR, Jarvik GP, Carrell DS, Ralston JD, Larson EB, Bielinski SJ, Olson JE, Ye Z, Kullo IJ, Abul-Husn NS, Scott SA, Bottinger E, Almoguera B, Connolly J, Chiavacci R, Hakonarson H, Rasmussen-Torvik LJ, Pan V, Persell SD, Smith M, Chisholm RL, Kitchner TE, He MM, Brilliant MH, Wallace JR, Doheny KF, Shoemaker MB, Li R, Manolio TA, Callis TE, Macaya D, Williams MS, Carey D, Kapplinger JD, Ackerman MJ, Ritchie MD, Denny JC, Roden DM
(2016) JAMA 315: 47-57
MeSH Terms: Aged, Aged, 80 and over, Alleles, Arrhythmias, Cardiac, Brugada Syndrome, ERG1 Potassium Channel, Electronic Health Records, Ether-A-Go-Go Potassium Channels, Female, Genetic Predisposition to Disease, Genetic Testing, Genetic Variation, Genomics, Heterozygote, Humans, Incidental Findings, Laboratories, Male, Middle Aged, Mutation, Missense, NAV1.5 Voltage-Gated Sodium Channel, Phenotype, Prospective Studies, Random Allocation, Statistics, Nonparametric, Young Adult
Show Abstract · Added April 6, 2017
IMPORTANCE - Large-scale DNA sequencing identifies incidental rare variants in established Mendelian disease genes, but the frequency of related clinical phenotypes in unselected patient populations is not well established. Phenotype data from electronic medical records (EMRs) may provide a resource to assess the clinical relevance of rare variants.
OBJECTIVE - To determine the clinical phenotypes from EMRs for individuals with variants designated as pathogenic by expert review in arrhythmia susceptibility genes.
DESIGN, SETTING, AND PARTICIPANTS - This prospective cohort study included 2022 individuals recruited for nonantiarrhythmic drug exposure phenotypes from October 5, 2012, to September 30, 2013, for the Electronic Medical Records and Genomics Network Pharmacogenomics project from 7 US academic medical centers. Variants in SCN5A and KCNH2, disease genes for long QT and Brugada syndromes, were assessed for potential pathogenicity by 3 laboratories with ion channel expertise and by comparison with the ClinVar database. Relevant phenotypes were determined from EMRs, with data available from 2002 (or earlier for some sites) through September 10, 2014.
EXPOSURES - One or more variants designated as pathogenic in SCN5A or KCNH2.
MAIN OUTCOMES AND MEASURES - Arrhythmia or electrocardiographic (ECG) phenotypes defined by International Classification of Diseases, Ninth Revision (ICD-9) codes, ECG data, and manual EMR review.
RESULTS - Among 2022 study participants (median age, 61 years [interquartile range, 56-65 years]; 1118 [55%] female; 1491 [74%] white), a total of 122 rare (minor allele frequency <0.5%) nonsynonymous and splice-site variants in 2 arrhythmia susceptibility genes were identified in 223 individuals (11% of the study cohort). Forty-two variants in 63 participants were designated potentially pathogenic by at least 1 laboratory or ClinVar, with low concordance across laboratories (Cohen κ = 0.26). An ICD-9 code for arrhythmia was found in 11 of 63 (17%) variant carriers vs 264 of 1959 (13%) of those without variants (difference, +4%; 95% CI, -5% to +13%; P = .35). In the 1270 (63%) with ECGs, corrected QT intervals were not different in variant carriers vs those without (median, 429 vs 439 milliseconds; difference, -10 milliseconds; 95% CI, -16 to +3 milliseconds; P = .17). After manual review, 22 of 63 participants (35%) with designated variants had any ECG or arrhythmia phenotype, and only 2 had corrected QT interval longer than 500 milliseconds.
CONCLUSIONS AND RELEVANCE - Among laboratories experienced in genetic testing for cardiac arrhythmia disorders, there was low concordance in designating SCN5A and KCNH2 variants as pathogenic. In an unselected population, the putatively pathogenic genetic variants were not associated with an abnormal phenotype. These findings raise questions about the implications of notifying patients of incidental genetic findings.
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26 MeSH Terms
Identification of a KCNQ1 polymorphism acting as a protective modifier against arrhythmic risk in long-QT syndrome.
Duchatelet S, Crotti L, Peat RA, Denjoy I, Itoh H, Berthet M, Ohno S, Fressart V, Monti MC, Crocamo C, Pedrazzini M, Dagradi F, Vicentini A, Klug D, Brink PA, Goosen A, Swan H, Toivonen L, Lahtinen AM, Kontula K, Shimizu W, Horie M, George AL, Trégouët DA, Guicheney P, Schwartz PJ
(2013) Circ Cardiovasc Genet 6: 354-61
MeSH Terms: Alleles, Case-Control Studies, Cohort Studies, Databases, Genetic, ERG1 Potassium Channel, Ether-A-Go-Go Potassium Channels, Female, Gene Frequency, Genotype, Heterozygote, Humans, KCNQ1 Potassium Channel, Long QT Syndrome, Male, Polymorphism, Single Nucleotide, Risk Factors
Show Abstract · Added March 7, 2014
BACKGROUND - Long-QT syndrome (LQTS) is characterized by such striking clinical heterogeneity that, even among family members carrying the same mutation, clinical outcome can range between sudden death and no symptoms. We investigated the role of genetic variants as modifiers of risk for cardiac events in patients with LQTS.
METHODS AND RESULTS - In a matched case-control study including 112 patient duos with LQTS from France, Italy, and Japan, 25 polymorphisms were genotyped based on either their association with QTc duration in healthy populations or on their role in adrenergic responses. The duos were composed of 2 relatives harboring the same heterozygous KCNQ1 or KCNH2 mutation: 1 with cardiac events and 1 asymptomatic and untreated. The findings were then validated in 2 independent founder populations totaling 174 symptomatic and 162 asymptomatic patients with LQTS, and a meta-analysis was performed. The KCNQ1 rs2074238 T-allele was significantly associated with a decreased risk of symptoms 0.34 (0.19-0.61; P<0.0002) and with shorter QTc (P<0.0001) in the combined discovery and replication cohorts.
CONCLUSIONS - We provide evidence that the KCNQ1 rs2074238 polymorphism is an independent risk modifier with the minor T-allele conferring protection against cardiac events in patients with LQTS. This finding is a step toward a novel approach for risk stratification in patients with LQTS.
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16 MeSH Terms
Identification and characterization of a compound that protects cardiac tissue from human Ether-à-go-go-related gene (hERG)-related drug-induced arrhythmias.
Potet F, Lorinc AN, Chaigne S, Hopkins CR, Venkataraman R, Stepanovic SZ, Lewis LM, Days E, Sidorov VY, Engers DW, Zou B, Afshartous D, George AL, Campbell CM, Balser JR, Li M, Baudenbacher FJ, Lindsley CW, Weaver CD, Kupershmidt S
(2012) J Biol Chem 287: 39613-25
MeSH Terms: Animals, Arrhythmias, Cardiac, Dose-Response Relationship, Drug, Drug Discovery, ERG1 Potassium Channel, Ether-A-Go-Go Potassium Channels, HEK293 Cells, Humans, Muscle Proteins, Myocardium, Naphthyridines, Phenethylamines, Potassium Channel Blockers, Pyridines, Rabbits, Structure-Activity Relationship, Sulfonamides
Show Abstract · Added March 7, 2014
The human Ether-à-go-go-related gene (hERG)-encoded K(+) current, I(Kr) is essential for cardiac repolarization but is also a source of cardiotoxicity because unintended hERG inhibition by diverse pharmaceuticals can cause arrhythmias and sudden cardiac death. We hypothesized that a small molecule that diminishes I(Kr) block by a known hERG antagonist would constitute a first step toward preventing hERG-related arrhythmias and facilitating drug discovery. Using a high-throughput assay, we screened a library of compounds for agents that increase the IC(70) of dofetilide, a well characterized hERG blocker. One compound, VU0405601, with the desired activity was further characterized. In isolated, Langendorff-perfused rabbit hearts, optical mapping revealed that dofetilide-induced arrhythmias were reduced after pretreatment with VU0405601. Patch clamp analysis in stable hERG-HEK cells showed effects on current amplitude, inactivation, and deactivation. VU0405601 increased the IC(50) of dofetilide from 38.7 to 76.3 nM. VU0405601 mitigates the effects of hERG blockers from the extracellular aspect primarily by reducing inactivation, whereas most clinically relevant hERG inhibitors act at an inner pore site. Structure-activity relationships surrounding VU0405601 identified a 3-pyridiyl and a naphthyridine ring system as key structural components important for preventing hERG inhibition by multiple inhibitors. These findings indicate that small molecules can be designed to reduce the sensitivity of hERG to inhibitors.
1 Communities
3 Members
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17 MeSH Terms
Voltage-gated potassium channel EAG2 controls mitotic entry and tumor growth in medulloblastoma via regulating cell volume dynamics.
Huang X, Dubuc AM, Hashizume R, Berg J, He Y, Wang J, Chiang C, Cooper MK, Northcott PA, Taylor MD, Barnes MJ, Tihan T, Chen J, Hackett CS, Weiss WA, James CD, Rowitch DH, Shuman MA, Jan YN, Jan LY
(2012) Genes Dev 26: 1780-96
MeSH Terms: Animals, COS Cells, Cell Cycle Checkpoints, Cell Proliferation, Cell Size, Cells, Cultured, Cercopithecus aethiops, Enzyme Activation, Ether-A-Go-Go Potassium Channels, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Gene Knockdown Techniques, HEK293 Cells, Humans, MAP Kinase Signaling System, Medulloblastoma, Mice, Mitosis, Survival Analysis
Show Abstract · Added January 18, 2013
Medulloblastoma (MB) is the most common pediatric CNS malignancy. We identify EAG2 as an overexpressed potassium channel in MBs across different molecular and histological subgroups. EAG2 knockdown not only impairs MB cell growth in vitro, but also reduces tumor burden in vivo and enhances survival in xenograft studies. Mechanistically, we demonstrate that EAG2 protein is confined intracellularly during interphase but is enriched in the plasma membrane during late G2 phase and mitosis. Disruption of EAG2 expression results in G2 arrest and mitotic catastrophe associated with failure of premitotic cytoplasmic condensation. While the tumor suppression function of EAG2 knockdown is independent of p53 activation, DNA damage checkpoint activation, or changes in the AKT pathway, this defective cell volume control is specifically associated with hyperactivation of the p38 MAPK pathway. Inhibition of the p38 pathway significantly rescues the growth defect and G2 arrest. Strikingly, ectopic membrane expression of EAG2 in cells at interphase results in cell volume reduction and mitotic-like morphology. Our study establishes the functional significance of EAG2 in promoting MB tumor progression via regulating cell volume dynamics, the perturbation of which activates the tumor suppressor p38 MAPK pathway, and provides clinical relevance for targeting this ion channel in human MBs.
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2 Members
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19 MeSH Terms
Cancer therapy-associated cardiotoxicity and signaling in the myocardium.
Zuppinger C, Suter TM
(2010) J Cardiovasc Pharmacol 56: 141-6
MeSH Terms: Angiogenesis Inhibitors, Anthracyclines, Antibodies, Monoclonal, Antibodies, Monoclonal, Humanized, Antineoplastic Agents, ERG1 Potassium Channel, ErbB Receptors, Ether-A-Go-Go Potassium Channels, Heart Diseases, Humans, Myocardium, Neoplasms, Neuregulin-1, Neuregulins, Receptor, ErbB-2, Receptor, ErbB-4, Signal Transduction, Trastuzumab
Show Abstract · Added September 25, 2014
The cardiotoxic potential of cytotoxic cancer chemotherapy is well known. Prime examples are the anthracyclines, which are highly efficacious agents for hemopoietic malignancies and solid tumors, but their clinical use is limited primarily by cardiotoxicity. Besides the conventional chemotherapeutics, new cancer drugs were developed in the last decade with the goal to specifically inhibit selected molecular targets such as growth factor receptors or intracellular tyrosine kinases in cancer cells. However, the outcome of combining conventional and newer cancer therapies could have unexpected side effects not anticipated so far and the long-term outcome is not known. Sometimes, however, unexpected side effects also shed light on previously unknown physiological functions. For example, the anti-HER2 cancer therapeutic trastuzumab (Herceptin), which can induce cardiac dysfunction, has demonstrated the importance of the ErbB/neuregulin signaling system in the adult heart. Subsequently, the role of endothelial-myocardial communication in maintaining phenotype and survival of adult cardiomyocytes has increasingly been recognized.
0 Communities
0 Members
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18 MeSH Terms
KCNH2 pharmacogenomics summary.
Oshiro C, Thorn CF, Roden DM, Klein TE, Altman RB
(2010) Pharmacogenet Genomics 20: 775-7
MeSH Terms: ERG1 Potassium Channel, Ether-A-Go-Go Potassium Channels, Humans, Pharmacogenetics, Polymorphism, Single Nucleotide
Added June 26, 2014
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1 Members
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5 MeSH Terms
Genetic variation in the rhythmonome: ethnic variation and haplotype structure in candidate genes for arrhythmias.
Bush WS, Crawford DC, Alexander C, George AL, Roden DM, Ritchie MD
(2009) Pharmacogenomics 10: 1043-53
MeSH Terms: African Americans, Algorithms, Alleles, Ankyrins, Arrhythmias, Cardiac, Asian Continental Ancestry Group, Bayes Theorem, Cell Line, Cluster Analysis, DNA, ERG1 Potassium Channel, Ether-A-Go-Go Potassium Channels, European Continental Ancestry Group, Gene Frequency, Genetic Markers, Genetic Variation, Genetics, Population, Genome-Wide Association Study, Haplotypes, Humans, KCNQ1 Potassium Channel, Linkage Disequilibrium, Mexican Americans, Monte Carlo Method, Muscle Proteins, NAV1.5 Voltage-Gated Sodium Channel, Polymorphism, Single Nucleotide, Potassium Channels, Voltage-Gated, Ryanodine Receptor Calcium Release Channel, Sodium Channels, Software, United States
Show Abstract · Added December 10, 2013
AIMS - The 'rhythmonome' is the term we have adopted to describe the set of genes that determine the normal coordinated electrical activity in the heart. Elements of this set include pore-forming ion channels, function-modifying proteins and intracellular calcium control elements. Rare mutations in many of these genes are known to cause unusual congenital monogenic arrhythmia syndromes, and single common variants have been reported to modify arrhythmia phenotypes. Here, we report an evaluation of the variation and haplotype structure in six key components of the rhythmonome.
MATERIALS & METHODS - SNPs were typed using DNA extracted from Coriell cell lines to survey allele frequencies and haplotype structure in six genes (ANK2, SCN5A, KCNE1 and 2 gene cluster, KCNQ1, KCNH2 and RYR2) across four human populations (African-American, European American, Han Chinese and Mexican American).
RESULTS - A total of 307 SNPs were analyzed across the six genes, revealing significant allele-frequency differences between populations and clear differences in haplotype structure.
CONCLUSIONS - The pattern of variation we report is an important step towards incorporating common variation across the rhythmonome in studies of arrhythmia susceptibility.
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32 MeSH Terms
The organic cation transporter, OCTN1, expressed in the human heart, potentiates antagonism of the HERG potassium channel.
McBride BF, Yang T, Liu K, Urban TJ, Giacomini KM, Kim RB, Roden DM
(2009) J Cardiovasc Pharmacol 54: 63-71
MeSH Terms: Anti-Arrhythmia Agents, Arrhythmias, Cardiac, Cation Transport Proteins, Electrophysiology, Ether-A-Go-Go Potassium Channels, Flecainide, Gene Expression, Heart, Humans, Immunohistochemistry, In Situ Hybridization, Inhibitory Concentration 50, Myocytes, Cardiac, Organic Cation Transport Proteins, Patch-Clamp Techniques, Potassium Channels, Quinidine, Sulfonamides
Show Abstract · Added June 26, 2014
BACKGROUND - Variable function and expression of drug transporters have been proposed as mechanisms contributing to variable response to drug therapy. Block of the HERG channel, encoding IKr, can lead to serious arrhythmias, and a key drug-blocking site in HERG has been identified on the intracellular face of the pore. We begin to advance the hypothesis that active drug uptake enhances IKr block.
METHODS AND RESULTS - Reverse transcriptase-polymerase chain reaction identified expression in the human atrium and ventricle of 14 of 31 candidate drug uptake and efflux transporters, including OCTN1 (SLC22A4), a known uptake transporter of the HERG channel blocker quinidine. In situ hybridization and immunostaining localized OCTN1 expression to cardiomyocytes. The IC50 for quinidine block of IKr in CHO cells transfected with HERG alone was significantly higher than cells transfected with HERG + OCTN1 (0.66 +/- 0.15 microM versus 0.14 +/- 0.06 microM [52% absolute increase in drug block; 95% confidence interval, 0.4-0.64 microM]), and this effect was further potentiated by a common genetic variant of OCTN1, L503F. In the absence of OCTN1, quinidine block could be 91% +/- 5% washed out, but with the transporter, washout was incomplete (57% +/- 6%). OCTN1 coexpression also facilitated HERG block by flecainide and ibutilide, but not erythromycin.
CONCLUSIONS - Coexpression of the organic cation transporter, OCTN1, expressed in human cardiac myocytes, intensifies quinidine-induced HERG block. These findings establish a critical hypothesis that variable drug transporter activity may be a potential risk factor for torsade de pointes.
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18 MeSH Terms