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1.  Screening for Acute IKr Block is Insufficient to Detect Torsades de Pointes Liability: Role of Late Sodium Current 
Circulation  2014;130(3):224-234.
Background
New drugs are routinely screened for acute IKr blocking properties thought to predict QT prolonging and arrhythmogenic liability. However, recent data suggest that chronic (hours) drug exposure to PI3 kinase (PI3K) inhibitors used in cancer can prolong QT by inhibiting potassium currents and increasing late sodium current (INa-L) in cardiomyocytes. We tested the extent to which IKr blockers with known QT liability generate arrhythmias through this pathway.
Methods and Results
Acute exposure to dofetilide, an IKr blocker without other recognized electropharmacologic actions, produced no change in ion currents or action potentials in adult mouse cardiomyocytes, which lack IKr. By contrast, 2–48 hours’ exposure to the drug generated arrhythmogenic afterdepolarizations and up to 15-fold increases in INa-L. Including PIP3, a downstream effector for the PI3K pathway, in the pipette inhibited these effects. INa-L was also increased, and inhibitable by PIP3, with hours of dofetilide exposure in human iPSC-derived cardiomyocytes and in CHO cells transfected with SCN5A, encoding INa. Cardiomyocytes from dofetilide-treated mice similarly demonstrated increased INa-L and afterdepolarizations. Other agents with variable IKr blocking potencies and arrhythmia liability produced a range of effects on INa-L, from marked increases (E-4031, d-sotalol, thioridazine, erythromycin) to little or no effect (haloperidol, moxifloxacin, verapamil).
Conclusions
Some but not all drugs designated as arrhythmogenic IKr blockers can generate arrhythmias by augmenting INa-L through the PI3K pathway. These data identify a potential mechanism for individual susceptibility to proarrhythmia and highlight the need for a new paradigm to screen drugs for QT prolonging and arrhythmogenic liability.
doi:10.1161/CIRCULATIONAHA.113.007765
PMCID: PMC4101031  PMID: 24895457
Late sodium current; IKr block; arrhythmogenic; phosphoinositide 3-kinase (PI3K) inhibition
2.  Personalized medicine to treat arrhythmias 
The efficacy of antiarrhythmic drug therapy is incomplete, with responses ranging from efficacy to no effect to severe adverse effects, including paradoxical drug-induced arrhythmia. Most antiarrhythmic drugs were developed at a time when mechanism underlying arrhythmias were not well-understood. In the last decade, a range of experimental approaches have advanced our understanding of the molecular and genomic contributors to the generation of an arrhythmia-prone heart, and this information is directly informing targeted therapy with existing drugs or the development of new ones. The development of inexpensive whole genome sequencing holds the promise of identifying patients susceptible to arrhythmias in a presymptomatic phase, and thus implementing preventive therapies.
doi:10.1016/j.coph.2013.11.013
PMCID: PMC3984450  PMID: 24721655
genomics; pharmacogenomics; arrhythmia; long QT syndrome; atrial fibrillation
3.  Dantrolene: From Better Bacon to a Treatment for Ventricular Fibrillation 
Circulation  2014;129(8):834-836.
doi:10.1161/CIRCULATIONAHA.113.007657
PMCID: PMC3959791  PMID: 24403562
dantrolene; Editorial; ventricular fibrillation; ryanodine receptor; excitation-contraction coupling
4.  Novel Rare Variants in Congenital Cardiac Arrhythmia Genes are Frequent in Drug-induced Torsades de Pointes 
The pharmacogenomics journal  2012;13(4):325-329.
Marked prolongation of the QT interval and polymorphic ventricular tachycardia following medication (drug-induced long QT syndrome, diLQTS) is a severe adverse drug reaction (ADR) that phenocopies congenital long QT syndrome (cLQTS) and one of the leading causes for drug withdrawal and relabeling. We evaluated the frequency of rare non-synonymous variants in genes contributing to the maintenance of heart rhythm in cases of diLQTS using targeted capture coupled to next generation sequencing. Eleven of 31 diLQTS subjects (36%) carried a novel missense mutation in genes with known congenital arrhythmia associations or a known cLQTS mutation. In the 26 Caucasian subjects, 23% carried a highly conserved rare variant predicted to be deleterious to protein function in these genes compared with only 2-4% in public databases (p < 0.003). We conclude that rare variation in genes responsible for congenital arrhythmia syndromes is frequent in diLQTS. Our findings demonstrate that diLQTS is a pharmacogenomic syndrome predisposed by rare genetic variants.
doi:10.1038/tpj.2012.14
PMCID: PMC3422407  PMID: 22584458
pharmacogenomics; sudden cardiac death; adverse drug reaction; next generation sequencing
5.  Exome Sequencing Implicates an Increased Burden of Rare Potassium Channel Variants in the Risk of Drug Induced Long QT Syndrome 
Objectives
To test the hypothesis that rare variants are associated with Drug-induced long QT syndrome (diLQTS) and torsade de pointes (TdP).
Background
diLQTS is associated with the potentially fatal arrhythmia TdP. The contribution of rare genetic variants to the underlying genetic framework predisposing diLQTS has not been systematically examined.
Methods
We performed whole exome sequencing (WES) on 65 diLQTS cases and 148 drug-exposed controls of European descent. We employed rare variant analyses (variable threshold [VT] and sequence kernel association test [SKAT]) and gene-set analyses to identify genes enriched with rare amino-acid coding (AAC) variants associated with diLQTS. Significant associations were reanalyzed by comparing diLQTS cases to 515 ethnically matched controls from the NHLBI GO Exome Sequencing Project (ESP).
Results
Rare variants in 7 genes were enriched in the diLQTS cases according to SKAT or VT compared to drug exposed controls (p<0.001). Of these, we replicated the diLQTS associations for KCNE1 and ACN9 using 515 ESP controls (p<0.05). A total of 37% of the diLQTS cases also had ≥1 rare AAC variant, as compared to 21% of controls (p=0.009), in a predefined set of seven congenital LQTS (cLQTS) genes encoding potassium channels or channel modulators (KCNE1,KCNE2,KCNH2,KCNJ2, KCNJ5,KCNQ1,AKAP9).
Conclusions
By combining WES with aggregated rare variant analyses, we implicate rare variants in KCNE1 and ACN9 as risk factors for diLQTS. Moreover, diLQTS cases were more burdened by rare AAC variants in cLQTS genes encoding potassium channel modulators, supporting the idea that multiple rare variants, notably across cLQTS genes, predispose to diLQTS.
doi:10.1016/j.jacc.2014.01.031
PMCID: PMC4018823  PMID: 24561134
exome; torsade des pointes; long QT syndrome; genetics, adverse drug event
6.  Genome- and Phenome-Wide Analysis of Cardiac Conduction Identifies Markers of Arrhythmia Risk 
Circulation  2013;127(13):1377-1385.
Background
Electrocardiographic QRS duration, a measure of cardiac intraventricular conduction, varies ~2-fold in individuals without cardiac disease. Slow conduction may promote reentrant arrhythmias.
Methods and Results
We performed a genome-wide association study (GWAS) to identify genomic markers of QRS duration in 5,272 individuals without cardiac disease selected from electronic medical record (EMR) algorithms at five sites in the Electronic Medical Records and Genomics (eMERGE) network. The most significant loci were evaluated within the CHARGE consortium QRS GWAS meta-analysis. Twenty-three single nucleotide polymorphisms in 5 loci, previously described by CHARGE, were replicated in the eMERGE samples; 18 SNPs were in the chromosome 3 SCN5A and SCN10A loci, where the most significant SNPs were rs1805126 in SCN5A with p=1.2×10−8 (eMERGE) and p=2.5×10−20 (CHARGE) and rs6795970 in SCN10A with p=6×10−6 (eMERGE) and p=5×10−27 (CHARGE). The other loci were in NFIA, near CDKN1A, and near C6orf204. We then performed phenome-wide association studies (PheWAS) on variants in these five loci in 13,859 European Americans to search for diagnoses associated with these markers. PheWAS identified atrial fibrillation and cardiac arrhythmias as the most common associated diagnoses with SCN10A and SCN5A variants. SCN10A variants were also associated with subsequent development of atrial fibrillation and arrhythmia in the original 5,272 “heart-healthy” study population.
Conclusions
We conclude that DNA biobanks coupled to EMRs provide a platform not only for GWAS but may also allow broad interrogation of the longitudinal incidence of disease associated with genetic variants. The PheWAS approach implicated sodium channel variants modulating QRS duration in subjects without cardiac disease as predictors of subsequent arrhythmias.
doi:10.1161/CIRCULATIONAHA.112.000604
PMCID: PMC3713791  PMID: 23463857
cardiac conduction; QRS duration; atrial fibrillation; genome-wide association study; phenome-wide association study; electronic medical records
7.  Stem Cell–Derived Cardiomyocytes as a Tool for Studying Proarrhythmia 
Circulation  2013;127(16):1641-1643.
doi:10.1161/CIRCULATIONAHA.113.002127
PMCID: PMC3954984  PMID: 23519759
Editorials; arrhythmias; cardiac; genetics; humans; pharmacology; stem cells
8.  Refining repolarization reserve 
doi:10.1016/j.hrthm.2011.06.024
PMCID: PMC3923504  PMID: 21708111
9.  Cardiovascular Pharmacogenomics: The Future of Cardiovascular Therapeutics? 
Responses to drug therapy vary from benefit to no effect to adverse effects which can be serious or occasionally fatal. Increasing evidence supports the idea that genetic variants can play a major role in this spectrum of responses. Well-studied examples in cardiovascular therapeutics include predictors of steady-state warfarin dosage, predictors of reduced efficacy among patients receiving clopidogrel for drug eluting stents, and predictors of some serious adverse drug effects. This review summarizes contemporary approaches to identifying and validating genetic predictors of variability in response to drug treatment. Approaches to incorporating this new knowledge into clinical care, and the barriers to this concept, are addressed.
doi:10.1016/j.cjca.2012.07.845
PMCID: PMC3529768  PMID: 23200096
10.  Genetic determinants of response to cardiovascular drugs 
Current opinion in cardiology  2012;27(3):10.1097/HCO.0b013e32835220e3.
Purpose of review
To survey genetic variation contributing to variable responsiveness and toxicity to important cardiovascular drugs and highlight recent developments in the field of cardiovascular pharmacogenomics and personalized medicine.
Recent findings
Previously recognized pharmacogenomic associations with drug efficacy have been further validated (e.g. with clopidogrel and warfarin) and shown to influence clinically important outcomes. The clinical significance of variants modulating toxicity (e.g. SLCO1B1 with simvastatin) has also been confirmed. The genetic contribution to variable efficacy and toxicity of other important classes of cardiovascular drugs, such as beta-blockers, is becoming increasingly recognized. Prospective trials testing whether the use of genomic information improves clinical care are underway. Guidance based on the most well-established pharmacogenomic findings has appeared in prescribing labeling and is in the early stages of being implemented into routine clinical care.
Summary
Clinically validated gene variants that modulate responsiveness to cardiovascular drugs continue to be discovered and validated. Early steps are underway to translate these discoveries into clinical care.
doi:10.1097/HCO.0b013e32835220e3
PMCID: PMC3874723  PMID: 22382501
personalized medicine; pharmacogenomics; variable drug response
11.  Deciphering Signaling Pathway Networks to Understand the Molecular Mechanisms of Metformin Action 
PLoS Computational Biology  2015;11(6):e1004202.
A drug exerts its effects typically through a signal transduction cascade, which is non-linear and involves intertwined networks of multiple signaling pathways. Construction of such a signaling pathway network (SPNetwork) can enable identification of novel drug targets and deep understanding of drug action. However, it is challenging to synopsize critical components of these interwoven pathways into one network. To tackle this issue, we developed a novel computational framework, the Drug-specific Signaling Pathway Network (DSPathNet). The DSPathNet amalgamates the prior drug knowledge and drug-induced gene expression via random walk algorithms. Using the drug metformin, we illustrated this framework and obtained one metformin-specific SPNetwork containing 477 nodes and 1,366 edges. To evaluate this network, we performed the gene set enrichment analysis using the disease genes of type 2 diabetes (T2D) and cancer, one T2D genome-wide association study (GWAS) dataset, three cancer GWAS datasets, and one GWAS dataset of cancer patients with T2D on metformin. The results showed that the metformin network was significantly enriched with disease genes for both T2D and cancer, and that the network also included genes that may be associated with metformin-associated cancer survival. Furthermore, from the metformin SPNetwork and common genes to T2D and cancer, we generated a subnetwork to highlight the molecule crosstalk between T2D and cancer. The follow-up network analyses and literature mining revealed that seven genes (CDKN1A, ESR1, MAX, MYC, PPARGC1A, SP1, and STK11) and one novel MYC-centered pathway with CDKN1A, SP1, and STK11 might play important roles in metformin’s antidiabetic and anticancer effects. Some results are supported by previous studies. In summary, our study 1) develops a novel framework to construct drug-specific signal transduction networks; 2) provides insights into the molecular mode of metformin; 3) serves a model for exploring signaling pathways to facilitate understanding of drug action, disease pathogenesis, and identification of drug targets.
Author Summary
A deep understanding of a drug’s mechanisms of actions is essential not only in the discovery of new treatments but also in minimizing adverse effects. Here, we develop a computational framework, the Drug-specific Signaling Pathway Network (DSPathNet), to reconstruct a comprehensive signaling pathway network (SPNetwork) impacted by a particular drug. To illustrate this computational approach, we used metformin, an anti-diabetic drug, as an example. Starting from collecting the metformin-related upstream genes and inferring the metformin-related downstream genes, we built one metformin-specific SPNetwork via random walk based algorithms. Our evaluation of the metformin-specific SPNetwork by using disease genes and genotyping data from genome-wide association studies showed that our DSPathNet approach was efficient to synopsize drug’s key components and their relationship involved in the type 2 diabetes and cancer, even the metformin anticancer activity. This work presents a novel computational framework for constructing individual drug-specific signal transduction networks. Furthermore, its successful application to the drug metformin provides some valuable insights into the mode of metformin action, which will facilitate our understanding of the molecular mechanisms underlying drug treatments, disease pathogenesis, and identification of novel drug targets and repurposed drugs.
doi:10.1371/journal.pcbi.1004202
PMCID: PMC4470683  PMID: 26083494
12.  The Organic Cation Transporter, OCTN1, Expressed in the Human Heart, Potentiates Antagonism of the HERG Potassium Channel 
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 μM versus 0.14 ± 0.06 μM [52% absolute increase in drug block; 95% confidence interval, 0.4–0.64 μM]), 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.
doi:10.1097/FJC.0b013e3181abc288
PMCID: PMC3745652  PMID: 19528813
antiarrhythmia agents; arrhythmia; pharmacology; pharmacokinetics; ion channels
13.  Genome-Wide Association Study of Serum Creatinine Levels during Vancomycin Therapy 
PLoS ONE  2015;10(6):e0127791.
Vancomycin, a commonly used antibiotic, can be nephrotoxic. Known risk factors such as age, creatinine clearance, vancomycin dose / dosing interval, and concurrent nephrotoxic medications fail to accurately predict nephrotoxicity. To identify potential genomic risk factors, we performed a genome-wide association study (GWAS) of serum creatinine levels while on vancomycin in 489 European American individuals and validated findings in three independent cohorts totaling 439 European American individuals. In primary analyses, the chromosome 6q22.31 locus was associated with increased serum creatinine levels while on vancomycin therapy (most significant variant rs2789047, risk allele A, β = -0.06, p = 1.1 x 10-7). SNPs in this region had consistent directions of effect in the validation cohorts, with a meta-p of 1.1 x 10-7. Variation in this region on chromosome 6, which includes the genes TBC1D32/C6orf170 and GJA1 (encoding connexin43), may modulate risk of vancomycin-induced kidney injury.
doi:10.1371/journal.pone.0127791
PMCID: PMC4452656  PMID: 26030142
14.  Phenotype-Driven Plasma Biobanking Strategies and Methods 
Journal of Personalized Medicine  2015;5(2):140-152.
Biobank development and integration with clinical data from electronic medical record (EMR) databases have enabled recent strides in genomic research and personalized medicine. BioVU, Vanderbilt’s DNA biorepository linked to de-identified clinical EMRs, has proven fruitful in its capacity to extensively appeal to numerous areas of biomedical and clinical research, supporting the discovery of genotype-phenotype interactions. Expanding on experiences in BioVU creation and development, we have recently embarked on a parallel effort to collect plasma in addition to DNA from blood specimens leftover after routine clinical testing at Vanderbilt. This initiative offers expanded utility of BioVU by combining proteomic and metabolomic approaches with genomics and/or clinical outcomes, widening the breadth for potential research and subsequent future impact on clinical care. Here, we describe the considerations and components involved in implementing a plasma biobank program from a feasibility assessment through pilot sample collection.
doi:10.3390/jpm5020140
PMCID: PMC4493492  PMID: 26110578
Keywords: biobanking; plasma; proteomics; BioVU; biorepository
15.  Blocking SCN10A channels in heart reduces late sodium current and is antiarrhythmic 
Circulation research  2012;111(3):322-332.
Rationale
While the sodium channel locus SCN10A has been implicated by genome-wide association studies as a modulator of cardiac electrophysiology, the role of its gene product Nav1.8 as a modulator of cardiac ion currents is unknown.
Objective
We determined the electrophysiological and pharmacological properties of Nav1.8 in heterologous cell systems and assessed the antiarrhythmic effect of Nav1.8 block on isolated mouse and rabbit ventricular cardiomyocytes.
Methods and results
We first demonstrated that Scn10a transcripts are identified in mouse heart and that the blocker A-803467 is highly specific for Nav1.8 current over that of Nav1.5, the canonical cardiac sodium channel encoded by SCN5A. We then showed that low concentrations of A-803467 selectively block “late” sodium current and shorten action potentials in mouse and rabbit cardiomyocytes. Exaggerated late sodium current is known to mediate arrhythmogenic early afterdepolarizations in heart, and these were similarly suppressed by low concentrations of A-803467.
Conclusion
SCN10A expression contributes to late sodium current in heart, and represents a new target for antiarrhythmic intervention.
doi:10.1161/CIRCRESAHA.112.265173
PMCID: PMC3412150  PMID: 22723299
SCN10A; sodium channels; heart; afterdepolarizations; arrhythmia
17.  Operational implementation of prospective genotyping for personalized medicine: The design of the Vanderbilt PREDICT project 
The promise of “personalized medicine” guided by an understanding of each individual’s genome has been fostered by increasingly powerful and economical methods to acquire clinically relevant features. We describe operational implementation of prospective genotyping linked to an advanced clinical decision support system to guide individualized healthcare in a large academic health center. This approach to personalized medicine includes patient and healthcare provider engagement, identifying relevant genetic variation for implementation, assay reliability, point-of-care decision support, and necessary institutional investments. In one year, approximately 3,000 patients, most scheduled for cardiac catheterization, were genotyped on a multiplexed platform including CYP2C19 variants that modulate response to the widely-used antiplatelet drug clopidogrel. These data are deposited into the Electronic Medical Record and point-of-care decision support is deployed when clopidogrel is prescribed for those with variant genotypes. The establishment of programs such as this is a first step toward implementing and evaluating strategies for personalized medicine.
doi:10.1038/clpt.2011.371
PMCID: PMC3581305  PMID: 22588608
Drug-Drug Interactions; Personalized Medicine; Pharmacogenetics; Translational Medicine; Adverse Drug Reactions
18.  A Large Candidate Gene Survey Identifies the KCNE1 D85N Polymorphism as a Possible Modulator of Drug-Induced Torsades de Pointes 
Background
Drug-induced long QT syndrome (diLQTS) is an adverse drug effect that has an important impact on drug use, development, and regulation. Here, we tested the hypothesis that common variants in key genes controlling cardiac electrical properties modify the risk of diLQTS.
Methods and Results
In a case-control setting, we included 176 patients of European descent from North America and Europe with diLQTS, defined as documented torsades de pointes during treatment with a QT prolonging drug. Control samples were obtained from 207 patients of European ancestry who displayed <50 msec QT lengthening during initiation of therapy with a QT-prolonging drug, and 837 controls from the population based KORA study. Subjects were successfully genotyped at 1,424 single nucleotide polymorphisms (SNPs) in 18 candidate genes including 1,386 SNPs tagging common haplotype blocks, and 38 non-synonymous ion channel gene SNPs. For validation we used a set of cases (n=57) and population-based controls of European descent. The SNP KCNE1 D85N (rs1805128), known to modulate an important potassium current in the heart, predicted diLQTS with an odds ratio of 9.0 (95% confidence interval: 3.5–22.9). The variant allele was present in 8.6% of cases, 2.9% of drug-exposed controls, and 1.8% of population controls. In the validation cohort the variant allele was present in 3.5% of cases, and in 1.4% of controls.
Conclusions
This high-density candidate SNP approach identified a key potassium channel susceptibility allele that may be associated with the rare adverse drug reaction torsades de pointes.
doi:10.1161/CIRCGENETICS.111.960930
PMCID: PMC3288202  PMID: 22100668
candidate genes; death, sudden; SNP; torsade de pointes; adverse drug events
19.  Clinically actionable genotypes among 10,000 patients with preemptive pharmacogenomic testing 
Since September 2010, over 10,000 patients have undergone preemptive, panel-based pharmacogenomic testing through the Vanderbilt Pharmacogenomic Resource for Enhanced Decisions in Care and Treatment (PREDICT) program. Analysis of the genetic data from the first 9,589 individuals reveals the frequency of genetic variants is concordant with published allele frequencies. Based on five currently implemented drug-genome interactions, the multiplexed test identified one or more actionable variants in 91% of the genotyped patients and in 96% of African-American patients. Using medication exposure data from electronic medical records, we compared a theoretical “reactive,” prescription-triggered, serial single-gene testing strategy to our preemptive, multiplexed genotyping approach. Reactive genotyping would have generated 14,656 genetic tests. These data highlight three advantages of preemptive genotyping: 1)the vast majority of patients carry at least one pharmacogene variant; 2)data are available at the point of care; and 3)there is a substantial reduction in testing burden compared to a reactive strategy.
doi:10.1038/clpt.2013.229
PMCID: PMC3961508  PMID: 24253661
Pharmacogenomics; Genetic Testing
20.  Common SCN10A variants modulate PR interval and heart rate response during atrial fibrillation 
Europace  2013;16(4):485-490.
Aims
SCN10A encodes the sodium channel Nav1.8 implicated by genome-wide association studies as a modulator of atrioventricular conduction (PR interval). In a cohort of patients with atrial fibrillation (AF), we examined whether there was an association between common variants in SCN10A and both the PR interval during normal sinus rhythm and the heart rate response during AF.
Methods and results
Patients prospectively enrolled in the Vanderbilt AF registry with electrocardiograms in normal sinus rhythm and/or AF within 1 year of enrollment were genotyped for two common SCN10A variants rs6795970 and rs12632942. Both variants were associated with the PR interval duration in a gene-dose effect on unadjusted analysis; after adjustment for the covariates age, gender, body mass index, hypertension, congestive heart failure, and medication usage, the association remained for rs6795970 only (P = 0.012, partial R2 = 0.0139). On unadjusted analysis, heart rate response during AF was associated with rs6795970 (P = 0.035, partial R2 = 0.015), but not with rs12632942 (P = 0.89), and neither association was significant after adjustment for covariates.
Conclusion
The common variant rs6795970 in SCN10A is associated with the PR interval duration among healthy patients and those with AF. In addition, this single nucleotide polymorphism trended towards an association with heart rate response during AF indicating the importance of this common SCN10A polymorphism as a marker of atrioventricular conduction.
doi:10.1093/europace/eut278
PMCID: PMC3977588  PMID: 24072447
Atrial fibrillation; SCN10A; PR interval
21.  Using Systems Approaches to Address Challenges for Clinical Implementation of Pharmacogenomics 
Many genetic variants have been shown to affect drug response through changes in drug efficacy and likelihood of adverse effects. Much of pharmacogenomic science has focused on discovering and clinically implementing single gene variants with large effect sizes. Given the increasing complexities of drug responses and their variability, a systems approach may be enabling for discovery of new biology in this area. Further, systems approaches may be useful in addressing challenges in moving these data to clinical implementation, including creation of predictive models of drug response phenotypes, improved clinical decision-making through complex biological models, improving strategies for integrating genomics into clinical practice, and evaluating the impact of implementation programs on public health.
doi:10.1002/wsbm.1255
PMCID: PMC3944797  PMID: 24319008
22.  Cardiovascular Pharmacogenomics 
Circulation research  2011;109(7):807-820.
Patients vary in their responses to drug therapy, and some of that variability is genetically-determined. This review outlines general approaches used to identify genetic variation that influences drug response. Examples from specific therapeutic areas are presented: cholesterol management, arrhythmias, heart failure, hypertension, warfarin anticoagulation, and anti-platelet agents. A brief view of potential pathways to implementation is presented.
doi:10.1161/CIRCRESAHA.110.230995
PMCID: PMC3201825  PMID: 21921273
genetics; pharmacogenetics; pharmacogenomics; drug therapy
23.  Striking in Vivo Phenotype of a Disease-Associated Human SCN5A Mutation Producing Minimal Changes in Vitro 
Circulation  2011;124(9):1001-1011.
Background
The D1275N SCN5A mutation has been associated with a range of unusual phenotypes including conduction disease and dilated cardiomyopathy (DCM) as well as atrial and ventricular tachyarrhythmias. However, when D1275N is studied in heterologous expression systems, most studies show near-normal sodium channel function. Thus, the relationship of the variant to the clinical phenotypes remains uncertain.
Methods and results
We identified D1275N in a patient with atrial flutter, atrial standstill, conduction disease, and sinus node dysfunction. There was no major difference in biophysical properties between wild-type and D1275N channels expressed in CHO or tsA201 cells in the absence or presence of β1 subunits. To determine D1275N function in vivo, the Scn5a locus was modified to knock out the mouse gene, and the full-length wild-type (H) or D1275N (DN) human SCN5A cDNAs were then inserted at the modified locus using recombinase mediated cassette exchange. Mice carrying the DN allele displayed slow conduction, heart block, atrial fibrillation, ventricular tachycardia, and a DCM phenotype, with no significant fibrosis or myocyte disarray on histological examination. The DN allele conferred gene-dose dependent increases in SCN5A mRNA abundance, but reduced sodium channel protein abundance and peak sodium current amplitudes (H/H, −41.0±2.9 pA/pF at −30mV; DN/H, 19.2±3.1 pA/pF, P<0.001 versus H/H; DN/DN, −9.3±1.1 pA/pF, P<0.001 versus H/H).
Conclusions
Although D1275N produces near normal currents in multiple heterologous expression experiments, our data establish this variant as a pathological mutation that generates conduction slowing, arrhythmias, and a DCM phenotype by reducing cardiac sodium current.
doi:10.1161/CIRCULATIONAHA.110.987248
PMCID: PMC3297976  PMID: 21824921
genetics; ion channels; cardiomyopathy; electrophysiology
24.  Informatic and functional approaches to identifying a regulatory region for the cardiac sodium channel 
Circulation research  2011;109(1):38-46.
Rationale
Although multiple lines of evidence suggest variable expression of the cardiac sodium channel gene SCN5A plays a role in susceptibility to arrhythmia, little is known about its transcriptional regulation.
Objective
We used in silico and in vitro experiments to identify possible non-coding sequences important for transcriptional regulation of SCN5A. The results were extended to mice in which a putative regulatory region was deleted.
Methods and Results
We identified 92 non-coding regions highly conserved (>70%) between human and mouse SCN5A orthologs. Three conserved non-coding sequences (CNS) showed significant (>5-fold) activity in luciferase assays. Further in vitro studies indicated one, CNS28 in intron 1, as potential regulatory region. Using Recombinase-Mediated Cassette Exchange (RMCE), we generated mice in which a 435 bp region encompassing CNS28 was removed. Animals homozygous for the deletion showed significant increases in SCN5A transcripts, NaV1.5 protein abundance, and sodium current measured in isolated ventricular myocytes. ECGs revealed a significantly shorter QRS (10.7±0.2ms in controls vs. 9.7±0.2ms in knockouts) indicating more rapid ventricular conduction. In vitro analysis of CNS28 identified a short 3′ segment within this region required for regulatory activity and including an E-box motif. Deletion of this segment reduced reporter activity to 3.6±0.3% of baseline in CHO cells and 16±3% in myocytes (both P<0.05), and mutation of individual sites in the E-box restored activity to 62±4% and 57±2% of baseline in CHO cells and myocytes, respectively (both P<0.05).
Conclusions
These findings establish that regulation of cardiac sodium channel expression modulates channel function in vivo, and identify a non-coding region underlying this regulation.
doi:10.1161/CIRCRESAHA.110.235630
PMCID: PMC3135383  PMID: 21566215
Gene Expression Regulation; Sodium Channels; Mice; Transgenic
25.  Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization 
Arking, Dan E. | Pulit, Sara L. | Crotti, Lia | van der Harst, Pim | Munroe, Patricia B. | Koopmann, Tamara T. | Sotoodehnia, Nona | Rossin, Elizabeth J. | Morley, Michael | Wang, Xinchen | Johnson, Andrew D. | Lundby, Alicia | Gudbjartsson, Daníel F. | Noseworthy, Peter A. | Eijgelsheim, Mark | Bradford, Yuki | Tarasov, Kirill V. | Dörr, Marcus | Müller-Nurasyid, Martina | Lahtinen, Annukka M. | Nolte, Ilja M. | Smith, Albert Vernon | Bis, Joshua C. | Isaacs, Aaron | Newhouse, Stephen J. | Evans, Daniel S. | Post, Wendy S. | Waggott, Daryl | Lyytikäinen, Leo-Pekka | Hicks, Andrew A. | Eisele, Lewin | Ellinghaus, David | Hayward, Caroline | Navarro, Pau | Ulivi, Sheila | Tanaka, Toshiko | Tester, David J. | Chatel, Stéphanie | Gustafsson, Stefan | Kumari, Meena | Morris, Richard W. | Naluai, Åsa T. | Padmanabhan, Sandosh | Kluttig, Alexander | Strohmer, Bernhard | Panayiotou, Andrie G. | Torres, Maria | Knoflach, Michael | Hubacek, Jaroslav A. | Slowikowski, Kamil | Raychaudhuri, Soumya | Kumar, Runjun D. | Harris, Tamara B. | Launer, Lenore J. | Shuldiner, Alan R. | Alonso, Alvaro | Bader, Joel S. | Ehret, Georg | Huang, Hailiang | Kao, W.H. Linda | Strait, James B. | Macfarlane, Peter W. | Brown, Morris | Caulfield, Mark J. | Samani, Nilesh J. | Kronenberg, Florian | Willeit, Johann | Smith, J. Gustav | Greiser, Karin H. | zu Schwabedissen, Henriette Meyer | Werdan, Karl | Carella, Massimo | Zelante, Leopoldo | Heckbert, Susan R. | Psaty, Bruce M. | Rotter, Jerome I. | Kolcic, Ivana | Polašek, Ozren | Wright, Alan F. | Griffin, Maura | Daly, Mark J. | Arnar, David O. | Hólm, Hilma | Thorsteinsdottir, Unnur | Denny, Joshua C. | Roden, Dan M. | Zuvich, Rebecca L. | Emilsson, Valur | Plump, Andrew S. | Larson, Martin G. | O'Donnell, Christopher J. | Yin, Xiaoyan | Bobbo, Marco | D'Adamo, Adamo P. | Iorio, Annamaria | Sinagra, Gianfranco | Carracedo, Angel | Cummings, Steven R. | Nalls, Michael A. | Jula, Antti | Kontula, Kimmo K. | Marjamaa, Annukka | Oikarinen, Lasse | Perola, Markus | Porthan, Kimmo | Erbel, Raimund | Hoffmann, Per | Jöckel, Karl-Heinz | Kälsch, Hagen | Nöthen, Markus M. | consortium, HRGEN | den Hoed, Marcel | Loos, Ruth J.F. | Thelle, Dag S. | Gieger, Christian | Meitinger, Thomas | Perz, Siegfried | Peters, Annette | Prucha, Hanna | Sinner, Moritz F. | Waldenberger, Melanie | de Boer, Rudolf A. | Franke, Lude | van der Vleuten, Pieter A. | Beckmann, Britt Maria | Martens, Eimo | Bardai, Abdennasser | Hofman, Nynke | Wilde, Arthur A.M. | Behr, Elijah R. | Dalageorgou, Chrysoula | Giudicessi, John R. | Medeiros-Domingo, Argelia | Barc, Julien | Kyndt, Florence | Probst, Vincent | Ghidoni, Alice | Insolia, Roberto | Hamilton, Robert M. | Scherer, Stephen W. | Brandimarto, Jeffrey | Margulies, Kenneth | Moravec, Christine E. | Fabiola Del, Greco M. | Fuchsberger, Christian | O'Connell, Jeffrey R. | Lee, Wai K. | Watt, Graham C.M. | Campbell, Harry | Wild, Sarah H. | El Mokhtari, Nour E. | Frey, Norbert | Asselbergs, Folkert W. | Leach, Irene Mateo | Navis, Gerjan | van den Berg, Maarten P. | van Veldhuisen, Dirk J. | Kellis, Manolis | Krijthe, Bouwe P. | Franco, Oscar H. | Hofman, Albert | Kors, Jan A. | Uitterlinden, André G. | Witteman, Jacqueline C.M. | Kedenko, Lyudmyla | Lamina, Claudia | Oostra, Ben A. | Abecasis, Gonçalo R. | Lakatta, Edward G. | Mulas, Antonella | Orrú, Marco | Schlessinger, David | Uda, Manuela | Markus, Marcello R.P. | Völker, Uwe | Snieder, Harold | Spector, Timothy D. | Ärnlöv, Johan | Lind, Lars | Sundström, Johan | Syvänen, Ann-Christine | Kivimaki, Mika | Kähönen, Mika | Mononen, Nina | Raitakari, Olli T. | Viikari, Jorma S. | Adamkova, Vera | Kiechl, Stefan | Brion, Maria | Nicolaides, Andrew N. | Paulweber, Bernhard | Haerting, Johannes | Dominiczak, Anna F. | Nyberg, Fredrik | Whincup, Peter H. | Hingorani, Aroon | Schott, Jean-Jacques | Bezzina, Connie R. | Ingelsson, Erik | Ferrucci, Luigi | Gasparini, Paolo | Wilson, James F. | Rudan, Igor | Franke, Andre | Mühleisen, Thomas W. | Pramstaller, Peter P. | Lehtimäki, Terho J. | Paterson, Andrew D. | Parsa, Afshin | Liu, Yongmei | van Duijn, Cornelia | Siscovick, David S. | Gudnason, Vilmundur | Jamshidi, Yalda | Salomaa, Veikko | Felix, Stephan B. | Sanna, Serena | Ritchie, Marylyn D. | Stricker, Bruno H. | Stefansson, Kari | Boyer, Laurie A. | Cappola, Thomas P. | Olsen, Jesper V. | Lage, Kasper | Schwartz, Peter J. | Kääb, Stefan | Chakravarti, Aravinda | Ackerman, Michael J. | Pfeufer, Arne | de Bakker, Paul I.W. | Newton-Cheh, Christopher
Nature genetics  2014;46(8):826-836.
The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal Mendelian Long QT Syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals we identified 35 common variant QT interval loci, that collectively explain ∼8-10% of QT variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 novel QT loci in 298 unrelated LQTS probands identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode for proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies novel candidate genes for ventricular arrhythmias, LQTS,and SCD.
doi:10.1038/ng.3014
PMCID: PMC4124521  PMID: 24952745
genome-wide association study; QT interval; Long QT Syndrome; sudden cardiac death; myocardial repolarization; arrhythmias

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