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Cardiac Arrhythmia

Electrocardiographic traits

QT interval

UK10k

Long QT Syndrome (LQTS)

Drug-induced Arrhythmia

PR interval

QRS interval

MRC mouse network


 

Electrocardiographic traits

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QT interval

QT interval is a measure of cardiac repolarisation associated with risk of ventricular arrhythmias and sudden cardiac death. We have been working on the heritability and underlying genetic determinants of QT interval using monozygotic and dizygotic twins from the TwinsUK cohort (www.twinsuk.ac.uk). We were one of the first groups to identify the role of the phospholamban gene in determining QT interval in the general population and showed that a combined risk score using 11 of the QT-associated loci only explain about 10% of the heritability of QT. We are now involved in a much larger collaboration – the QT Interval International Consortium of Genome-wide Association Studies (QT-IGC). We work very closely with Prof Harold Snieder, a genetic epidemiologist with specific expertise in cardiovascular disease, obesity and type 2 diabetes, and his team (Dr Ilja Nolte, Dr Harriette Riese) based at the University of Groningen.

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UK10k

http://www.uk10k.org/

The Wellcome Trust-funded UK10k project is using next generation sequencing to understand the role of rare variants in health and disease. We are leading the ECG traits (QT interval and heart rate) analysis as part of the UK10k project, in which we have 2,000 twins from the TwinsUK cohort (www.twinsuk.ac.uk) who are extremely well phenotyped and have ECG data available, in addition to whole genome sequences. We are currently looking through the first results with the aim of confirming novel loci by imputation into the remaining cohort (~3,000 twins) and replication in other cohorts.

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Long QT Syndrome (LQTS)

Between 5-25% of individuals with LongQT syndrome do not harbour mutations in the known LQT genes. We are using whole exome sequencing to try and identify novel causal mutations, in addition to targeted resequencing of loci identified in published and unpublished meta-analyses of QT interval.

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Drug-induced Arrhythmia

Use of antiarrhythmic drugs is limited by the high incidence of serious adverse events including QT prolongation and torsades de pointes (TdP). We have previously shown that NOS1AP gene variants play a role in modulating QT intervals in healthy subjects, and other groups have shown that severity of presentation in LQTS is also modulated by NOS1AP variants. In collaboration with Dr Elijah Behr and Prof J Camm, Prof P Munroe and Prof D Roden, we were the first to show that common variations in the NOS1AP gene are associated with a significant increase in the risk of drug induced LQTS/TdP.

 

One of the main problems in identifying genetic markers of risk for TdP, which could be used to screen patients before prescription of a particular drug, is the rarity of the event that precludes accumulation of large case numbers. We are currently developing induced pluripotent stem cell derived cardiomyocytes from patients who have experience drug induced TdP in order to investigate further the mechanisms and pathways that lead to the adverse events. We hope that a greater understanding of the mechanisms will provide novel candidate genes to investigate for mutations in patients. 

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PR interval

The electrocardiographic PR interval reflects atrial and atrioventricular nodal conduction, disturbances of which increase risk of atrial fibrillation. As part of a large consortium (PRIMA – led by Dr Nona Sotoodehnia, Seattle), we are carrying out a meta-analysis of PR interval to identify further genetic determinants.

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QRS interval

The QRS interval, from the beginning of the Q wave to the end of the S wave on an electrocardiogram, reflects ventricular depolarization and conduction time and is a risk factor for mortality, sudden death and heart failure. We have recently identified common variants in 22 loci, which are associated with QRS duration and cardiac ventricular conduction. We are now in the process of following up these loci in individuals with Brugada syndrome who do not harbour mutations in the SCN5A gene (which account for ~30% of cases with Brugada syndrome).

 

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View our recent publications here.

 

MRC Mouse Network

We are involved in the Cardiovascular Trait Consortium: Blood pressure, electrocardiographic measures, ventricular dysfunction and heart failure. The MRC Mouse Network has been created in order to provide UK scientists with a forum to engage with a new and exciting international program systematically mutating every gene in the mouse genome and determining the resultant phenotypes of the mouse lines - the International Mouse Phenotyping Consortium or IMPC (www.mousephenotype.org). As part of the Cardiovascular Trait Consortium we have been able to nominate a list of genes we are most interested in working on, mostly selected based on published and unpublished Genome Wide Association Studies (GWAS) for which mutant mice will be made at Harwell.

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