TY - JOUR
T1 - Quantitative trait loci for electrocardiographic parameters and arrhythmia in the mouse
AU - Scicluna, Brendon P.
AU - Tanck, Michael W. T.
AU - Remme, Carol Ann
AU - Beekman, Leander
AU - Coronel, Ruben
AU - Wilde, Arthur A. M.
AU - Bezzina, Connie R.
PY - 2011
Y1 - 2011
N2 - Cardiac arrhythmias associated with sudden death are influenced by multiple biological pathways and are modulated by numerous genetic and environmental factors. Elevated heart rate and prolonged ECG indices of conduction and repolarization have been associated with risk of sudden death. Insight into the genetic underpinnings of these parameters thus provides an important means to the dissection of the genetic components modulating risk of sudden cardiac death. In this study we mapped quantitative trait loci (QTL) modulating heart rate, ECG indices of conduction and repolarization, and susceptibility to arrhythmia, in a conduction disease-sensitized F-2 mouse population. Heart rate, P-duration, PR-, QRS- and QT-interval were measured at baseline (n = 502) and after flecainide administration (n = 370) in mutant F2 progeny (F-2-MUT) resulting from the FVB/NJ-Scn5a1798(insD/+) X 129P2-Scn5a1798(insD/+) mouse cross. Episodes of sinus arrhythmia and ventricular tachyarrhythmia occurring post-flecainide were treated as binary traits. F2-MUT mice were genotyped using a genome-wide 768 single nucleotide polymorphism (SNP) panel. Interval mapping uncovered multiple QTL for ECG parameters and arrhythmia. A sex-interacting scan identified QTL displaying sex-dependency, and a two-dimensional QTL scan unmasked locus-locus (epistasis) interactions influencing ECG traits. A number of QTL coincided at specific chromosomal locations, suggesting pleiotropic effects at these loci. Through transcript profiling in myocardium from the parental mouse strains we identified genes co-localizing at the identified QTL that constitute highly relevant candidates for the observed effects. The detection of QTL influencing ECG indices and arrhythmia is an essential step towards identifying genetic networks for sudden, arrhythmic, cardiac death. (C) 2010 Elsevier Ltd. All rights reserved
AB - Cardiac arrhythmias associated with sudden death are influenced by multiple biological pathways and are modulated by numerous genetic and environmental factors. Elevated heart rate and prolonged ECG indices of conduction and repolarization have been associated with risk of sudden death. Insight into the genetic underpinnings of these parameters thus provides an important means to the dissection of the genetic components modulating risk of sudden cardiac death. In this study we mapped quantitative trait loci (QTL) modulating heart rate, ECG indices of conduction and repolarization, and susceptibility to arrhythmia, in a conduction disease-sensitized F-2 mouse population. Heart rate, P-duration, PR-, QRS- and QT-interval were measured at baseline (n = 502) and after flecainide administration (n = 370) in mutant F2 progeny (F-2-MUT) resulting from the FVB/NJ-Scn5a1798(insD/+) X 129P2-Scn5a1798(insD/+) mouse cross. Episodes of sinus arrhythmia and ventricular tachyarrhythmia occurring post-flecainide were treated as binary traits. F2-MUT mice were genotyped using a genome-wide 768 single nucleotide polymorphism (SNP) panel. Interval mapping uncovered multiple QTL for ECG parameters and arrhythmia. A sex-interacting scan identified QTL displaying sex-dependency, and a two-dimensional QTL scan unmasked locus-locus (epistasis) interactions influencing ECG traits. A number of QTL coincided at specific chromosomal locations, suggesting pleiotropic effects at these loci. Through transcript profiling in myocardium from the parental mouse strains we identified genes co-localizing at the identified QTL that constitute highly relevant candidates for the observed effects. The detection of QTL influencing ECG indices and arrhythmia is an essential step towards identifying genetic networks for sudden, arrhythmic, cardiac death. (C) 2010 Elsevier Ltd. All rights reserved
U2 - https://doi.org/10.1016/j.yjmcc.2010.09.009
DO - https://doi.org/10.1016/j.yjmcc.2010.09.009
M3 - Article
C2 - 20854825
SN - 0022-2828
VL - 50
SP - 380
EP - 389
JO - Journal of molecular and cellular cardiology
JF - Journal of molecular and cellular cardiology
IS - 3
ER -