Filamin C variants are associated with a distinctive clinical and immunohistochemical arrhythmogenic cardiomyopathy phenotype.

BACKGROUND: Pathogenic variants in the filamin C (FLNC) gene are associated with inherited cardiomyopathies including dilated cardiomyopathy with an arrhythmogenic phenotype. We evaluated FLNC variants in arrhythmogenic cardiomyopathy (ACM) and investigated the disease mechanism at a molecular level. METHODS: 120 gene-elusive ACM patients who fulfilled diagnostic criteria for arrhythmogenic right ventricular cardiomyopathy (ARVC) were screened by whole exome sequencing. Fixed cardiac tissue from FLNC variant carriers who had died suddenly was investigated by histology and immunohistochemistry. RESULTS: Novel or rare FLNC variants, four null and five variants of unknown significance, were identified in nine ACM probands (7.5%). In FLNC null variant carriers (including family members, n = 16) Task Force diagnostic electrocardiogram repolarization/depolarization abnormalities were uncommon (19%), echocardiography was normal in 69%, while 56% had >500 ventricular ectopics/24 h or ventricular tachycardia on Holter and 67% had late gadolinium enhancement (LGE) on cardiac magnetic resonance imaging (CMRI). Ten gene positive individuals (63%) had abnormalities on ECG or CMRI that are not included in the current diagnostic criteria for ARVC. Immunohistochemistry showed altered key protein distribution, distinctive from that observed in ARVC, predominantly in the left ventricle. CONCLUSIONS: ACM associated with FLNC variants presents with a distinctive phenotype characterized by Holter arrhythmia and LGE on CMRI with unremarkable ECG and echocardiographic findings. Clinical presentation in asymptomatic mutation carriers at risk of sudden death may include abnormalities which are currently non-diagnostic for ARVC. At the molecular level, the pathogenic mechanism related to FLNC appears different to classic forms of ARVC caused by desmosomal mutations

Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization.

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 loci associated with QT interval that collectively explain ∼8-10% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 new QT interval-associated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode 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 new candidate genes for ventricular arrhythmias, LQTS and SCD

Genome Wide Analysis of Drug-Induced Torsades de Pointes: Lack of Common Variants with Large Effect Sizes

Marked prolongation of the QT interval on the electrocardiogram associated with the polymorphic ventricular tachycardia Torsades de Pointes is a serious adverse event during treatment with antiarrhythmic drugs and other culprit medications, and is a common cause for drug relabeling and withdrawal. Although clinical risk factors have been identified, the syndrome remains unpredictable in an individual patient. Here we used genome-wide association analysis to search for common predisposing genetic variants. Cases of drug-induced Torsades de Pointes (diTdP), treatment tolerant controls, and general population controls were ascertained across multiple sites using common definitions, and genotyped on the Illumina 610k or 1M-Duo BeadChips. Principal Components Analysis was used to select 216 Northwestern European diTdP cases and 771 ancestry-matched controls, including treatment-tolerant and general population subjects. With these sample sizes, there is 80% power to detect a variant at genome-wide significance with minor allele frequency of 10% and conferring an odds ratio of ≥2.7. Tests of association were carried out for each single nucleotide polymorphism (SNP) by logistic regression adjusting for gender and population structure. No SNP reached genome wide-significance; the variant with the lowest P value was rs2276314, a non-synonymous coding variant in C18orf21 (p  =  3×10(-7), odds ratio = 2, 95% confidence intervals: 1.5-2.6). The haplotype formed by rs2276314 and a second SNP, rs767531, was significantly more frequent in controls than cases (p  =  3×10(-9)). Expanding the number of controls and a gene-based analysis did not yield significant associations. This study argues that common genomic variants do not contribute importantly to risk for drug-induced Torsades de Pointes across multiple drugs

Obesity reveals an association between blood pressure and the G-protein beta 3-subunit gene: a study of female dizygotic twins

The 825C>T polymorphism of the G-protein beta3-subunit gene (GNB3) has been associated with hypertension, although results are not entirely consistent In a sample of 282 female Caucasian dizygotic twins aged 21-80 years, we aimed to investigate the associations between blood pressure and five single nucleotide polymorphisms (SNPs) including the 825C>T and haplotypes of the GNB3 gene. The polymorphisms (-350A>G, 657A>T, 814G>A, 825C>T and 1429C>T) were genotyped by polymerase chain reaction-restriction enzyme assays. Regular association tests did not show a significant effect on blood pressure for any of the five SNPs. However, strongly significant interactions between the -350A>G, 825C>T and 1429C>T loci and adiposity (both body mass index and waist circumference) were observed for systolic blood pressure (Ps<0.01) as well as diastolic blood pressure (Ps<0.05), suggesting increases in adiposity amplify the effects of the SNPs on blood pressure. Haplotype analyses confirmed the effects of the GNB3 gene-obesity interaction on hypertension risk. Additionally, sib-transmission disequilibrium tests (sib-TDTs) showed significant associations with blood pressure for the 825C>T and 1429C>T loci. In summary, the presence of obesity reveals an association between blood pressure and the GNB3 gene in White females. Our data suggest that adiposity is a final pathway through which gene-lifestyle interactions may exert their effects on the development of hypertension. Our results from the combined SNIP, haplotype and sib-TDT analyses also support the hypothesis that the 825C>T is a susceptibility locus for hypertension, whereas effects of other loci on blood pressure may result from their strong linkage disequilibrium with the 825C>T locus. (C) 2004 Lippincott Williams Wilkins

Novel genotype-phenotype associations demonstrated by high-throughput sequencing in patients with hypertrophic cardiomyopathy

10.1136/heartjnl-2014-306387Heart1014294-30

Heritability of QT interval: How much is explained by genes for resting heart rate ?

Heritability of QT Interval. Introduction: Objective of this study was to determine the optimal (most heritable) phenotype for gene finding studies of QT interval in the general population. We also studied the extent to which heritability of QT interval can be explained by genes that also influence resting heart rate.Methods and Results: Subjects in this classic twin study were 105 monozygotic and 256 dizygotic female twin pairs (mean age: 49.9 +/- 11.5). ECG parameters were measured electronically using the Cardiofax ECG-9020. Quantitative genetic modeling was performed with Mx software. Best-fitting univariate models showed significant heritabilities for resting heart rate (0.55, 95% CI: 0.44-0.65), uncorrected QT interval (0.60, 95% CI: 0.49-0.69), and the Framingham QTc interval (0.50, 95% CI: 0.39-0.60). Familial resemblance of Bazett's QTc was best explained by shared environmental factors (0.34, 95% CI: 0.24-0.43) rather than genes. Simultaneously modeling heart rate and the uncorrected QT interval confirmed considerable heritabilities of 56% and 60%, respectively. Forty-four percent of the variance in QT interval was due to genes in common with heart rate, whereas 16% was due to genes specific to QT interval. The heritability of QT interval after the removal of effects shared with heart rate within the bivariate model (cf. QTc) was 51%.Conclusion: About a quarter of the QT interval heritability is due to genes specific for QT interval, while the majority is shared with genes for heart rate. Differences in QTc heritability estimates indicate that use of correction formulae is best avoided in gene finding studies to avoid erroneous results