Background - The KCNH2-encoded Kv11.1 (hERG) potassium channel is a critical regulator of cardiomyocyte (CM) action potential duration (APD). The majority of type 2 long QT syndrome (LQT2) stems from trafficking defective KCNH2 mutations. Recently, FDA-approved cystic fibrosis protein trafficking chaperone, lumacaftor (LUM), has been proposed as novel therapy for LQT2. Here, we test the efficacy of

Background - Mutation/variant-site specific risk stratification in long-QT syndrome type 1 (LQT1) has been well investigated, but it is still challenging to adapt current enormous genomic information to clinical aspects caused by each mutation/variant. We assessed a novel variant-specific risk stratification in LQT1 patients.Methods - We classified a pathogenicity of 141 KCNQ1 variants among 927 LQT1

Background - Sequence variation at chromosome 9p21.3 accounts for 20% of myocardial infarctions (MIs) in several populations. Whereas the risk conferred by the 9p21.3 locus appears to act independently of traditional risk factors, studies suggest that the association between 9p21.3 and MI is modified by glucose homeostasis and lifestyle. We examined if the 9p21.3 variant rs1333049, along with the previously

Background - Ischemic stroke is a devastating complication affecting children with sickle cell anemia (SCA). Genetic factors are likely to be important in determining the risk of stroke but are very poorly defined.Methods - We have studied a cohort of 19 children who had an overt ischaemic stroke before 4 years of age. We predicted genetic determinants of stroke would be more prominent in this group

Background - Missense variants in the MYH7-encoded beta myosin heavy chain 7 represent a leading cause of hypertrophic cardiomyopathy (HCM). MYH7-specific American College of Medical Genetics and Genomics (ACMG) variant classification guidelines were released recently, but have yet to be assessed independently. We set out to assess the performance of the MYH7-specific ACMG guidelines and determine

Background - Cardiac troponin I (TNNI3) gene mutations account for 3% of hypertrophic cardiomyopathy and carriers have a heterogeneous phenotype, with increased risk of sudden cardiac death. Only one mutation (p.Arg21Cys) has been reported in the N-terminus of the protein. In model organisms, it impairs protein kinase A phosphorylation, increases calcium sensitivity, and causes diastolic dysfunction

Background - Genetic analysis is a first-tier test in dilated cardiomyopathy (DCM). Electrical phenotypes are common in genetic DCM but their exact contribution to the clinical course and outcome is unknown. We determined the prevalence of pathogenic gene variants in a large unselected DCM population, and determined the role of electrical phenotypes in association with outcome.Methods - This study

Background - Resistin, a protein linked with inflammation and cardiometabolic diseases, is one of few proteins for which GWAS consistently report variants within and near the coding gene (RETN). Here, we took advantage of the reduced linkage disequilibrium in African populations to infer genetic causality for circulating resistin levels by performing GWAS, whole-exome analysis, fine-mapping, Mendelian

Background - Childhood-onset cardiomyopathy (CMP) is a heterogenous group of conditions the etiology of which is largely unknown. The influence of consanguinity on the genetics of CMP has not been addressed at a large scale.Methods - To unravel the genetic etiology of childhood-onset CMP in a consanguineous population a categorized approach was adopted. Cases with childhood-onset CMP were consecutively

Background - Familial sitosterolemia is a rare Mendelian disorder characterized by hyperabsorption and decreased biliary excretion of dietary sterols. Affected individuals typically have complete genetic deficiency - homozygous loss-of-function (LoF) variants - in the ATP-binding cassette transporter G5 (ABCG5) or G8 (ABCG8) genes and have substantially elevated plasma sitosterol and low-density lipoprotein

Background - Whole genome sequencing (WGS) costs are falling, yet, outside oncology, this information is seldom used in adult clinics. We piloted a rapid WGS (rWGS) workflow, focusing initially on estimating power for a feasibility study of introducing genome information into acute cardiovascular care.Methods - A prospective implementation study was conducted to test the feasibility and clinical utility

Background - Pathogenic variants in MYBPC3, encoding cardiac MyBP-C, are the most common cause of familial hypertrophic cardiomyopathy. A large number of unique MYBPC3 variants and relatively small genotyped HCM cohorts have precluded detailed genotype-phenotype correlations.Methods - Patients with HCM and MYBPC3 variants were identified from the Sarcomeric Human Cardiomyopathy Registry (SHaRe). Variant

Background - The P-wave duration (PWD) is an electrocardiographic (ECG) measurement that represents cardiac conduction in the atria. Shortened or prolonged PWD is associated with atrial fibrillation (AF). We used exome chip data to examine the associations between common and rare variants with PWD.Methods - Fifteen studies comprising 64,440 individuals (56,943 European, 5,681 African, 1,186 Hispanic

Background - LMNA is a known causative gene of dilated cardiomyopathy and familial conduction disturbance. Nonsense-mediated mRNA decay (NMD), normally caused by nonsense mutations, is a safeguard process to protect cells from deleterious effects of inappropriate proteins from mutated genes. NMD induced by non-stop codon mutations is rare. We investigated the effect of an LMNA missense mutation identified

Background - To assess the genetic architecture of hypertrophic cardiomyopathy (HCM) in patients of predominantly Chinese ancestry.Methods - We sequenced HCM disease genes in Singaporean patients (n=224) and Singaporean controls (n=3,634), compared findings with additional populations and Caucasian HCM cohorts (n=6,179) and performed in vitro functional studies.Results - Singaporean HCM patients had

Background - Inherited cardiac conditions (ICCs) present with a wide range of symptoms and may even result in sudden cardiac death (SCD). Relatives of probands with a confirmed pathogenic genetic variant are advised predictive DNA testing to enable prevention and treatment. In two previous cohort studies of 115 probands with a pathogenic variant, family-uptake of genetic counseling was assessed in

Background - The blood metabolome incorporates cues from the environment as well as the host's genetic background, potentially offering a holistic view of an individual's health status.Methods - We have compiled a vast resource of 1H-NMR metabolomics and phenotypic data encompassing over 25,000 samples derived from 26 community and hospital-based cohorts.Results - Using this resource, we constructed

Background - Familial hypercholesterolemia (FH) is a common autosomal co-dominant genetic disorder, which causes elevated levels of low-density lipoprotein cholesterol (LDL-C) and increased risk of premature atherosclerotic cardiovascular disease (ASCVD). Even among individuals with monogenic FH, there is substantial interindividual variability in LDL-C levels and risk of ASCVD. We assessed the influence

Background - Coronary artery disease (CAD) is accelerated in subjects with type 2 diabetes (T2D).Methods - To test whether this reflects differential genetic influences on CAD-risk in subjects with T2D, we performed a systematic assessment of genetic overlap between CAD and T2D in 66,643 subjects (27,708 with CAD and 24,259 with T2D). Variants showing apparent association with CAD in stratified analyses

Background:De novo genic and copy number variants are enriched in patients with congenital heart disease, particularly those with extra-cardiac anomalies. The impact of de novo damaging variants on outcomes following cardiac repair is unknown.Methods:We studied 2517 patients with congenital heart disease who had undergone whole-exome sequencing as part of the CHD GENES study (Congenital Heart Disease

Background:For most disease-related traits the magnitude of the contribution of genetic factors in adolescents remains unclear.Methods:Twenty continuous traits related to anthropometry, cardiovascular and renal function, metabolism, and inflammation were selected from the ongoing prospective Tracking Adolescents’ Individual Lives Survey cohort in the Netherlands with measurements of up to 5 waves from

Background:Abnormal QT interval responses to heart rate (QT dynamics) is an independent risk predictor for cardiovascular disease in patients, but its genetic basis and prognostic value in a population-based cohort have not been investigated.Methods:QT dynamics during exercise and recovery were derived in 56 643 individuals from UK Biobank without a history of cardiovascular events. Genome-wide association

Background:Left ventricular noncompaction (LVNC) is a hereditary type of cardiomyopathy. Although it is associated with high morbidity and mortality, the related ion channel gene variants in children have not been fully investigated. This study aimed to elucidate the ion channel genetic landscape of LVNC and identify genotype-phenotype correlations in a large Japanese cohort.Methods:We enrolled 206

Background:Dilated cardiomyopathy (DCM) is a genetically heterogeneous cardiac disease characterized by progressive ventricular enlargement and reduced systolic function. Here, we report genetic and functional analyses implicating the rat sarcoma signaling protein, SOS1 (Son of sevenless homolog 1), in DCM pathogenesis.Methods:Exome sequencing was performed on 412 probands and family members from our

Background:Left ventricular ejection fraction (EF) is an indicator of cardiac function, usually assessed in individuals with heart failure and other cardiac conditions. Although family studies indicate that EF has an important genetic component with heritability estimates up to 0.61, to date only 6 EF-associated loci have been reported.Methods:Here, we conducted a genome-wide association study (GWAS)

Background:We examined how expanding electrocardiographic trait genome-wide association studies to include ancestrally diverse populations, prioritize more precise phenotypic measures, and evaluate evidence for shared genetic effects enabled the detection and characterization of loci.Methods:We decomposed 10 seconds, 12-lead electrocardiograms from 34 668 multi-ethnic participants (15% Black; 30% Hispanic/Latino)

Background:Genetic factors that influence kidney traits have been understudied for low-frequency and ancestry-specific variants.Methods:This study used imputed whole-genome sequencing from the Trans-Omics for Precision Medicine project to identify novel loci for estimated glomerular filtration rate and urine albumin-to-creatinine ratio in up to 12 207 Hispanics/Latinos. Replication was performed in

Background:The increase in serum triglyceride (TG) concentrations in response to a meal is considered a risk factor for cardiovascular disease. We aimed to elucidate the genetics of the postprandial TG response through genome-wide association studies (GWAS).Methods:Participants of the NEO (Netherlands Epidemiology of Obesity) study (n=5630) consumed a liquid mixed meal after an overnight fast. GWAS

Background:DNA methylation patterns associated with habitual diet have not been well studied.Methods:Diet quality was characterized using a Mediterranean-style diet score and the Alternative Healthy Eating Index score. We conducted ethnicity-specific and trans-ethnic epigenome-wide association analyses for diet quality and leukocyte-derived DNA methylation at over 400 000 CpGs (cytosine-guanine dinucleotides)

Background:The discovery that much of the non–protein-coding genome is transcribed and plays a diverse functional role in fundamental cellular processes has led to an explosion in the development of tools and technologies to investigate the role of these noncoding RNAs in cardiovascular health. Furthermore, identifying noncoding RNAs for targeted therapeutics to treat cardiovascular disease is an emerging

Advances in human genetics are improving the understanding of a variety of inherited cardiovascular diseases, including cardiomyopathies, arrhythmic disorders, vascular disorders, and lipid disorders such as familial hypercholesterolemia. However, not all cardiovascular practitioners are fully aware of the utility and potential pitfalls of incorporating genetic test results into the care of patients

Background:Increasing use of genetic tests have identified many variants of uncertain significance (VUS) in genes associated with inherited arrhythmias and cardiomyopathies. Evaluation of clinical practices, including medical management recommendations for VUS patients and their families, is important to prevent over- or under-treatment that may result in morbidity or mortality. The purpose of this

Background:While postoperative myocardial injury remains a major driver of morbidity and mortality, the ability to accurately identify patients at risk remains limited despite decades of clinical research. The role of genetic information in predicting myocardial injury after noncardiac surgery (MINS) remains unknown and requires large scale electronic health record and genomic data sets.Methods:In

Background:Warfarin is an effective treatment for thromboembolic disease but has a narrow therapeutic index; optimal anticoagulation dosage can differ tremendously among individuals. We aimed to evaluate whether genotype-guided warfarin dosing is superior to routine clinical dosing for the outcomes of interest in Chinese patients.Methods:We conducted a multicenter, randomized, single-blind, parallel-controlled

Background:Alcohol intake influences plasma lipid levels, and such effects may be moderated by genetic variants. We aimed to characterize the role of aggregated rare and low-frequency protein-coding variants in gene by alcohol consumption interactions associated with fasting plasma lipid levels.Methods:In the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, fasting plasma triglycerides

Background:Brugada syndrome (BrS) is an oligogenic arrhythmic disease with increased risk of sudden cardiac arrest. Several BrS or ECG traits-related single-nucleotide polymorphisms (SNPs) were identified through previous genome-wide association studies in white patients. We aimed to validate these SNPs in BrS patients in the Taiwanese population, assessing the cumulative effect of risk alleles and

Background:Long-QT syndrome (LQTS) is characterized by a prolonged heart rate–corrected QT interval (QTc). Genome-wide association studies identified common genetic variants that collectively explain ≈8% to 10% of QTc variation in the general population.Methods:Overall, 423 patients with LQT1, LQT2, or LQT3 were genotyped for 61 QTc-associated genetic variants used in a prototype QTc–polygenic risk

BACKGROUND Genome-wide association studies provided many biological insights into coronary artery disease (CAD), but these studies were mainly performed in Europeans. Genome-wide association studies in diverse populations have the potential to advance our understanding of CAD. METHODS We conducted 2 genome-wide association studies for CAD in the Japanese population, which included 12 494 cases and

BACKGROUND Aortic stenosis (AS) contributes to cardiovascular mortality and morbidity but disease mechanisms remain largely unknown. Recent evidence associates a single nucleotide polymorphism rs174547 within the FADS1 gene, encoding FADS1 (fatty acid desaturase 1), with risk of several cardiovascular outcomes, including AS. FADS1 encodes a rate-limiting enzyme for ω-3 and ω-6 fatty acid metabolism

BACKGROUND Common chromosome 9p21 single nucleotide polymorphisms (SNPs) increase coronary heart disease risk, independent of traditional lipid risk factors. However, lipids comprise large numbers of structurally related molecules not measured in traditional risk measurements, and many have inflammatory bioactivities. Here, we applied lipidomic and genomic approaches to 3 model systems to characterize

BACKGROUND The causal role of alcohol consumption for cardiovascular disease remains unclear. We used Mendelian randomization (MR) to predict the effect of alcohol consumption on 8 cardiovascular diseases. METHODS Up to 94 single-nucleotide polymorphisms were used as instrumental variables for alcohol consumption. Genetic association estimates for cardiovascular diseases were obtained from large-scale

BACKGROUND Atrial fibrillation is a common cardiovascular disorder, characterized by irregular electrical activity in the upper chambers of the heart. Both chronic cardiometabolic risk factors and genetics have been shown to contribute to the development of atrial fibrillation. Birthweight has also been associated with risk of atrial fibrillation. METHODS In the current study, we utilized a genetic

BACKGROUND Triadin knockout syndrome (TKOS) is a potentially lethal arrhythmia disorder caused by recessively inherited null variants in TRDN-encoded cardiac triadin. Despite its malignant phenotype, the prevalence of TKOS in sudden infant death syndrome and sudden unexplained death in the young is unknown. METHODS Exome sequencing was performed on 599 sudden infant death syndrome and 258 sudden unexplained

BACKGROUND The common intronic deletion, MYBPC3Δ25, detected in 4% to 8% of South Asian populations, is reported to be associated with cardiomyopathy, with ≈7-fold increased risk of disease in variant carriers. Here, we examine the contribution of MYBPC3Δ25 to hypertrophic cardiomyopathy (HCM) in a large patient cohort. METHODS Sequence data from 2 HCM cohorts (n=5393) was analyzed to determine MYBPC3Δ25