Background:Mitral valve prolapse (MVP) is a common cardiac valve disease, which affects 1 in 40 in the general population. Previous genome-wide association study have identified 6 risk loci for MVP. But these loci explained only partially the genetic risk for MVP. We aim to identify additional risk loci for MVP by adding data set from the UK Biobank.Methods:We reanalyzed 1007/479 cases from the MVP-France

Background:Brugada syndrome (BrS) is associated with mutations in the cardiac sodium channel gene, SCN5A. However, genetic studies of patients with BrS with arrhythmic events have been limited. We sought to compare various clinical, ECG, and electrophysiological parameters according to SCN5A genotype in a large cohort of BrS probands with first arrhythmic event.Methods:Survey on Arrhythmic Events in

Background:Current lipid guidelines suggest measurement of Lp(a) (lipoprotein[a]) and ApoB (apolipoprotein B) for atherosclerotic cardiovascular disease risk assessment. Polygenic risk scores (PRSs) for Lp(a) and ApoB may identify individuals unlikely to have elevated Lp(a) or ApoB and thus reduce such suggested testing.Methods:PRSs were developed using LASSO regression among 273 222 and 356 958 UK

Background:Polygenic risk scores (PRS) may enhance risk stratification for coronary heart disease among young adults. Whether a coronary heart disease PRS improves prediction beyond modifiable risk factors in this population is not known.Methods:Genotyped adults aged 18 to 35 years were selected from the CARDIA study (Coronary Artery Risk Development in Young Adults; n=1132) and FOS (Framingham Offspring

Background:Atrial fibrillation (AF) risk estimation using clinical factors with or without genetic information may identify AF screening candidates more accurately than the guideline-based age threshold of ≥65 years.Methods:We analyzed 4 samples across the United States and Europe (derivation: UK Biobank; validation: FINRISK, Geisinger MyCode Initiative, and Framingham Heart Study). We estimated AF

Background:The p.Val142Ile variant, predominantly found among people of African descent, is the most common cause of variant transthyretin amyloidosis and carriers predominantly develop a cardiomyopathy (variant transthyretin amyloidosis cardiomyopathy) phenotype. Yet, there are conflicting data on the prevalence and outcomes of p.Val142Ile variant carriers.Methods:We performed a systematic review

Background:Heterozygous TTN truncating variants cause 10% to 20% of idiopathic dilated cardiomyopathy (DCM). Although variants which disrupt canonical splice signals (ie, invariant dinucleotide of splice donor site, invariant dinucleotide of the splice acceptor site) at exon-intron junctions are readily recognized as TTN truncating variants, the effects of other nearby sequence variations on splicing

Genomics research has improved our understanding of the genetic basis for human traits and diseases. This progress is now being translated into clinical care as we move toward a future of precision medicine. Many hope that expanded use of genomic testing will improve disease screening, diagnosis, risk stratification, and treatment. In many respects, cardiovascular medicine is leading this charge. However

Genetic diseases that affect the cardiovascular system are relatively common and include cardiac channelopathies, cardiomyopathies, aortopathies, hypercholesterolemias, and structural diseases of the heart and great vessels. The rapidly expanding availability of clinical genetic testing leverages decades of research into the genetic origins of these diseases, helping inform diagnosis, clinical management

Background:Acute coronary syndrome (ACS) is a clinically significant presentation of coronary heart disease. Genetic information has been proposed to improve prediction beyond well-established clinical risk factors. While polygenic scores (PS) can capture an individual’s genetic risk for ACS, its prediction performance may vary in the context of diverse correlated clinical conditions. Here, we aimed

Background:Myocarditis is one of the most common causes leading to heart failure in children and a possible genetic background has been postulated. We sought to characterize the clinical and genetic characteristics in patients with myocarditis ≤18 years of age to predict outcome.Methods:A cohort of 42 patients (Genetics in Pediatric Myocarditis) with biopsy-proven myocarditis underwent genetic testing

Background:Genetic testing is indicated for children with a personal or family history of hereditary cardiomyopathy to determine appropriate management and inform risk stratification for family members. The implications of a positive genetic result for children can potentially impact emotional well-being. Given the nuances of cardiomyopathy genetic testing for minors, this study aimed to understand

Background:Lp(a) (lipoprotein [a]) levels are higher in individuals of African ancestry (AA) than in individuals of European ancestry (EA). We examined associations of genetically predicted Lp(a) levels with (1) atherosclerotic cardiovascular disease subtypes: coronary heart disease, cerebrovascular disease, peripheral artery disease, and abdominal aortic aneurysm and (2) nonatherosclerotic cardiovascular

Background:Coronary artery calcification (CAC) and carotid artery intima-media thickness (cIMT) are measures of subclinical atherosclerosis in asymptomatic individuals and strong risk factors for cardiovascular disease. Type 2 diabetes (T2D) is an independent cardiovascular disease risk factor that accelerates atherosclerosis.Methods:We performed meta-analyses of genome-wide association studies in

Background:Acute myocarditis (AM) is a well-known cause of sudden death and heart failure, often caused by prevalent viruses. We previously showed that some pediatric AM correlates with putatively damaging variants in genes related to cardiomyocyte structure and function. We sought to evaluate whether deleterious cardiomyopathic variants were enriched among fatal pediatric AM cases in New York City

Background:Alterations in electrocardiographic (ECG) intervals are well-known markers for arrhythmia and sudden cardiac death (SCD) risk. While the genetics of arrhythmia syndromes have been studied, relations between electrocardiographic intervals and rare genetic variation at a population level are poorly understood.Methods:Using a discovery sample of 29 000 individuals with whole-genome sequencing

Background:Tetralogy of Fallot (TOF)—the most common cyanotic heart defect in newborns—has evidence of multiple genetic contributing factors. Identifying variants that are clinically relevant is essential to understand patient-specific disease susceptibility and outcomes and could contribute to delineating pathomechanisms.Methods:Using a clinically driven strategy, we reanalyzed exome sequencing data

Background:Elevated Lp(a) (Lipoprotein(a)) levels are associated with coronary artery disease (CAD), ischemic stroke (IS), and calcific aortic valve stenosis (CAVS). Studies investigating the association between Lp(a) levels and these diseases in women have yielded inconsistent results.Methods:To investigate the association of Lp(a) with sex-specific cardiovascular outcomes, we determined the association

Background:The proliferation of genetic profiling has revealed many associations between genetic variations and disease. However, large-scale phenotyping efforts in largely healthy populations, coupled with DNA sequencing, suggest variants currently annotated as pathogenic are more common in healthy populations than previously thought. In addition, novel and rare variants are frequently observed in

Background:ChREBP (carbohydrate responsive element binding protein) is a transcription factor that responds to sugar consumption. Sugar-sweetened beverage (SSB) consumption and genetic variants in the CHREBP locus have separately been linked to HDL-C (high-density lipoprotein cholesterol) and triglyceride concentrations. We hypothesized that SSB consumption would modify the association between genetic

Background:Branched-chain amino acids (BCAAs; isoleucine, leucine, and valine) correlate with insulin resistance and poor glucose control, which may in part explain associations between type 2 diabetes and cardiovascular disease. However, the relationships of BCAAs with other cardiometabolic pathways, including inflammation and dyslipidemia, are unclear. We hypothesized that plasma BCAAs would correlate

Recent advances in next-genetic sequencing technology have facilitated an expansion in the use of exome and genome sequencing in the research and clinical settings. While this has aided in the genetic diagnosis of individuals with atypical clinical presentations, there has been a marked increase in the number of incidentally identified variants of uncertain diagnostic significance in genes identified

Historically marginalized racial and ethnic groups and Indigenous peoples are burdened by significant health inequities that are compounded by their underrepresentation in genetic and genomic research. Of all genome-wide association study participants, ≈79% are of European descent, despite this group constituting only 16% of the global population. For underrepresented populations, polygenic risk scores

In the April 2021 issue of Circulation: Genomic and Precision Medicine, the license for the article by Riveros-Mckay et al (Integrated Polygenic Tool Substantially Enhances Coronary Artery Disease Prediction. Circ Genom Precis Med.2021;14:e003304) has been changed in compliance with funding requirements. The article is published under the creative commons license CC BY. This correction has been made

Background:Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited disease characterized by ventricular arrhythmias and progressive ventricular dysfunction. Genetic testing is recommended, and a pathogenic variant in an ARVC-associated gene is a major criterion for diagnosis according to the 2010 Task Force Criteria. As incorrect attribution of a gene to ARVC can contribute to misdiagnosis

Background:Polygenic risk scores (PRS) for coronary heart disease (CHD) may contribute to assess the overall risk of CHD. We evaluated how PRS may influence CHD risk when the distribution of age-at-onset, sex, and family health history differ significantly.Methods:Our study included 3 family-based ascertainments: LLFS (Long Life Family Study, NIndividuals=4572), which represents a low CHD risk, and

Background:Genetic testing can determine family screening strategies and has prognostic and diagnostic value in hypertrophic cardiomyopathy (HCM). However, it can also pose a significant psychosocial burden. Conventional scoring systems offer modest ability to predict genotype positivity. The aim of our study was to develop a novel prediction model for genotype positivity in patients with HCM by applying

Background:Following an unexplained cardiac arrest, clinical genetic testing is increasingly becoming standard of care. Periodic review of variant classification is required, as reinterpretation can change the diagnosis, prognosis, and management of patients and their relatives.Methods:This study aimed to develop and validate a standardized algorithm to facilitate clinical application of the 2015 American

Background:Prior epidemiological studies demonstrated that the p.D85N-Potassium voltage-gated channel subfamily E member 1 (KCNE1) common variant reduces repolarization reserve and predisposes to drug-induced QT prolongation/torsades de pointes. We sought to develop a cellular model for drug-induced long QT syndrome using a patient-specific induced pluripotent stem cell-derived cardiomyocyte (iPSC-CM)

Background:Polygenic risk scores (PRSs) are associated with coronary artery disease (CAD), but the clinical potential of using PRSs at the single-patient level for risk stratification has yet to be established. We investigated whether adding a PRS to clinical risk factors (CRFs) improves risk stratification in patients referred to coronary computed tomography angiography on a suspicion of obstructive

Background:ECG markers of ventricular depolarization and repolarization are associated with an increased risk of arrhythmia and sudden cardiac death. Our prior work indicated lower serum calcium concentrations are associated with longer QT and JT intervals in the general population. Here, we investigate whether serum calcium is a causal risk factor for changes in ECG measures using Mendelian randomization

Background:Atrial fibrillation (AF) is associated with a five-fold increased risk of ischemic stroke. A portion of this risk is heritable; however, current risk stratification tools (CHA2DS2-VASc) do not include family history or genetic risk. We hypothesized that we could improve ischemic stroke prediction in patients with AF by incorporating polygenic risk scores (PRS).Methods:Using data from the

Background:Increased left ventricular (LV) mass is associated with adverse cardiovascular events including heart failure (HF). Both increased LV mass and HF disproportionately affect Black individuals. To understand the underlying mechanisms, we undertook a proteomic screen in a Black cohort and compared the findings to results from a White cohort.Methods:We measured 1305 plasma proteins using the

Background:It remains unclear whether the plasma proteome adds value to established predictors in heart failure (HF) with reduced ejection fraction (HFrEF). We sought to derive and validate a plasma proteomic risk score (PRS) for survival in patients with HFrEF (HFrEF-PRS).Methods:Patients meeting Framingham criteria for HF with EF<50% were enrolled (N=1017) and plasma underwent SOMAscan profiling

Background:The identification and understanding of therapeutic targets for atherosclerotic cardiovascular disease is of fundamental importance given its global health and economic burden. Inhibition of ANGPTL3 (angiopoietin-like 3) has demonstrated a cardioprotective effect, showing promise for atherosclerotic cardiovascular disease treatment, and is currently the focus of ongoing clinical trials.

Mitochondrial cytopathies caused by mitochondrial DNA (mtDNA) mutations have an estimated prevalence of 1/5000 adults.1 Cardiac manifestations are common (up to 40%) and include hypertrophic cardiomyopathy (HCM). Some mtDNA mutations (eg,m.3243A>G,m.8344A>G,m.4300A>G) are well-recognized causes of cardiomyopathy and may occur as part of a multi-organ syndrome, such as Mitochondrial Encephalomyopathy

Cardiovascular disease and cancer are the leading causes of death in the United States, and hormone-dependent cancers (breast and prostate cancer) are the most common noncutaneous malignancies in women and men, respectively. The hormonal (endocrine-related) therapies that serve as a backbone for treatment of both cancers improve survival but also increase cardiovascular morbidity and mortality among

In the article by Liu et al., “Whole-Transcriptome Profiling of Human Heart Tissues Reveals the Potential Novel Players and Regulatory Networks in Different Cardiomyopathy Subtypes of Heart Failure,” which published on February 1, 2021, and appeared in the February 2021 issue of the journal (Circulation: Genomic and Precision Medicine. 2021;14:e003142. 10.1161/CIRCGEN.120.003142), corrections were

Background:Postoperative atrial fibrillation (PoAF) remains a significant risk factor for increased morbidity and mortality after cardiac surgery. The ability to accurately identify patients at risk through clinical risk factors is limited. There is growing evidence that polygenic risk contributes significantly to PoAF and incorporating measures of genetic risk could enhance prediction.Methods:A retrospective

Background:Arrhythmogenic cardiomyopathy (ACM) is an inherited cardiac disease characterized by fibrofatty replacement of the right and left ventricle, often causing ventricular dysfunction and life-threatening arrhythmias. Variants in desmosomal genes account for up to 60% of cases. Our objective was to establish the prevalence and clinical features of ACM stemming from pathogenic variants in the

Background:Randomized clinical trials indicate that the immune response plays a significant role in coronary artery disease (CAD), a disorder impacting the lifespan potential. However, the identification of targets critical to the immune response in atheroma is still hampered by a lack of solid inference.Methods:Herein, we implemented a system genetics approach to identify causally associated immune

Background:Transcriptome sequencing can improve genetic diagnosis of Mendelian diseases but requires access to tissue expressing disease-relevant transcripts. We explored genetic testing of hypertrophic cardiomyopathy using transcriptome sequencing of patient-specific human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMs). We also explored whether antisense oligonucleotides (AOs) could

Background:There is considerable interest in whether genetic data can be used to improve standard cardiovascular disease risk calculators, as the latter are routinely used in clinical practice to manage preventative treatment.Methods:Using the UK Biobank resource, we developed our own polygenic risk score for coronary artery disease (CAD). We used an additional 60 000 UK Biobank individuals to develop

Background:Genomic screening holds great promise for presymptomatic identification of hidden disease, and prevention of dramatic events, including sudden cardiac death associated with arrhythmogenic cardiomyopathy (ACM). Herein, we present findings from clinical follow-up of carriers of ACM-associated pathogenic/likely pathogenic desmosome variants ascertained through genomic screening.Methods:Of 64

Background:It is known that certain cardiovascular diseases (CVD) are associated, like atrial fibrillation and stroke. However, for other CVDs, the links and temporal trends are less studied. In this longitudinal study, we have investigated temporal epidemiological and genetic associations between different CVDs.Methods:The ULSAM (Uppsala Longitudinal Study of Adult Men; 2322 men aged 50 years) has

Background:The randomized, placebo-controlled COLCOT (Colchicine Cardiovascular Outcomes Trial) has shown the benefits of colchicine 0.5 mg daily to lower the rate of ischemic cardiovascular events in patients with a recent myocardial infarction. Here, we conducted a post hoc pharmacogenomic study of COLCOT with the aim to identify genetic predictors of the efficacy and safety of treatment with colchicine

Background:KCNMA1 encodes the α-subunit of the large-conductance Ca2+-activated K+ channel, KCa1.1, and lies within a linkage interval for atrial fibrillation (AF). Insights into the cardiac functions of KCa1.1 are limited, and KCNMA1 has not been investigated as an AF candidate gene.Methods:The KCNMA1 gene was sequenced in 118 patients with familial AF. The role of KCa1.1 in normal cardiac structure

Following the neutral results of the dal-OUTCOMES trial, a genome-wide study identified the rs1967309 variant in the adenylate cyclase type 9 (ADCY9) gene on chromosome 16 as being associated with the risk of future cardiovascular events only in subjects taking dalcetrapib, a CETP (cholesterol ester transfer protein) modulator. Homozygotes for the minor A allele (AA) were protected from recurrent cardiovascular

In the article by Åkerborg et al, “High-Resolution Regulatory Maps Connect Vascular Risk Variants to Disease-Related Pathways” which appeared in the March 2019 issue of the journal (Circ Cardiovasc Genet.2019;12:e002353), a correction is needed. The following Disclosure was added: The computations and data handling were enabled by resources provided by the Swedish National Infrastructure for Computing

In the December 2020 issue of Circulation: Genomic and Precision Medicine, the license for the article by O’Donnell et al (Steps Toward Minimal Reporting Standards for Lipidomics Mass Spectrometry in Biomedical Research Publications. Circ Genom Precis Med.2020;13:e003019) has been changed in compliance with funding requirements. The article is published under the creative commons license CC BY.

The authors of the following article in Circulation: Genomic and Precision Medicine have requested that it be retracted: Kashiwa A, Aiba T, Makimoto H, Shimamoto K, Yamagata K, Kamakura T, Wada M, Miyamoto K, Inoue-Yamada Y, Ishibashi K, Noda T, Nagase S, Miyazaki A, Sakaguchi H, Shiraishi I, Yagihara N, Watanabe H, Aizawa Y, Makiyama T, Itoh H, Hayashi K, Yamagishi M, Sumitomo N, Yoshinaga M, Morita

Background:Both lifestyle and genetic factors confer risk for cardiovascular diseases, type 2 diabetes, and dyslipidemia. However, the interactions between these 2 groups of risk factors were not comprehensively understood due to previous poor estimation of genetic risk. Here we set out to develop enhanced polygenic risk scores (PRS) and systematically investigate multiplicative and additive interactions

Background:Hypoplastic left heart syndrome (HLHS) with risk of poor outcome has been linked to MYH6 variants, implicating overlap in genetic etiologies of structural and myopathic heart disease.Methods:Whole genome sequencing was performed in 197 probands with HLHS, 43 family members, and 813 controls. Data were filtered for rare, segregating variants in 3 index families comprised of an HLHS proband

Background:Loss-of-function mutations in the LDL (low-density lipoprotein) receptor gene (LDLR) cause elevated levels of LDL cholesterol and premature cardiovascular disease. To date, a gain-of-function mutation in LDLR with a large effect on LDL cholesterol levels has not been described. Here, we searched for sequence variants in LDLR that have a large effect on LDL cholesterol levels.Methods:We analyzed

Background:Approximately 25% of patients with pulmonary arterial hypertension (PAH) have been found to harbor rare mutations in disease-causing genes. To identify missing heritability in PAH, we integrated deep phenotyping with whole-genome sequencing data using Bayesian statistics.Methods:We analyzed 13 037 participants enrolled in the NBR study (NIHR BioResource—Rare Diseases), of which 1148 were

Background:The Val122Ile mutation in Transthyretin (TTR) gene causes a rare, difficult to diagnose hereditary form of cardiac amyloidosis. This mutation is most common in the United States and mainly present in people of African descent. The carriers have an increased risk of congestive heart failure, peripheral edema, and several other noncardiac phenotypes such as carpal tunnel syndrome, and arthroplasty

Background:Venous thromboembolism (VTE) is a major cause of cardiovascular morbidity and mortality and has a known genetic contribution. We tested the performance of a genetic risk score for its ability to predict VTE in 3 cohorts of patients with cardiometabolic disease.Methods:We included patients from the FOURIER (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Patients With Elevated

Background:The clinical implications of a polygenic risk score (PRS) for LDL-C (low-density lipoprotein cholesterol) are not well understood, both within the general population and individuals with familial hypercholesterolemia (FH).Methods:We developed the LDL-C PRS using Least Absolute Shrinkage and Selection Operator regression in 377 286 White British participants from UK Biobank and tested its

Background:Congenital heart disease (CHD) is the most common birth defect and affects roughly 1% of the global population. There have been many large CHD sequencing projects in developing countries but none in sub-Saharan Africa. In this exome sequencing study, we recruited families from Lagos, Nigeria, affected by structural heart disease.Methods:Ninety-eight participants with CHD and an average age

Background:The genomic structure that contributes to the risk of coronary artery disease (CAD) can be evaluated as a risk score of multiple variants. However, sex differences have not been fully examined in applications of genetic risk score (GRS) of CAD.Methods:Using data from the UK Biobank, we constructed a CAD-GRS based on all known loci, 3 mediating trait-based (blood pressure, lipids, and body