Meta-analysis of genome-wide associations and polygenic risk prediction for atrial fibrillation in more than 180,000 cases.

Atrial fibrillation (AF) is the most common heart rhythm abnormality and is a leading cause of heart failure and stroke. This large-scale meta-analysis of genome-wide association studies increased the power to detect single-nucleotide variant associations and found more than 350 AF-associated genetic loci. We identified candidate genes related to muscle contractility, cardiac muscle development and cell-cell communication at 139 loci.

Genetics of cardiovascular outcomes in individuals with chronic kidney disease: the Chronic Renal Insufficiency Cohort (CRIC) study.

Genome-wide association studies (GWAS) identified multiple loci for cardiovascular disease, but their relevance to individuals with chronic kidney disease (CKD), who are at higher risk of cardiovascular disease, is unknown. In this study, we performed GWAS analyses of coronary heart disease (CHD) or all-cause stroke in African (AFR) and European (EUR) American participants with CKD of the Chronic Renal Insufficiency Cohort (CRIC). Mixed- effect logistic regression models were race-stratified and adjusted for age, sex, site of recruitment, estimated glomerular filtration rate (eGFR), and principal components, followed by meta-analysis.

Capturing the Additional Cardiovascular Benefits of SGLT2 Inhibitors and GLP-1 Receptor Agonists Beyond the Control of Traditional Risk Factors in People With Diabetes.

Objectives: This study aimed to quantify the additional cardioprotective effects of sodium-glucose cotransporter 2 inhibitors (SGLT2is) and glucagon-like peptide-1 receptor agonists (GLP-1RAs) beyond the traditional risk factors control in individuals with type 2 diabetes. This helps calibrate the Building, Relating, Assessing, and Validating Outcomes (BRAVO) diabetes simulation model to capture the total cardiovascular benefits of new diabetes medications accurately.

Methods: We extracted patient characteristics and treatment efficacy data from 4 cardiovascular outcome trials (CVOTs) of SGLT2is and 4 CVOTs of GLP-1RAs completed before May 2023.

Large-scale multi-omics identifies drug targets for heart failure with reduced and preserved ejection fraction.

Heart failure (HF) has limited therapeutic options. In this study, we differentiated the pathophysiological underpinnings of the HF subtypes-HF with reduced ejection fraction (HFrEF) and HF with preserved ejection fraction (HFpEF)-and uncovered subtype-specific therapeutic strategies. We investigated the causal roles of the human proteome and transcriptome using Mendelian randomization on more than 420,000 participants from the Million Veteran Program (27,799 HFrEF and 27,579 HFpEF cases).

Cardiovascular Reactivity to Mental Stress and Adverse Cardiovascular Outcomes in Patients With Coronary Artery Disease.

Background: Acute psychological stress may induce physiological changes predisposing individuals to adverse health outcomes through hemodynamic and vascular effects. We studied the association between the aggregated stress-induced changes in hemodynamic and vascular function tests with adverse cardiovascular outcomes in patients with coronary artery disease, after adjusting for sociodemographic and clinical factors.

Methods And Results: Individuals with stable coronary artery disease from 2 prospective cohort studies were studied.

The impact of common and rare genetic variants on bradyarrhythmia development.

To broaden our understanding of bradyarrhythmias and conduction disease, we performed common variant genome-wide association analyses in up to 1.3 million individuals and rare variant burden testing in 460,000 individuals for sinus node dysfunction (SND), distal conduction disease (DCD) and pacemaker (PM) implantation. We identified 13, 31 and 21 common variant loci for SND, DCD and PM, respectively.

Proteomics-Based Soluble Urokinase Plasminogen Activator Receptor Levels Are Associated With Incident Heart Failure Risk.

Background: Higher soluble urokinase plasminogen activator receptor (suPAR) levels are associated with adverse outcomes in chronic heart failure (HF).

Objectives: The authors assessed the association between proteomics-based suPAR levels and incident HF risk in the general population.

Methods: In 40,418 UK Biobank participants without HF or coronary artery disease at enrollment, the association between Olink-based suPAR levels measured as relative protein expression levels and incident all-cause, ischemic, and nonischemic HF was analyzed by competing-risk regression, while accounting for all-cause death as a competing risk.

Epigenome-Wide and Methylation Risk Score Analysis of Body Mass Index Among People with HIV.

People with HIV (PWH) on antiretroviral therapy (ART) often gain weight, which increases their risk of type 2 diabetes and cardiovascular disease. The role of DNA methylation (DNAm) markers in obesity among PWH is understudied. This research explores the relationship between body mass index (BMI) and epigenetic patterns to better understand and manage obesity-related risks in PWH.

Genome-Wide European Ancestry Study Identifies Coronary Artery Disease-Associated Loci Through Gene-Sex Hormone Interaction.

Background: Although sex differences in coronary artery disease (CAD) risk have been observed, little is known about the role of sex hormones in CAD genetics. Accounting for sex hormone levels may help identify CAD-risk loci and extend our knowledge of its genetic architecture.

Methods And Results: A total of 365 662 individuals of European ancestry enrolled in the UK Biobank were considered.

Epigenetic associations with kidney disease in individuals of African ancestry with APOL1 high-risk genotypes and Human Immunodeficiency Virus.

Background: Apolipoprotein L1 (APOL1) high-risk variants are major determinants of chronic kidney disease (CKD) in people of African ancestry. Previous studies have identified epigenetic changes in relation to kidney function and CKD, but not in individuals with APOL1 high-risk genotypes. We conducted an epigenome-wide analysis of CKD and estimated glomerular filtration rate (eGFR) in in people of African ancestry and APOL1 high-risk genotypes with HIV.

A novel GWAS locus influences microvascular response to mental stress and predicts adverse cardiovascular events.

Excessive peripheral microvascular constriction during acute psychological stress reflects similar changes in coronary blood flow and is a predictor of adverse cardiovascular outcomes. Among individuals with coronary artery disease (CAD), we sought to determine if genetic factors contribute to the degree of microvascular constriction during mental stress. A total of 580 stable CAD individuals from two prospective cohort studies underwent mental stress testing.

A Multivariable Mendelian Randomization Study of Systolic and Diastolic Blood Pressure, Lipid Profile, and Heart Failure Subtypes.

Heart failure (HF) is a significant health burden, with two major clinical subtypes: HF with reduced (HFrEF) and preserved ejection fraction (HFpEF). Blood pressure and lipid profile are established risk factors of HF. We performed univariable and multivariable Mendelian randomization (MR) analyses to assess potential causal effects of blood pressures and lipids on HF subtypes.

Comparison of methods for building polygenic scores for diverse populations.

Polygenic scores (PGSs) are a promising tool for estimating individual-level genetic risk of disease based on the results of genome-wide association studies (GWASs). However, their promise has yet to be fully realized because most currently available PGSs were built with genetic data from predominantly European-ancestry populations, and PGS performance declines when scores are applied to target populations different from the populations from which they were derived. Thus, there is a great need to improve PGS performance in currently under-studied populations.

Characterising the genetic architecture of changes in adiposity during adulthood using electronic health records.

Obesity is a heritable disease, characterised by excess adiposity that is measured by body mass index (BMI). While over 1,000 genetic loci are associated with BMI, less is known about the genetic contribution to adiposity trajectories over adulthood. We derive adiposity-change phenotypes from 24.

SMIM1 absence is associated with reduced energy expenditure and excess weight.

Background: Obesity rates have nearly tripled in the past 50 years, and by 2030 more than 1 billion individuals worldwide are projected to be obese. This creates a significant economic strain due to the associated non-communicable diseases. The root cause is an energy expenditure imbalance, owing to an interplay of lifestyle, environmental, and genetic factors.