Biomedical subjects

Emelia J Benjamin

Publications and source records attributed to Emelia J Benjamin.

5 recordsLinked to original sources

PubMed2025

Prediction of Atrial Fibrillation From the ECG in the Community Using Deep Learning: A Multinational Study.

BACKGROUND: We aimed to refine and validate a deep neural network model from the ECG to predict atrial fibrillation (AF) risk, using samples from diverse backgrounds: the Framingham Heart Study (FHS), UK Biobank, and Estudo Longitudinal da Saúde do Adulto (ELSA-Brasil). We compared the model's performance to the clinical Cohorts for Heart and Aging Research in Genomic Epidemiology consortium (CHARGE-AF) risk score and evaluated the association with other cardiovascular outcomes. METHODS: The ECG-derived deep-learning prediction of AF (ECG-AF) model was refined using 60% of FHS samples free of AF. Its performance was then tested in the remaining FHS samples, UK Biobank, and ELSA-Brasil, with discrimination assessed by the area under the receiver operating characteristic curve. The association of ECG-AF with cardiovascular outcomes was assessed using Cox proportional hazards models. RESULTS: The study sample included 10 097 FHS participants (mean age 53±12 years; 54.9% women), 49 280 participants from the UK Biobank (mean age 64±8 years, 47.9% women), and 12 284 participants from ELSA-Brasil (mean age 53±8 years, 54.7% women). The ECG-AF model showed moderate discrimination for incident AF (area under the curve, 0.82 [95% CI, 0.80-0.84]) in the FHS, comparable to the CHARGE-AF score (area under the curve, 0.83 [95% CI, 0.81-0.85]), and incremental when combined (area under the curve, 0.85 [95% CI, 0.83-0.87]). In UK Biobank and ELSA-Brasil, combining ECG-AF and CHARGE also improved prediction. Higher ECG-AF scores were associated with increased risks of heart failure, myocardial infarction, stroke, and all-cause mortality in all 3 cohorts. CONCLUSIONS: In multinational cohort studies, the single-input ECG-AF deep neural network model demonstrated good performance in predicting AF and other cardiovascular outcomes, comparable to a multivariable clinical risk score, with improved performance when combined.

Humans↗

PubMed2025

Epigenetic mechanisms underlying variation of IL-6, a well-established inflammation biomarker and risk factor for cardiovascular disease.

BACKGROUND AND AIMS: Cardiovascular disease (CVD) is one of the leading causes of morbidity and mortality worldwide, yet the underlying molecular mechanisms remain less understood. Chronic low-grade inflammation is a complex immune response contributing to the pathophysiology of cardiovascular disease. This response is signaled in part by interleukin-6 (IL-6), a pleiotropic, pro-inflammatory cytokine. Phenotypic variance in circulating IL-6 level may be explained in part by DNA methylation which is increasingly being associated with cardiovascular effects. METHODS: In this study we evaluated methylated DNA (CpG sites) associated with blood IL-6 levels across ∼4,400 ancestrally diverse individuals (81 % self-reported White; 9 % Black or African American, 8 % Hispanic or Latino/a, and 2 % Chinese American). RESULTS: We identified 178 CpG sites associated with IL-6 (p<0.05/∼395,000). Among the sites, cg04437762 is located within the transcription unit of IL6R, a current therapeutic target for inflammatory disease, and cg26692003 and cg00464927 were significant for IL6 and IL6ST trans-CpG-gene transcripts. Functional gene expression downstream of methylation identified cellular response to IL-6 and B-cell regulation and activation pathways. Four genes were linked with both a genetic component of cardiovascular disease and an IL-6 associated CpG site. Three CpG sites identified through Mendelian randomization analyses supported inference of a causal effect on IL-6 levels, including the LYN gene that regulates immune cell signaling and has been previously associated with atherosclerosis. CONCLUSIONS: Overall, we identified several novel IL-6-CpG sites and downstream pathways affected by methylation. Follow-up functional studies including the regulation of IL-6 would complement current knowledge of CVD pathophysiology and potential therapeutic targets.

Humans↗

PubMed2025

Unveiling the Genetic Landscape of Coronary Artery Disease Through Common and Rare Structural Variants.

BACKGROUND: Genome-wide association studies have identified several hundred susceptibility single nucleotide variants for coronary artery disease (CAD). Despite single nucleotide variant-based genome-wide association studies improving our understanding of the genetics of CAD, the contribution of structural variants (SVs) to the risk of CAD remains largely unclear. METHOD AND RESULTS: We leveraged SVs detected from high-coverage whole genome sequencing data in a diverse group of participants from the National Heart Lung and Blood Institute's Trans-Omics for Precision Medicine program. Single variant tests were performed on 58 706 SVs in a study sample of 11 556 CAD cases and 42 907 controls. Additionally, aggregate tests using sliding windows were performed to examine rare SVs. One genome-wide significant association was identified for a common biallelic intergenic duplication on chromosome 6q21 (P=1.54E-09, odds ratio=1.34). The sliding window-based aggregate tests found 1 region on chromosome 17q25.3, overlapping USP36, to be significantly associated with coronary artery disease (P=1.03E-10). USP36 is highly expressed in arterial and adipose tissues while broadly affecting several cardiometabolic traits. CONCLUSIONS: Our results suggest that SVs, both common and rare, may influence the risk of coronary artery disease.

Humans↗

PubMed2025

GWAS of CRP response to statins further supports the role of APOE in statin response: A GIST consortium study.

Statins are first-line treatments in the primary and secondary prevention of cardiovascular disease. Clinical studies show statins act independently of lipid-lowering mechanisms to decrease C-reactive protein (CRP), an inflammation marker. We aim to elucidate genetic loci associated with CRP statin response. CRP statin response is the change in log-CRP between off-treatment and on-treatment measurements. Cohort-level Genome-Wide Association Studies (GWAS) of CRP response were performed using 1000 Genomes imputed data, testing ∼10 million common genetic variants. GWAS meta-analysis combined results from seven cohorts and clinical trials totalling 14,070 statin-treated individuals of European ancestry within the GIST consortium. Secondary analyses included statin-by-placebo interaction analyses, and lookups in African ancestry cohorts. Our GWAS identified two genome-wide significant (P < 5e-8) loci: APOE and HNF1A for CRP statin response corrected for baseline CRP. The missense lead variant rs429358 at APOE, contributing to the APOE-E4 haplotype, is a risk locus for dyslipidaemia, Alzheimer's and coronary artery disease (CAD). The HNF1A locus is associated with diabetes, cholesterol levels, and CAD. Both loci are also associated with baseline CRP levels, and neither locus achieved a significant (P < 0.05) result from the statin v. placebo interaction meta-analysis using randomized clinical trial data. However, the interaction result (P-int=0.09) for APOE was suggestive and possibly underpowered. The APOE-E4 signal may therefore be associated with both CRP and LDL-cholesterol statin response. Combined with suggestions in the literature that APOE also leads to differential statin benefit in Alzheimer's, the APOE locus warrants further investigation for potential genetic effects on healthcare with statin treatment.

Humans↗

PubMed2025

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. Four well-known loci (SCN5A/SCN10A, CCDC141, TBX20 and CAMK2D) were shared for SND and DCD, while others were more specific for SND or DCD. SND and DCD showed a moderate genetic correlation (rg = 0.63). Cardiomyocyte-expressed genes were enriched for contributions to DCD heritability. Rare-variant analyses implicated LMNA for all bradyarrhythmia phenotypes, SMAD6 and SCN5A for DCD and TTN, MYBPC3 and SCN5A for PM. These results show that variation in multiple genetic pathways (for example, ion channel function, cardiac developmental programs, sarcomeric structure and cellular homeostasis) appear critical to the development of bradyarrhythmias.

Humans↗