Single-cell transcriptomic analyses of skin vascular endothelial cells in sedentary and voluntary wheel running young mice.

Physical activity (PA) is a fundamental aspect of preventive medicine, offering profound benefits for cardiovascular health and overall well-being. Despite its widespread benefits, the molecular mechanisms underlying PA-induced improvements in microvascular functions remain poorly understood. The skin microvasculature is uniquely affected by exercise-induced shear stress, especially during thermoregulation.

Replication of a GWAS signal near with AML using a disease-only cohort and external population-based controls.

Acute myeloid leukemia (AML) is the most common type of acute leukemia in adults. Genome-wide association studies have identified 4 common inherited variants associated with AML risk, but these findings have not yet been confirmed in many independent data sets. Here, we performed a replication study with 567 AML cases from the Leucegene cohort and 1865 controls from the population-based cohort CARTaGENE (CaG).

Polygenic prediction of body mass index and obesity through the life course and across ancestries.

Polygenic scores (PGSs) for body mass index (BMI) may guide early prevention and targeted treatment of obesity. Using genetic data from up to 5.1 million people (4.

A multi-ancestry genetic reference for the Quebec population.

While international efforts have characterized genetic variation in millions of individuals, the interplay of environmental, social, cultural, and genetic factors is poorly understood for most worldwide populations. The province of Quebec in Canada has been the site of numerous genetic studies, often focusing on individual Mendelian diseases in founder sub-populations. Here, we profiled and analyzed genome-wide genotyped variation in 29,337 Quebec residents from the large population-based cohort CARTaGENE (CaG), including rich phenotype and environmental data.

Deconstructing the GWAS library: next-generation GWAS.

Genome-wide association studies (GWAS) have identified numerous common genetic variants associated with cardiovascular traits and diseases. These studies have increased our understanding of the genetic architecture of cardiac diseases and have facilitated the identification of genetic risk factors in patients. Furthermore, they have spurred the development of novel effective therapies by targeting the causal disease pathways.

Quercetin Reduces Vascular Senescence and Inflammation in Symptomatic Male but Not Female Coronary Artery Disease Patients.

Recent studies suggest that vascular senescence and its associated inflammation fuel the inflammaging to favor atherogenesis; whether these pathways can be therapeutically targeted in coronary artery disease (CAD) patients remains unknown. In a randomized, double-blind trial, 97 patients (78 men) undergoing coronary artery bypass graft surgery were treated with either quercetin (500 mg twice daily, 47 patients) or placebo (50 patients) for two days pre-surgery through hospital discharge. Primary outcomes were reduced inflammation and improved endothelial function ex vivo.

Single-nucleus multi-omics implicates androgen receptor signaling in cardiomyocytes and NR4A1 regulation in fibroblasts during atrial fibrillation.

The dysregulation of gene expression programs in the human atria during persistent atrial fibrillation (AF) is not completely understood. Here, we reanalyze bulk RNA-sequencing datasets from two studies (N = 242) and identified 755 differentially expressed genes in left atrial appendages of individuals with persistent AF and non-AF controls. We combined the bulk RNA-sequencing differentially expressed genes with a left atrial appendage single-nucleus multi-omics dataset to assign genes to specific atrial cell types.

Clinical Effect of Genetic Testing in Inherited Cardiovascular Diseases: A 14-Year Retrospective Study.

Background: The clinical impact of genetic testing in a contemporary real-life cohort of patients with heritable cardiomyopathies or arrhythmias is not well defined. Additionally, the genetic spectrum of these conditions in the French-Canadian population is unknown, and interpretation of genetic variants can be challenging because of a known founder effect.

Objectives: This study sought to evaluate the clinical utility of arrhythmia and cardiomyopathy genetic testing and assess the utility of allele frequency data from a local reference population.

FLT1 and other candidate fetal haemoglobin modifying loci in sickle cell disease in African ancestries.

Known fetal haemoglobin (HbF)-modulating loci explain 10-24% variation of HbF level in Africans with Sickle Cell Disease (SCD), compared to 50% among Europeans. Here, we report fourteen candidate loci from a genome-wide association study (GWAS) of HbF level in patients with SCD from Cameroon, Tanzania, and the United States of America. We present results of cell-based experiments for FLT1 candidate, demonstrating expression in early haematopoiesis and a possible involvement in hypoxia associated HbF induction.

Using omics data and genome editing methods to decipher GWAS loci associated with coronary artery disease.

Coronary artery disease (CAD) is due to atherosclerosis, a pathophysiological process that involves several cell-types and results in the accumulation of lipid-rich plaque that disrupt the normal blood flow through the coronary arteries to the heart. Genome-wide association studies have identified 1000s of genetic variants robustly associated with CAD or its traditional risk factors (e.g.

A replication study of novel fetal hemoglobin-associated genetic variants in sickle cell disease-only cohorts.

Sickle cell disease (SCD) is the most common monogenic disease in the world and is caused by mutations in the β-globin gene (HBB). Notably, SCD is characterized by extreme clinical heterogeneity. Inter-individual variation in fetal hemoglobin (HbF) levels strongly contributes to this patient-to-patient variability, with high HbF levels associated with decreased morbidity and mortality.

Senescence and Inflamm-Aging Are Associated With Endothelial Dysfunction in Men But Not Women With Atherosclerosis.

Coronary artery disease (CAD) is more prevalent in men than in women, with endothelial dysfunction, prodromal to CAD, developing a decade earlier in middle-aged men. We investigated the molecular basis of this dimorphism ex vivo in arterial segments discarded during surgery of CAD patients. The results reveal a lower endothelial relaxant sensitivity in men, and a senescence-associated inflammaging transcriptomic signature in endothelial cells.

Joint genotypic and phenotypic outcome modeling improves base editing variant effect quantification.

CRISPR base editing screens enable analysis of disease-associated variants at scale; however, variable efficiency and precision confounds the assessment of variant-induced phenotypes. Here, we provide an integrated experimental and computational pipeline that improves estimation of variant effects in base editing screens. We use a reporter construct to measure guide RNA (gRNA) editing outcomes alongside their phenotypic consequences and introduce base editor screen analysis with activity normalization (BEAN), a Bayesian network that uses per-guide editing outcomes provided by the reporter and target site chromatin accessibility to estimate variant impacts.

Joint genotypic and phenotypic outcome modeling improves base editing variant effect quantification.

CRISPR base editing screens are powerful tools for studying disease-associated variants at scale. However, the efficiency and precision of base editing perturbations vary, confounding the assessment of variant-induced phenotypic effects. Here, we provide an integrated pipeline that improves the estimation of variant impact in base editing screens.

Association Analyses of Predicted Loss-of-Function Variants Prioritized 15 Genes as Blood Pressure Regulators.

Background: Hypertension, clinically defined by elevated blood pressure (BP), is an important cause of mortality and morbidity worldwide. Many risk factors for hypertension are known, including a positive family history, which suggests that genetics contribute to interindividual BP variation. Genome-wide association studies (GWAS) have identified > 1000 loci associated with BP, yet the identity of the genes responsible for these associations remains largely unknown.

Systematic elucidation of genetic mechanisms underlying cholesterol uptake.

Genetic variation contributes greatly to LDL cholesterol (LDL-C) levels and coronary artery disease risk. By combining analysis of rare coding variants from the UK Biobank and genome-scale CRISPR-Cas9 knockout and activation screening, we substantially improve the identification of genes whose disruption alters serum LDL-C levels. We identify 21 genes in which rare coding variants significantly alter LDL-C levels at least partially through altered LDL-C uptake.

Multimodal CRISPR perturbations of GWAS loci associated with coronary artery disease in vascular endothelial cells.

Genome-wide association studies have identified >250 genetic variants associated with coronary artery disease (CAD), but the causal variants, genes and molecular mechanisms remain unknown at most loci. We performed pooled CRISPR screens to test the impact of sequences at or near CAD-associated genetic variants on vascular endothelial cell functions. Using CRISPR knockout, inhibition and activation, we targeted 1998 variants at 83 CAD loci to assess their effect on three adhesion proteins (E-selectin, ICAM1, VCAM1) and three key endothelial functions (nitric oxide and reactive oxygen species production, calcium signalling).

Major cell-types in multiomic single-nucleus datasets impact statistical modeling of links between regulatory sequences and target genes.

Epigenomic profiling, including ATACseq, is one of the main tools used to define enhancers. Because enhancers are overwhelmingly cell-type specific, inference of their activity is greatly limited in complex tissues. Multiomic assays that probe in the same nucleus both the open chromatin landscape and gene expression levels enable the study of correlations (links) between these two modalities.

Systematic elucidation of genetic mechanisms underlying cholesterol uptake.

Genetic variation contributes greatly to LDL cholesterol (LDL-C) levels and coronary artery disease risk. By combining analysis of rare coding variants from the UK Biobank and genome-scale CRISPR-Cas9 knockout and activation screening, we have substantially improved the identification of genes whose disruption alters serum LDL-C levels. We identify 21 genes in which rare coding variants significantly alter LDL-C levels at least partially through altered LDL-C uptake.

Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis.

Background: Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery.

Results: To expand our understanding of the underlying biological pathways and mechanisms controlling blood lipid levels, we leverage a large multi-ancestry meta-analysis (N = 1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches.