Extreme LDL-C concentration is associated with increased cardiovascular disease in women with homozygous familial hypercholesterolemia.

Background: Homozygous familial hypercholesterolemia (HoFH) is a rare genetic disease of low-density lipoprotein cholesterol (LDL-C) metabolism. Despite the devastating effect of this disease on atherosclerotic cardiovascular health, the disease phenotype and severity are more heterogeneous than previously thought. The predictors of atherosclerotic cardiovascular disease (ASCVD) in HoFH patients have never been systematically studied.

Long Noncoding RNA TRIBAL Links the 8q24.13 Locus to Hepatic Lipid Metabolism and Coronary Artery Disease.

Background: Genome-wide association studies identified a 20-Kb region of chromosome 8 (8q24.13) associated with plasma lipids, hepatic steatosis, and risk for coronary artery disease. The region is proximal to , and given its well-established role in lipid regulation in animal models, TRIB1 has been proposed to mediate the contribution of the 8q24.

Medications for Lipid Control: Statins vs Newer Drugs.

In the primary and secondary prevention of atherosclerotic cardiovascular disease (ASCVD), statins are the primary pharmacologic intervention for ASCVD risk reduction. Statins have proven efficacy and safety in reducing cardiovascular events and total mortality in patients with and without clinically evident ASCVD. The purpose of this brief review is to provide a stepwise approach to lipid management, including lifestyle recommendations and medical therapy.

Regulation of TRIB1 abundance in hepatocyte models in response to proteasome inhibition.

Tribbles related homolog 1 (TRIB1) contributes to lipid and glucose homeostasis by facilitating the degradation of cognate cargos by the proteasome. In view of the key metabolic role of TRIB1 and the impact of proteasome inhibition on hepatic function, we continue our exploration of TRIB1 regulation in two commonly used human hepatocyte models, transformed cell lines HuH-7 and HepG2. In both models, proteasome inhibitors potently upregulated both endogenous and recombinant TRIB1 mRNA and protein levels.

Homozygous Familial Hypercholesterolemia in Canada: An Observational Study.

Background: Homozygous familial hypercholesterolemia (HoFH) is a rare genetic disease characterized by very high levels of low-density lipoprotein cholesterol (LDL-C). Untreated patients present with extensive xanthomas and premature atherosclerosis. Lipid-lowering therapy is highly efficacious and has dramatically increased life expectancy of patients with HoFH.

Gene Sequencing Identifies Perturbation in Nitric Oxide Signaling as a Nonlipid Molecular Subtype of Coronary Artery Disease.

Background: A key goal of precision medicine is to disaggregate common, complex diseases into discrete molecular subtypes. Rare coding variants in the low-density lipoprotein receptor gene () are identified in 1% to 2% of coronary artery disease (CAD) patients, defining a molecular subtype with risk driven by hypercholesterolemia.

Methods: To search for additional subtypes, we compared the frequency of rare, predicted loss-of-function and damaging missense variants aggregated within a given gene in 41 081 CAD cases versus 217 115 controls.

Profound Elevation in LDL Cholesterol Level Following a Ketogenic Diet: A Case Series.

The ketogenic diet (KD) is currently popular for the achievement of weight loss and improvement in glycemic variables. The diet allows consumption of foods high in fat and protein, with strict limitation of carbohydrates. We present a case series of substantial increases in total cholesterol and low-density lipoprotein cholesterol following the initiation of a KD, with improvements in cholesterol levels once the KD was stopped.

Genome-wide screening identifies DNA methylation sites that regulate the blood proteome.

Identifying DNA methylation sites that regulate the blood proteome is important for biomedical purposes. Here the authors performed a genome-wide search to find DNA methylation sites that impact proteins.  The authors identified 165 methylation sites associated with 138 proteins.

A novel anti-inflammatory role links the CARS2 locus to protection from coronary artery disease.

Background And Aims: Genome-wide association studies (GWAS) identified a coronary artery disease (CAD) risk locus on 13.q34 tagged by rs61969072 (T/G). This variant lies in an intergenic region, proximal to ING1, CARKD and CARS2 but its causal relationship to CAD is unknown.

Genetically Determined Reproductive Aging and Coronary Heart Disease: A Bidirectional 2-sample Mendelian Randomization.

Background: Accelerated reproductive aging, in women indicated by early natural menopause, is associated with increased coronary heart disease (CHD) risk in observational studies. Conversely, an adverse CHD risk profile has been suggested to accelerate menopause.

Objectives: To study the direction and evidence for causality of the relationship between reproductive aging and (non-)fatal CHD and CHD risk factors in a bidirectional Mendelian randomization (MR) approach, using age at natural menopause (ANM) genetic variants as a measure for genetically determined reproductive aging in women.

Association of muscle fiber type with measures of obesity: A systematic review.

Obesity derives from an extended period of positive energy imbalance due to a complex interplay of environmental and biological factors. Muscle fiber type and physiology have been hypothesized to affect metabolism and energy expenditure and thus to affect an individual's propensity to gain weight. However, there have been conflicting reports regarding a relationship between muscle fiber type and obesity.

Common Polymorphism That Protects From Cardiovascular Disease Increases Fibronectin Processing and Secretion.

Background: Fibronectin () is an essential regulator of homodynamic processes and tissue remodeling that have been proposed to contribute to atherosclerosis. Moreover, recent large-scale genome-wide association studies (GWAS) have linked common genetic variants within the gene to coronary artery disease risk.

Methods: Public databases were analyzed by 2-Sample Mendelian Randomization.

Rare coding variants in 35 genes associate with circulating lipid levels-A multi-ancestry analysis of 170,000 exomes.

Large-scale gene sequencing studies for complex traits have the potential to identify causal genes with therapeutic implications. We performed gene-based association testing of blood lipid levels with rare (minor allele frequency < 1%) predicted damaging coding variation by using sequence data from >170,000 individuals from multiple ancestries: 97,493 European, 30,025 South Asian, 16,507 African, 16,440 Hispanic/Latino, 10,420 East Asian, and 1,182 Samoan. We identified 35 genes associated with circulating lipid levels; some of these genes have not been previously associated with lipid levels when using rare coding variation from population-based samples.

miR1908-5p regulates energy homeostasis in hepatocyte models.

We previously identified genomic variants that are quantitative trait loci for circulating miR-1908-5p and then showed this microRNA to causally associate with plasma levels of LDL-C, fasting blood glucose and HbA1c. The link to LDL-C was subsequently validated and clarified by the identification of a miR1908-5p-TGFB-LDLR regulatory axis. Here, we continue our investigations on miR1908-5p function by leveraging human primary hepatocytes and HuH-7 hepatoma models.

Colchicine for Prevention of Atherothrombotic Events in Patients With Coronary Artery Disease: Review and Practical Approach for Clinicians.

A better understanding of the central role of inflammation in the development of coronary artery disease (CAD) has been the impetus for the evaluation of therapeutic strategies targeting the interleukin-1ß/interleukin-6 cytokine signaling pathway, involved in both chronic atherogenesis and in triggering of atherosclerotic plaque rupture. As an inexpensive pharmacologic agent with relatively few adverse effects that tend to be mild and tolerable, the role of colchicine in secondary prevention of atherothrombotic events has been the focus of multiple recent large-scale randomized controlled trials involving patients with stable CAD (Low-Dose Colchicine [LoDoCo] and LoDoCo2 trials), a recent myocardial infarction (Colchicine Cardiovascular Outcome Trial [COLCOT], Colchicine in Patients With Acute Coronary Syndrome [COPS], and Colchicine and Spironolactone in Patients With Myocardial Infarction/Synergy Stent Registry [CLEAR SYNERGY] trials), and undergoing percutaneous coronary interventions (Colchicine in Percutaneous Coronary Intervention [COLCHICINE-PCI] trial). Based on this evidence, low-dose colchicine (0.

Epigenome-Wide Study Identified Methylation Sites Associated with the Risk of Obesity.

Here, we performed a genome-wide search for methylation sites that contribute to the risk of obesity. We integrated methylation quantitative trait locus (mQTL) data with BMI GWAS information through a SNP-based multiomics approach to identify genomic regions where mQTLs for a methylation site co-localize with obesity risk SNPs. We then tested whether the identified site contributed to BMI through Mendelian randomization.

A Common Polymorphism in the Locus Links miR1908 to Low-Density Lipoprotein Cholesterol Through BMP1.

OBJECTIVE: Leveraging microRNA-Seq data and the 1000 Genomes imputed genotypes, we identified rs174561 as a strong microRNA quantitative trait loci for circulating microRNA-1908-5p with higher miR-1908-5p and reduced LDL (lowdensity lipoprotein)-cholesterol, fasting glucose and A1c concentrations in carriers of the rs-174561-C allele. Here, we have investigated the molecular mechanism(s) linking miR-1908-5p to LDL-C concentrations. APPROACH AND RESULTS: Transfection experiments demonstrate that the presence of the C allele significantly increases miR- 1908-5p abundance relative to the T allele.

Correction: A missense variant in Mitochondrial Amidoxime Reducing Component 1 gene and protection against liver disease.

[This corrects the article DOI: 10.1371/journal.pgen.

2021 Canadian Cardiovascular Society Guidelines for the Management of Dyslipidemia for the Prevention of Cardiovascular Disease in Adults.

The 2021 guidelines primary panel selected clinically relevant questions and produced updated recommendations, on the basis of important new findings that have emerged since the 2016 guidelines. In patients with clinical atherosclerosis, abdominal aortic aneurysm, most patients with diabetes or chronic kidney disease, and those with low-density lipoprotein cholesterol ≥ 5 mmol/L, statin therapy continues to be recommended. We have introduced the concept of lipid/lipoprotein treatment thresholds for intensifying lipid-lowering therapy with nonstatin agents, and have identified the secondary prevention patients who have been shown to derive the largest benefit from intensification of therapy with these agents.

Convergence of biomarkers and risk factor trait loci of coronary artery disease at 3p21.31 and HLA region.

Here we seek to identify molecular biomarkers that mediate the effect of risk factors on coronary artery disease (CAD). We perform a SNP-based multiomics data analysis to find biomarkers (probes) causally associated with the risk of CAD within known genomic loci for its risk factors. We identify 78 biomarkers, the majority (64%) of which are methylation probes.

Factors affecting weight loss variability in obesity.

Current obesity treatment strategies include diet, exercise, bariatric surgery, and a limited but growing repertoire of medications. Individual weight loss in response to each of these strategies is highly variable. Here we review research into factors potentially contributing to inter-individual variability in response to treatments for obesity, with a focus on studies in humans.