Coronary artery disease is the leading global cause of mortality. Long recognized to be heritable, recent advances have started to unravel the genetic architecture of the disease. Common variant association studies have linked approximately 60 genetic loci to coronary risk. Large-scale gene sequencing efforts and functional studies have facilitated a better understanding of causal risk factors, elucidated underlying biology and informed the development of new therapeutics. Moving forwards, genetic testing could enable precision medicine approaches by identifying subgroups of patients at increased risk of coronary artery disease or those with a specific driving pathophysiology in whom a therapeutic or preventive approach would be most useful.

Genetics of coronary artery disease: discovery, biology and clinical translation

Genetic factors contribute importantly to the risk of coronary artery disease (CAD), and in the past decade, there has been major progress in this area. The tools applied include genome-wide association studies encompassing >200 000 individuals complemented by bioinformatic approaches, including 1000 Genomes imputation, expression quantitative trait locus analyses, and interrogation of Encyclopedia of DNA Elements, Roadmap, and other data sets. close to 60 common SNPs (minor allele frequency>0.05) associated with CAD risk and reaching genome-wide significance ( P −8 ) have been identified. Furthermore, a total of 202 independent signals in 109 loci have achieved a false discovery rate ( q

Genetics of Coronary Artery Disease

http://www.svemonline.org/wp-content/uploads/2015/07/endotips-vol-01-1.pdf

New insights into the pathophysiology of dyslipidemia in type 2 diabetes

Atherosclerosis is a chronic inflammatory disease promoted by hyperlipidemia. Several studies support FOXP3-positive regulatory T cells (Tregs) as inhibitors of atherosclerosis; however, the mechan ...

/pdf/depletion-of-foxp3-regulatory-t-cells-promotes-4gsk9j1yzk.pdf

Depletion of FOXP3+ regulatory T cells promotes hypercholesterolemia and atherosclerosis.

Despite the well-documented association between insulin resistance and cardiovascular disease, the key targets of insulin relevant to the development of cardiovascular disease are not known. Here, using non-biased profiling methods, we identify the enzyme flavin-containing monooxygenase 3 (Fmo3) to be a target of insulin. FMO3 produces trimethylamine N-oxide (TMAO), which has recently been suggested to promote atherosclerosis in mice and humans. We show that FMO3 is suppressed by insulin in vitro, increased in obese/insulin resistant male mice and increased in obese/insulin-resistant humans. Knockdown of FMO3 in insulin-resistant mice suppresses FoxO1, a central node for metabolic control, and entirely prevents the development of hyperglycaemia, hyperlipidemia and atherosclerosis. Taken together, these data indicate that FMO3 is required for FoxO1 expression and the development of metabolic dysfunction.

/pdf/flavin-containing-monooxygenase-3-as-a-potential-player-in-2njdih04xf.pdf

Flavin-containing monooxygenase 3 as a potential player in diabetes-associated atherosclerosis

Genome-wide association studies (GWAS) have identified a genetic variant at a locus on chromosome 1p13 that is associated with reduced risk of myocardial infarction, reduced plasma levels of LDL cholesterol (LDL-C), and markedly increased expression of the gene sortilin-1 (SORT1) in liver. Sortilin is a lysosomal sorting protein that binds ligands both in the Golgi apparatus and at the plasma membrane and traffics them to the lysosome. We previously reported that increased hepatic sortilin expression in mice reduced plasma LDL-C levels. Here we show that increased hepatic sortilin not only reduced hepatic apolipoprotein B (APOB) secretion, but also increased LDL catabolism, and that both effects were dependent on intact lysosomal targeting. Loss-of-function studies demonstrated that sortilin serves as a bona fide receptor for LDL in vivo in mice. Our data are consistent with a model in which increased hepatic sortilin binds intracellular APOB-containing particles in the Golgi apparatus as well as extracellular LDL at the plasma membrane and traffics them to the lysosome for degradation. We thus provide functional evidence that genetically increased hepatic sortilin expression both reduces hepatic APOB secretion and increases LDL catabolism, providing dual mechanisms for the very strong association between increased hepatic sortilin expression and reduced plasma LDL-C levels in humans.

/pdf/hepatic-sortilin-regulates-both-apolipoprotein-b-secretion-1p0iu64z6y.pdf

Margaret Ye Wang

Papers

Hepatic sortilin regulates both apolipoprotein B secretion and LDL catabolism