Genetics of Coronary Artery Disease

Abstract

Abstract:There is almost no data on the genetics of acute coronary syndromes, so this review discusses primarily the 50 genetic risk variants associated with coronary artery disease that are of genome-wide significance in the discovery population and replicated in an independent population. All of these risk variants are extremely common with more than half occurring in >50% of the general population. They increased only minimally the relative risk for coronary artery disease. The most striking finding is that 35 of the 50 risk variants act independently of known risk factors, indicating there are several pathways yet to be appreciated, contributing to the pathogenesis of coronary atherosclerosis and myocardial infarction. All of the genetic variants seem to act through atherosclerosis, except for the ABO blood groups, which show that A and B are associated with increased risk for myocardial infarction, mediated by a prolonged von Willebrand plasma half life leading to thrombosis. The potential molecular mechanisms of 9p21 are discussed, including cell cycle kinase inhibitors. Discovery of risk variants associated with PCSK9 has led to the development of novel treatment for plasma low-density lipoprotein cholesterol. A monoclonal antibody inhibiting PCSK9 has already undergone phase I and II clinical trials, showing it is a potent inhibitor of low-density lipoprotein cholesterol and is mediated through more rapid removal of low-density lipoprotein cholesterol from the plasma. This therapy complements that of statin therapy, which inhibits the synthesis of cholesterol. The benefits of Mendelian randomization to assess safety and efficacy and their limitations are discussed along with future directions.

A conditional piggyBac transposition system for genetic screening in mice identifies oncogenic networks in pancreatic cancer

“…12 and 13). In addition, polymorphisms in this region on human chromosome 9p21.3 have been associated with coronary artery disease 34 and have been shown to be related to enhancers that physically interact with CDKN2A and CDKN2B 35 . Targeted deletion of the 70-kb risk interval for coronary artery disease in mice 36 identified cis (but not trans) regulatory effects on Cdkn2a expression.…”

Network-Based Identification and Prioritization of Key Regulators of Coronary Artery Disease Loci

“…CAD is highly heritable with genetic risk accounting for 40% to 60% of the susceptibility to CAD. 4 Empowered by the genomic technologies, a total of ≈206 CAD susceptibility loci (58 genome-wide significant and 148 suggestive) have been identified by human genome-wide association studies (GWAS). 5 The mechanisms of these loci/genes seem to be diverse.…”

Genome-Wide Significant Loci: How Important Are They?

“…These CAD-associated loci are strikingly pervasive across the population, but generally have weak effects. As recently reviewed (8), 50% of the CAD-associated variants occur in over one-half of the population, and at least 25% occur in over 75% of the population. However, each variant usually confers a minimal to modest increase in relative risk, averaging only 18% (corresponding to an odds ratio of 1.18).…”

“…A study design was instead chosen that analyzed increasingly dense genomic markers in thousands of mostly unrelated individuals in case-control association studies. From these lines of argument, the genome-wide association study (GWAS) design was born (8). …”

“…Of the 50 candidate genes proposed for 46 loci confirmed in a meta-analysis of GWA datasets, 10 are involved in regulating plasma lipid levels (7 for LDL, 1 for high-density lipoprotein, and 2 for triglycerides) (8). Plasma lipids are primarily of importance for driving early atherosclerosis development, consistent with the notion that loci identified by GWAS will be more useful for primary prevention and with the experimental finding that atherosclerosis regression in response to LDL lowering is much greater for early lesions than for mature and advanced lesions (22).…”