Genetic lipoprotein disorders are frequently seen in patients with premature coronary artery disease (CAD). An example of strong genetic predisposition is the disorder: familial hypercholesterolemia, where a single gene defect (the low density lipoprotein receptor) contributes to most of the familial expression of CAD.
Conversely, lifestyle, diabetes, dyslipidemia, cigarette smoking and hypertension contribute to most of the population-attributable risk in the large, international INTERHEART study of acute myocardial infarction (heart attacks). The identification of single gene disorders may pave the way to a better understanding of complex metabolic pathways. Understanding the genes that regulate high density lipoprotein (HDL) metabolism may lead to novel therapeutic approaches. This has been emphasized by two therapeutic approaches for the treatment of CAD:
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The infusion of apo AI containing proteoliposomes, using wild-type or a mutant form of apo AI, apo AIMilano, in patients with acute coronary syndromes;
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The long-term treatment of subjects with low HDL-C with the cholesteryl ester transfer protein (CETP) inhibitor Torcertapib. While Torcetrapib proved to have off-target toxic effects, two other CETP inhibitors (Anacetrapib and Delcetrapib) are being tested clinically. Experimentally, however, CETP inhibitors may not reduce atherosclerosis
Novel therapeutic approaches using agonists of the LxR/RxR pathway to up-regulate the ABCA1 transporter, or the transcriptional regulation of apo AI, are being explored.
Epidemiology of HDL and risk of coronary artery disease CAD risk
Plasma (or serum) level of HDL-C is a continuous and graded negative cardiovascular risk factor. Most international CAD prevention guidelines define HDL-C as a categorical risk factor and the absolute level of HDL-C is used in a multivariate model to predict cardiovascular risk and determine the need and intensity of preventive therapies. A low HDL-C is considered a diagnostic criterion for the metabolic syndrome.
To underlie the importance of plasma lipoproteins in the pathogenesis of CAD and acute myocardial infarction, the largest case-control study of myocardial infarction (INTERHEART) has shown that the apo B/apo AI ratio (respectively an index of atherogenic lipoproteins and protective lipoproteins) accounts for approximately half (49%) of the population-attributable risk of acute myocardial infarction. The prevalence of a low HDL-C in patients with CAD has been examined in several case-control and prospective studies. It is estimated that approximately 40% of patients with premature CAD have a low HDL-C and this represents the most common lipoprotein disorder in patients with CAD. Most patients with a low HDL-C have multiple cardiovascular risk factors and features of the metabolic syndrome, with obesity (predominantly abdominal), elevated plasma triglyceride levels, high blood pressure and hyperglycemia, insulin resistance or diabetes. Despite the strong association between metabolic disorders and HDL-C, plasma levels of HDL-C are strongly genetically determined. Experimental evidence shows that the atheroprotective effects of HDL are pleiotropic and extend beyond removing cholesterol from lipid-laden macrophages in the atherosclerotic plaque. HDL are known to have anti-inflammatory effects, to prevent oxidation of low-density lipoproteins (LDL), possess anti-thrombotic properties, modulate vasomotor tone and may improve endothelial cell survival (by preventing apoptosis), migration and proliferation. Nonetheless, the major cardio-protective effect of HDL has been attributed to its key role in reverse cholesterol transport, a process in which cholesterol from peripheral tissues such as foam cells is selectively returned to the liver for excretion in the bile. Mutations in any ofthe proteins regulating this complex metabolic pathway may potentially decrease HDL-C levels and accelerate CAD.
Genes that affect HDL-C levels