Genetic Basis of Lipoprotein Disorders

Abstract

Lipoprotein disorders result from abnormal synthesis, processing, or catabolism of plasma lipoprotein particles. These particles consist of a core of cholesterol ester and triglyceride enclosed in a coat of phospholipids and apolipoproteins. More than half of patients with angiographically confirmed coronary artery disease (CAD) before age 60 years have a familial lipoprotein disorder.1 The association is most striking among younger patients and declines with increasing age at first myocardial infarction (MI). This suggests the presence of genetic factors that accelerate age-associated cardiovascular changes seen in the general population.2 Severe hyperlipidemia (total cholesterol >300 mg/dL or triglycerides >500 mg/dL) usually indicates a genetic disorder, and xanthomas almost always signal an underlying genetic defect. These findings warrant examination of the patient’s first-degree relatives.2 Four types of lipoprotein abnormalities are observed: elevated LDL cholesterol; reduced HDL cholesterol, usually with increased triglycerides and very-low-density lipoprotein (VLDL) cholesterol; elevated levels of chylomicron remnants and intermediate-density lipoproteins (IDL); and elevated levels of lipoprotein (a) [Lp(a)] particles.3 Lipoprotein transport genes have been implicated in each of these abnormal lipoprotein phenotypes (Table 1⇓). View this table: Table 1. Genetic Factors in Lipoprotein Abnormalities Cholesterol levels >240 mg/dL are associated with a threefold increased risk of death from ischemic heart disease in men relative to cholesterol levels <200 mg/dL, and there is a continuous risk gradient as cholesterol rises.2 Elevated total cholesterol primarily reflects elevated LDL cholesterol, which constitutes 70% of plasma cholesterol. Disorders characterized by elevation of cholesterol alone are classified as Fredrickson type IIa hyperlipoproteinemia. LDL particles are a constituent of the endogenous (nondietary) fat transport pathway and are formed via action of lipases on precursor particles. Excess carbohydrate or fat reaching the liver that is not required for energy or synthetic purposes is converted into triglycerides, packaged with apolipoproteins, and secreted as VLDL particles. Lipoprotein …