Dyslipidemias and Atherosclerotic Thrombotic Disease

Abstract

Article 1. Familial combined hypercholesterolemia (FCH) is the most common inherited hyperlipidemia complicated by premature atherothrombotic complications, but its genetic and metabolic basis has not been elucidated. FCH, according to the traditional criteria of total cholesterol (TC) and/or triglyceride (TG), is heterogeneous. The diagnosis of FCH on the basis of TC and TG levels is inconsistent and insufficient. Other major characteristics of FCH include elevated apolipoprotein B (apoB), the preponderance of small dense low-density lipoprotein (sdLDL), and decreased high-density lipoprotein (HDL). FCH is associated with insulin resistance and visceral obesity, indicating similarities and/or overlap with the metabolic syndrome. Insulin resistance and obesity do not fully account for elevated apoB. The clinical and laboratory phenotypes of FCH are influenced by environmental factors including lifestyle, diet, and exercise. TG is the strongest and apoB the second most important predictor of FCH. The diagnosis of FCH is best established by ageand gender-adjusted elevated apoB levels combined with TC and TG. A not yet identified major gene affecting free fatty acid (FFA) metabolism in adipose tissue influences apoB, TG levels, and insulin resistance. The presence of sdLDL variants of FCH might result from the combination of a dominant major gene and several modifier genes influencing plasma lipid levels. Article 2. Autosomal recessive hypercholesterolemia (ARH) is a phenotype copy of classical familial hypercholesterolemia (FH) and premature atherothrombosis caused by LDL receptor mutations, but less severe and more responsive to lipid-lowering therapy. Most of the patients with ARH are homozygous for the same allele from consanguineous parents or heterozygous for two different alleles of the ARH gene. ARH protein is clearly required for normal LDL receptor–mediated endocytosis of LDL in hepatocytes. All but one of the described ARH mutations are nonsense mutations that fail to produce ARH protein. Missense mutations do not appear to influence plasma ARH levels (polymorphism). ARH is required for normal LDL receptor function. Homozygosity or double heterozygosity for ARH nonsense mutations is featured by elevated LDL but to a lesser extent as in FH. Heterozygotes for ARH nonsense mutations have normal LDL levels. In contrast to those with homozygous FH, the majority of homozygous ARH patients respond well to lipid-lowering drug therapy. Article 3. Three polymorphisms of apoE can be distinguished and designated as apoE2, apoE3, and apoE4 with allele frequencies of 0.10, 0.75, and 015, respectively. ApoE2 upregulates LDL receptor, enhances LDL clearance, and impairs conversion of apoE2 containing very-low-density lipoprotein (VLDL) via intermediate-density lipoprotein (IDL) to LDL. Subjects with the apoE2 allele have high levels of apoE2 and low levels of TC, LDL, and apoB, whereas apoE4 is associated with the opposite. ApoE4 carriers are at higher risk of Alzheimer’s disease and apoE4 carriers in male myocardial survivors have a twofold higher mortality risk compared with non-apoE4 carriers. Homozygosity of apoE2 can result in familial recessive dysbetalipoproteinemia (FD), also designated as type III hyperlipidemia or broad b or remnant disease. Rare apoE variants result in FD with a dominant inheritance (apoE3-Leiden, aApoE2[Lys146Gln]). FD is characterized by increased TC, TG, and IDL, decreased LDL, and decreased HDL but to a lesser extent and the presence of b-VLDL on agarose gel electrophoresis. Homozygosity for apoE2 causes symptomatic FD, characterized by peripheral artery disease (PAD) as frequently as coronary artery disease (CAD), in less than 20% of adults. FD rarely occurs before adulthood and is more prevalent in men than in women, who do not express atherothrombotic disease until menopause. The asymptomatic apoE2 homozygotes are normolipidemic with b-VLDL in their plasma. Other factors such as insulin resistance, gender, age, and LPL mutations contribute to the phenotypic expression of FD. FD patients are usually very responsive to statin and lifestyle diet interventions. Article 4. ApoB is the structural moiety of LDL particles and acts as a ligand in the cellular binding and uptake of LDL. Normal receptor binding between LDL and apoB is positioned in the carboxy terminal apoB protein created by amino acid residues 3359–3369. Absence of the arginines R3480, R3500, and R3531 in the terminal apoB gene hampers cellular uptake of LDL