Chapter 1. Introduction

Coronary artery disease (CAD) is still the main cause of death among men aged over 45 years and women aged over 65 in Europe. The risk factors for CAD are elevated blood cholesterol, male sex, family history of CAD, cigarette smoking, hypertension, diabetes mellitus and severe obesity. It has been postulated that all the other risk factors would be cholesterol-dependent (Roberts 1992), as atherosclerotic events are rare in populations with an average serum total cholesterol level below 3.9 mmol/l. Decreases in the risk factors, such as lowering of blood cholesterol, have been shown to associate with a decrease in mortality from ischaemic heart disease in men and women (Scandinavian Simvastatin Study Group 1994, Shepherd et al. 1995).

Lipoproteins are the particles responsible for lipid transport in the blood. Apolipoprotein B (apo B) is the main protein constituent of LDL and also the main ligand for the LDL receptor in the liver. Apo B is highly polymorphic, and several mutations and polymorphisms of the apo B gene have been described (Humphries et al. 1995), some of which are associated with variations in blood lipid levels. Another particle associated with atherosclerosis (Dahlén et al. 1986, Armstrong 1986, Frick et al. 1987), myocardial infarction (Murai et al. 1986, Rhoads et al. 1986, Dahlén et al. 1975) and stroke (Murai et al. 1986, Woo et al. 1991) is lipoprotein(a) (Lp(a)), which is formed when an LDL particle is attached to an apolipoprotein(a) (Lipid Research Clinics Program 1984a).

Apolipoprotein E (apo E) is a lipoprotein that interferes with the lipid metabolism by affecting the intestinal absorption of cholesterol and by modifying the catabolism of LDL and its precursors, and it can also modify the reverse cholesterol transport (Kinoshita et al. 1993, Martin et al. 1993, Huang et al. 1995). Apo E is a polymorphic lipoprotein with three common alleles: E2, E3 and E4.

Cholesterol is transported from the tissues to the liver by high density lipoprotein (HDL) to be excreted from the body. Apolipoprotein A1 (apo A1), the main protein constituent of HDL, is the primary acceptor for cholesterol in HDL. The cholesteryl ester transfer protein (CETP) is bound to the apo A1-HDL particles and mediates the exchange of HDL cholesteryl esters with the triglycerides of apo B containing lipoproteins (Tall 1995).

Familial hypercholesterolemia (FH) is a disease characterised by a lifelong elevation of the blood levels of low density lipoprotein (LDL) cholesterol due to defective functioning of the LDL receptors (Brown & Goldstein 1986). These patients develop coronary disease 10-20 years earlier than the rest of the population (Thompson 1996).

The clinical diagnosis of FH can be difficult in patients with moderately elevated cholesterol values, and tests to detect the genetic errors of FH are therefore urgently needed. The inherited differences other than FH in plasma lipids and lipid-transporting proteins, and their influence on individual plasma lipid levels and eventually on the hypocholesterolemic efficacy of drugs could facilitate the choice of an ideal diet-drug combination for each hypercholesterolemic individual.