Genetic factors in the development of atherosclerosis

Abstract

Atherosclerosis is a complex multifactorial disease of the arterial wall, dependent on genetic disposition and multiple other risk factors. There are probably several candidate genes, that determine the individual susceptibility of the vessel wall to develop atherosclerosis. In recent years, a growing number of gene polymorphisms, associated with an elevated risk of myocardial infarction, has been identified. These genes and gene clusters play a crucial role in lipid metabolism, regulation of blood pressure and clotting. In contrast to rare monogenetic diseases with severe clinical signs and symptoms (e.g. familial hypercholesterolemia), genetic polymorphisms are relatively frequent. Due to their frequency, there is a high probability that one individual carries several alleles predisposing to coronary heart disease. Genetic polymorphisms become clinically important by interacting with lifestyle, environmental factors or endogenous metabolic disorders. We have recently established an animal model of rabbits, which may prove useful in the search for new genes predisposing to or protecting from atherosclerosis. Rabbits with high atherosclerotic response (HAR) show more than 70% atherosclerotic involvement of the aorta when fed a high cholesterol diet. In contrast, rabbits with low atherosclerotic response (LAR) show less than 20% atherosclerosis in spite of comparably high plasma cholesterol levels. Preliminary studies indicate that macrophages of LAR rabbits have a high scavenger receptor activity and high apolipoprotein E expression and thus appear to be very efficient in uptake and elimination of modified lipoproteins. This may result in a more efficient removal of cholesterol from the arterial wall and thus protect the animals from developing atherosclerosis. Today we are only at the beginning of understanding the complexity of gene interaction in atherosclerosis. Further identification of genetic factors of atherosclerosis will no doubt lead to a more efficient and economic prevention of coronary heart disease in the future.