Hyperlipidemia in coronary heart disease: A biochemical genetic approach

A population genetic study was carried out in order to identify and classify the clinical forms of familial hyperlipidemia that predispose to coronary heart disease. Five hundred consecutive survivors of myocardial infarction in Seattle were ascertained, and extensive family studies were then performed. Three simply inherited forms of hyperlipidemia were identified - familial hypercholesterolemia, familial hypertriglyceridemia, and familial combined hyerlipidemia. Together, these three disorders were present in 20 per cent of the survivors under 60 years of age. To us, the most exciting finding was that each of these disorders appeared to be transmitted by a single gene mechanism, indicating that each disorder may be caused by a single biochemical defect that should be identifiable at the molecular level. On the negative side, we were disappointed to find that there was no consistent relationship between the plasma lipoprotein pattern in a given patient and his genetic disorder. None of the lipoprotein types proved specific for any of the three familial disorders; and conversely, none of the familial disorders were specified by a single lipoprotein type. From these studies, we concluded that lipoprotein typing would be of limited use in the search for the basic defects. At this piont, it seemed clear that a new sytem was needed that would allow delineation of underlying defects in lipid or lipoprotein metabolism in these genetically determined disorders. Two years ago in Dallas, we began a series of studies to search for these molecular lesions. Familial hypercholesterolemia was the disorder that we first chose to study. Of all the hereditary forms of hyperlipidemia, this disorder is the outstanding example of a single-gene mutation producing both elevated cholesterol and atherosclerosis. Moreover, familial hypercholesterolemia is one of the most common genetic diseases affecting man. About 1 out of 500 people in the general population is a heterozygote for the dominant familial hypercholesterolemia gene, making this disorder more common than either cystic fibrosis or sickle cell anemia.