An inherited polymorphism in the human apolipoprotein A-I gene locus related to the development of atherosclerosis.

Epidemiological studies have identified elevated low density lipoprotein (LDL) and diminished high density lipoprotein (HDL) cholesterol levels as risk factors for coronary artery disease. The major protein component of HDL is apoprotein A-I (apo A-I), a polypeptide of 243 amino acids of known primary amino acid sequence. This apoprotein serves as a cofactor for the plasma lecithin-cholesterol acyltransferase (LCAT) enzyme responsible for the formation of most cholesteryl esters in plasma, and also promotes cholesterol efflux from cells. The primary translation product of apo A-I contains both a pre and a pro segment, and post-translational processing of apo A-I may be involved in the formation of the functional plasma apo A-I isoproteins. Defective apo A-I processing may be the underlying problem in Tangier disease, in which patients have low plasma HDL and apo A-I levels despite normal apo A-I synthesis. Patients have been reported with conditions distinct from Tangier disease in whom severe deficiency or absence of apo A-I has been associated with very low HDL levels and severe coronary artery disease. We have now examined the apo A-I gene in two such patients and their first degree relatives. These patients have been reported to have skin and tendon xanthomas, corneal clouding and severe premature coronary atherosclerosis associated with very low HDL levels and deficiencies of two apoproteins, apo A-I and apo C-III. We show that both probands are homozygous for a defect in the apo A-I gene locus.