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

Abstract

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.

Clinical, biochemical, and genetic features in familial disorders of high density lipoprotein deficiency.

“…When DNA was isolated from the white cells of the two probands, subjected to EcoRI digestion, and analyzed by Southern blot analysis by using an apo A-l gene probe, the probe hybridized to a unique 6.5 kb band in contrast to the normal 13 kb band. Similar experiments 103 in heterozygotes demonstrated the presence of both the normal 13 kb band and the abnormal 6.5 kb band. Recent data 104 has documented that the apo C-lll gene is approximately 2.6 kilobases downstream of the 3' end of the apo A-l gene, accounting for the observed genetic linkage.…”

“…103 ' 104 ' 140 ' 156 -158 A specific apo A-l gene abnormality has been reported based on the Southern blot analysis in familial deficiency of apolipoproteins A-l and C-lll. 1031104 No such abnormality exists in familial apolipoprotein A-l and C-lll deficiency or Tangier disease.…”

Apolipoprotein AI-CIII gene polymorphisms in Japanese myocardial infarction survivors

“…In the case of Japanese, however, our data indicate that both the $2 and M2 alleles are common and not associated with coronary atherosclerosis. The apo CII1 Sst-I polymorphism arises from a C-G transversion in the 3'-non-coding region of the apo CIII gene (Karathanasis et al, 1983a). The apo A1 Msp-I polymorphism arises from the presence or absence of a Msp-I site in the third intron of the apo AI gene (Seilhamer et al, 1984).…”

“…The human apo AI and apo CIII genes are tightly linked and form a gene complex together with the apo AIV gene on the long arm of the chromosome 11 (Karathanasis, 1985). A mutation of the apo AI gene is associated with low plasma HDL and premature atherosclerosis (Karathanasis et al, 1983a(Karathanasis et al, , 1983b. In addition, restriction fragment length polymorphisms related to the apo AI and apo CIII genes have been reported to be associated with coronary atherosclerosis and familial hypoalphalipoproteinemia in Caucasians (Ferns et aI., 1985;Rees et al, 1985;Sidoli et al, 1985;Ferns and Galton, 1986;Ordovas et al, 1986;Buraczynska et al, 1986;Deeb et al, 1986;Acton et al, 1986).…”

Cloning and structure analysis of the rat apolipoprotein A-1 cDNA

“…Epidemiological studies have demonstrated that HDL cholesterol levels are negatively correlated with susceptibility to atherosclerosis and coronary artery disease [4,5]. A linkage between the human apoA-I and apolipoprotein C-I11 genes [6], as well as genetic polymorphisms associated with apoA-I and apoC-111 deficiency [7] or hypertriglyceridemia [8] have been recently reported.…”