Associations of the ABO blood groups with cardiovascular disease and serum lipid levels have been established, but the exact relation to lipoproteins and atherosclerosis remains to be determined.
We still need to know which tissues take up the most LDL; we need to know how much LDL is cleared by the liver and whether this clearance involves the same LDL receptor that operates in extra-hepatic cells; we need to know the mechanism for the clearance of the one-half to two-thirds of LDL that leaves the plasma by receptor-independent pathways; and finally we need to know how an abnormal accumulation of LDL in the plasma leads to the deposition of cholesterol in scavenger cells and produces atherosclerosis.
We have recently isolated and characterized the human apo A-I gene and have shown that apo A-I and apolipoprotein C-III (apo C-III) genes are physically linked and that a polymorphism (of unknown frequency in the general population) of the apo A-I gene is inherited as a mendelian trait linked to premature atherosclerosis in an affected family (not the same polymorphism as has previously been reported to be associated with hypertriglyceridaemia).
A six-year-old girl with severe hypercholesterolemia and atherosclerosis had two defective genes at the low-density-lipoprotein (LDL) receptor locus, as determined by biochemical studies of cultured fibroblasts.
In addition to the three major isoforms of apolipoprotein E (apo E-4, E-3, and E-2) and the new one (apo E-5) which was recently found in this laboratory, we have discovered an additional series of components, which showed themselves as at least three bands on an isoelectric focusing gel in the region of E-VII through E-V, in four patients with hyperlipidemia and atherosclerosis.
Patients affected by mixed hyperlipidemia should be investigated for their apolipoprotein E polymorphism because of the possible linkage of apolipoprotein E2/2 homozygosity, hyperlipidemia, and atherosclerosis.
We have recently reported that the human apolipoprotein A-I (apoA-I) and apolipoprotein C-III (apoC-III) genes are physically linked and that the presence of a DNA insertion in the apoA-I gene is correlated with apoA-I-apoC-III deficiency in patients with premature atherosclerosis.
We have recently reported that the human apolipoprotein A-I (apoA-I) and apolipoprotein C-III (apoC-III) genes are physically linked and that the presence of a DNA insertion in the apoA-I gene is correlated with apoA-I-apoC-III deficiency in patients with premature atherosclerosis.
A genetic analysis of atherosclerotic patients as well as healthy subjects using an apoA-I gene specific probe confirmed that an EcoRI restriction fragment length polymorphism is related to the development of atherosclerosis.
These results indicate that absence of transcripts with correct apoAI and apoCIII mRNA sequences causes apoAI and apoCIII deficiency in the plasma of these patients and suggest that these apolipoproteins are involved in cholesterol homeostasis and protection against premature atherosclerosis.
Since human arterial SMC in culture express receptors for and are mitogenically responsive to platelet-derived growth factor, transcription of the sis gene by cells within lesions, whether these cells are SMC themselves, macrophages, endothelial cells, or another cell type, suggests that an autocrine and/or paracrine proliferative mechanism is important in the pathogenesis of atherosclerosis.
We compare the nucleotide sequences of the region encompassing the putative LDL receptor-binding sites from four pig alleles, including one implicated directly in atherosclerosis.