Genetic linkage between the antigenic group (Ag) variation and the apolipoprotein B gene: assignment of the Ag locus.

Abstract

The antigenic group (Ag) system of homospecific human serum antigens of low density lipoprotein is detected by antiserum from multiply transfused patients. A complex series of common Ag alleles has been described, but the biochemical nature of this polymorphism is uncertain. Here we report that DNA polymorphisms at the human apolipoprotein B (apoB) locus are very closely linked to alleles of the Ag system. We also show a strong association between Ag(x) and a polymorphism detected with the restriction endonuclease Xba I. We conclude that the immunologically determined Ag system represents protein polymorphism of apoB rather than primary genetic differences in posttranslational processing or lipid binding. These studies therefore demonstrate that the Ag locus is located on the short arm of human chromosome 2 in the region p23-p24 to which the apoB gene has been assigned. Since the Ag(x) antigen is associated with altered plasma lipid levels, this determinant may indicate a functionally important domain of apoB.Epidemiological studies have shown a strong correlation between high plasma low density lipoprotein (LDL) cholesterol levels and premature coronary heart disease. Plasma LDL is responsible for the transport of cholesterol between peripheral tissues and the liver. LDL concentration is regulated by its rate of production from very low density lipoprotein and clearance by the hepatic LDL receptor. The sole protein component of LDL is apolipoprotein B (apoB), which is essential for the structural integrity ofthe particle and is the ligand that mediates its clearance by the LDL receptor pathway (1-3).The antigenic group (Ag) system of homospecific human serum alloantigens was detected in 1961 by the use of an antiserum from a multiply transfused patient (4). Subsequently, the Ag system was shown to reside in LDL and a complex series of alleles has since been described (5). These variants have been shown to behave as autosomal dominant or codominant traits in families and to have differences in gene frequency between populations. Linkage between the Ag system and other genetic markers has not been demonstrated and the biochemical nature of this polymorphism has not been elucidated (6). It is not known, therefore, whether the Ag antigenic determinants reside in apoB, the carbohydrate side chains of apoB, or in LDL lipid. Homospecific polymorphism of LDL has also been found in most animal species that have been studied and appears to be a ubiquitous phenomenon (6).Plasma LDL concentration is profoundly affected by hereditary factors. Thus defects of the LDL receptor gene cause familial hypercholesterolemia with a marked increase in LDL and severe premature atherosclerosis (1, 2).

Association between a specific apolipoprotein B mutation and familial defective apolipoprotein B-100.

“…These allotypic variants have been shown to be closely linked to DNA polymorphisms in the apoB gene (21). Furthermore, comparison offive complete and several partial published human apoB gene sequences revealed more than 60 nucleotide substitutions, the majority of which affect the amino acid sequence of the protein (10).…”

Association of DNA polymorphism at the apolipoprotein B gene locus with coronary heart disease and serum very low density lipoprotein levels.

“…This polymorphism has been associated with the Ag(x/y) and the Ag(c/g) immunochemicaJ polymorphism 10 ' 11 and with elevated serum levels of apo B, 12 cholesterol, and .triglycerides. 12 ' 1314 In patients with type III hyperlipidemia, the allele frequency for the Xba IRFLP differed significantly from the frequency in normolipidemic individuals and in those with other types of hyperiipidemias.…”

Two DNA restriction fragment length polymorphisms associated with Ag(t/z) and Ag(g/c) antigenic sites of human apolipoprotein B.

“…A recent report 9 shows a significant correlation between the Xbal polymorphism and another Ag locus, Ag(x). From the data presented in that report, it appears that not having the Ag(x) antigen, that is, being Ag(x -) -or, presumably, being Ag(y/y) since x and y are antithetical alleles -is associated with possessing two Xbal X1 alleles.…”

“…Unpublished results quoted by Berg et al 9 state: The EcoRI site polymorphism alters the apo B protein sequence by substituting lys (AAA) for glu (GAA) at residue 4154 in the mature protein" and ". .…”

“…The probability that five individuals selected at random would all be Ag(g/g) was 0.49 s = 0.028. The probability that nine additional individuals selected at random would include at least eight who were Ag(g/c) was 8(0.24) 8 (0.58) + (0.42) 9 = 0.005. The probability that three additional individuals selected at random would include at least one Ag(c/c) was 1 -(0.91) 3 = 0.25.…”