Does the EcoRI polymorphism in the human apolipoprotein B gene affect the binding of low density lipoprotein to the low density lipoprotein receptor?
In human populations, there is an association between coronary artery disease and a polymorphism in the apolipoprotein B (apo B) gene detected with the enzyme EcoRI. This polymorphism gives rise to two apo B alleles, one (E+) encoding glutamic acid and the other (E-) encoding lysine at position 4,154 in apo B-100, the protein of low density lipoprotein (LDL). We have tested the hypothesis that this amino acid substitution indirectly influences proneness to coronary artery disease by affecting the binding of LDL to LDL receptors. The receptor-binding affinities of LDLs from eight pairs of subjects with genotypes E+/+ and E-/- who were matched for other apo B genotypes were determined in vitro. There was no significant difference between the binding affinities of LDLs from the two groups of subjects. Our results strongly suggest that the amino acid at position 4,154 does not influence the function of the receptor-binding domain in apo B-100 and that the association between coronary artery disease and the EcoRI polymorphism is not mediated by an effect of the polymorphism on serum LDL concentration. In view of our findings, it would be of interest to examine the effect of the amino acid substitution on the binding of LDL to arterial proteoglycans and on the oxidizability of LDL by cells in culture.
Gallagher
J J
JJ
MRC Lipoprotein Team, Hammersmith Hospital, London, England.
Myant
N B
NB
D001055:Apolipoproteins B / Q000235:genetics*; D001667:Binding, Competitive; D015246:Deoxyribonuclease EcoRI; D005796:Genes; D006801:Humans; D008077:Lipoproteins, LDL / Q000378:metabolism*; D009994:Osmolar Concentration; D011110:Polymorphism, Genetic; D011956:Receptors, Cell Surface / Q000378:metabolism*; D018110:Receptors, Lipoprotein
D001055:Apolipoproteins B; D008077:Lipoproteins, LDL; D011956:Receptors, Cell Surface; D018110:Receptors, Lipoprotein; D015246:Deoxyribonuclease EcoRI