The Xba1 polymorphism of the apolipoprotein B gene influences the degradation of low density lipoprotein in vitro.

This study examines the influence of variation in the apolipoprotein B (apoB) gene, the major protein of low-density lipoprotein (LDL), on the LDL degradation rate in vitro. Previously we have shown (Demant et al. (1988) J. Clin. Invest. 82, 797-802) that there is an association between the fractional catabolic rate of LDL in vivo and the apoB polymorphism detected using the Xba1 restriction enzyme. Subjects with genotype X1X1 (X1 = absence of cutting site) cleared LDL more rapidly from the plasma compartment than those with the X2X2 genotype. In this study, the LDL degradation rate on dermal fibroblasts was measured for 33 individuals of genotype X1X1 or X2X2. These were subdivided into three groups: (1) young normolipidaemic, (2) older normolipidaemic and (3) older hypercholesterolaemic subjects, because age is known to markedly affect the plasma LDL concentration and may independently influence the population of LDL particles under study. In all experiments, the degradation rate of one type of LDL was compared directly in the cell culture dish with that from an individual of the alternate genotype by labelling them separately with the two iodine isotopes 125I and 131I. In the group of young normals (mean cholesterol 5.03 mmol/l, mean age 31 years), no significant difference was observed between the degradation rates of LDL derived from X1X1 individuals versus X2X2. However, in the older group of normals (mean cholesterol 5.4 mmol/l, mean age 48 years), LDL from subjects with X1X1 genotype was catabolised 17% faster than that from X2X2 subjects (P less than 0.001). A similar result was seen in hypercholesterolaemics (mean cholesterol 8.3 mmol/l, mean age 57 years) with LDL isolated from X1X1 subjects being degraded 22% more rapidly than that from X2X2 subjects. This in vitro evidence adds further weight to the hypothesis that genetic variation in the apoB gene leads to structural changes in LDL than alter its potential for degradation via the LDL receptor.