Use of DNA polymorphisms of the apolipoprotein genes to study the role of genetic variation in the determination of serum lipid levels.

Cloned DNA probes for the apolipoprotein B (apoB) gene and the gene cluster for apoA-I/C-III/A-IV were used to detect restriction fragment length polymorphisms (RFLPs) at these two loci. Samples have been obtained from clinically well individuals, and the RFLP genotypes of each individual have been determined. The data show that at the locus for apoB, genetic variation associated with an RFLP detected by the enzyme XbaI (but not that associated with RFLPs detected by MspI or EcoRI) is involved in determining the normal levels of serum total cholesterol and low density lipoprotein (LDL) cholesterol. In our study, genetic variation associated with the XbaI RFLP accounts for 14% of the total phenotypic variance in cholesterol levels. Information from all three RFLPs can be used in conjunction to give a better definition of the underlying genetic variation. Data from a second study show that genetic variation in the apoA-I/C-III/A-IV gene cluster, associated with the PstI RFLP, is involved in determining the level of apoA-I and, to a lesser extent, the levels of high density lipoprotein (HDL). When genotypes from three RFLPs were used in conjunction as a haplotype, genetic variation in this gene cluster was shown to account for 16% of the phenotypic variance in apoA-I concentration and for 8% of the phenotypic variance in HDL concentration in our sample. These associations suggest that the isolation and sequencing of the apoB and the apoA-I/C-III/A-IV genes from different individuals will give useful information about how changes in the DNA sequence of these genes may lead to alterations in the levels of their respective apolipoproteins, in the level of the lipoproteins with which they are associated and, possibly, in the levels of lipids in the serum.