DNA polymorphisms of the apolipoprotein B gene (XbaI, EcoRI, and MspI RFLPs) in Norwegians at risk of atherosclerosis and healthy controls.

OBJECTIVES: Apo B is the exclusive protein constituent of LDL and is ligand on LDL, recognized and bound by the LDL receptor. Several restriction fragment length polymorphisms (RFLPs) of the apo B gene have been shown to be associated with variation in serum lipid levels in different populations. In this study we sought to determine the frequency of XbaI, EcoRI, and MspI polymorphisms and the haplotypes generated by these three polymorphic sites of the apo B gene and their influence on lipid levels in a sample of Norwegian subjects at risk of atherosclerosis and healthy control subjects. METHODS AND
RESULTS: 108 White Norwegians at risk of atherosclerosis (cases) and 64 healthy individuals (controls) were examined for possible association between the alleles at the XbaI (X), EcoRI (R), and MspI (M) polymorphic restriction sites of the apolipoprotein B gene and serum lipid levels. The frequency of the M allele (absence of restriction site) was significantly higher in cases with high total cholesterol (TC), high low-density lipoprotein cholesterol (LDLC), and high apolipoprotein B (apo B) than in controls with normal TC, LDLC, and apo B (P < 0.04, P < 0.02, and P < 0.01, respectively). The frequencies of apo B genotypes detected with XbaI, EcoRI, and MspI did not differ significantly between cases and control subjects. A significant association between MspI genotypes and TC (P < 0.02), LDLC (P = 0.03), and apo B (P = 0.001) was observed only in cases. However, cases with the genotype M+/M+ had the lowest and those with the genotype M+/M- had the highest levels of serum TC, LDLC, and apo B. We did not observe any significant association between the alleles or genotypes detected with XbaI or EcoRI and serum lipid levels. In cases, genotypes defined by EcoRI and MspI RFLP paired loci differed significantly for apo B (chi 2 = 19; P = 0.007) but not for other blood lipids. EcoRI and MspI RFLPs change glutamic acid (Glu) 4154 to lysine (Lys) and arginine (Arg) 3611 to glutamine (Gln), respectively, which lie near the low density lipoprotein receptor binding region of apo B. Haplotypes containing "Lys/Arg Lys/Arg" (all basic amino acids) in cases were associated with low serum TC, LDLC, and apo B. In individuals at risk of atherosclerosis the concentration of serum lipids tends to be inversely related to the number of lysine and arginine.
CONCLUSION: We conclude that variations in the apo B gene, resulting in changes of charged amino acids, affect the circulating blood lipids and that these may contribute to the risk of atherosclerosis.