ASSOCIATION OF MUTATIONS IN THE APOLIPOPROTEIN-B GENE WITH HYPERCHOLESTEROLEMIA AND THE RISK OF ISCHEMIC-HEART-DISEASE

Background Familial hypercholesterolemia leads to premature ischemic h eart disease and is often caused by mutations in the gene for the low- density lipoprotein receptor. Mutations in the apolipoprotein B gene, which encodes a ligand for this receptor, may also result in this phen otype, Methods We studied the genotypes of 9255 women and men from the general population, 948 patients with ischemic heart disease, and 36 patients with familial hypercholesterolemia, all from Denmark, for thr ee mutations in the apolipoprotein B gene: Arg3500Gln, Arg3531Cys, and Arg3500Trp. Results The prevalence of heterozygotes in the general po pulation was 0.08 percent (95 percent confidence interval, 0.03 to 0.1 6 percent) for both the Arg3500Gln and the Arg3531Cys mutations, and 0 .00 percent (95 percent confidence interval, 0.00 to 0.18 percent) for the Arg3500Trp mutation. Among carriers of the Arg3500Gln mutation, c holesterol levels were significantly higher than among noncarriers in the general population - by 100 mg per deciliter (2.6 mmol per liter) among carriers in the general population, 154 mg per deciliter (4.0 mm ol per liter) among patients with ischemic heart disease, and 172 mg p er deciliter (4.5 mmol per liter) among patients with familial hyperch olesterolemia. Heterozygous carriers of the Arg3500Gln mutation were s ignificantly more common among patients with ischemic heart disease (o dds ratio, 7.0; 95 percent confidence interval, 2.2 to 22; P=0.003) an d patients with familial hypercholesterolemia (odds ratio, 78; 95 perc ent confidence interval, 16 to 388; P=0.001) than in the general popul ation. Heterozygous carriers of the Arg3531Cys mutation in the general population did not have higher-than-normal plasma cholesterol levels or an increased risk of ischemic heart disease (odds ratio; 1.4; 95 pe rcent confidence interval, 0.2 to 11; P=0.54), Conclusions The Arg3500 Gln mutation in the apolipoprotein B gene, which is responsible for fa milial defective apolipoprotein B-100 and is present in approximately 1 in 1000 persons in Denmark, causes severe hypercholesterolemia and i ncreases the risk of ischemic heart disease. (C) 1998, Massachusetts M edical Society.