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Previous Volume 338:1577-1584 May 28, 1998 Number 22 Next

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ABSTRACT

Background Familial hypercholesterolemia leads to premature ischemic heart 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 phenotype.

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 three mutations in the apolipoprotein B gene: Arg3500Gln, Arg3531Cys, and Arg3500Trp.

Results The prevalence of heterozygotes in the general population was 0.08 percent (95 percent confidence interval, 0.03 to 0.16 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, cholesterol 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 mmol per liter) among patients with ischemic heart disease, and 172 mg per deciliter (4.5 mmol per liter) among patients with familial hypercholesterolemia. Heterozygous carriers of the Arg3500Gln mutation were significantly more common among patients with ischemic heart disease (odds ratio, 7.0; 95 percent confidence interval, 2.2 to 22; P=0.003) and patients with familial hypercholesterolemia (odds ratio, 78; 95 percent confidence interval, 16 to 388; P=0.001) than in the general population. 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 percent confidence interval, 0.2 to 11; P=0.54).

Conclusions The Arg3500Gln mutation in the apolipoprotein B gene, which is responsible for familial defective apolipoprotein B-100 and is present in approximately 1 in 1000 persons in Denmark, causes severe hypercholesterolemia and increases the risk of ischemic heart disease.

Source Information

From the Department of Clinical Biochemistry, Herlev University Hospital, University of Copenhagen, Herlev (A.T.-H., B.G.N.); and the Department of Medicine B, Division of Cardiology (R.S., H.M.), and the Copenhagen City Heart Study (A.T.-H., P.S., B.G.N.), Rigshospitalet, National University Hospital, University of Copenhagen, Copenhagen — both in Denmark.

Address reprint requests to Dr. Tybjærg-Hansen at the Department of Clinical Biochemistry 54M1, Herlev University Hospital, Herlev Ringvej 75, DK-2730 Herlev, Denmark.

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Association of Mutations in the Apolipoprotein B Gene with Hypercholesterolemia and the Risk of Ischemic Heart Disease
Gaffney D., Pullinger C., Kane J., Schaefer J. R., Herzum M., Maisch B., Tybjærg-Hansen A., Nordestgaard B. G.
Extract | Full Text  
N Engl J Med 1998; 339:1640-1642, Nov 26, 1998. Correspondence

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