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(Arteriosclerosis, Thrombosis, and Vascular Biology. 1999;19:1535-1540.)
© 1999 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Mutations in the lipoprotein lipase Gene Associated With Ischemic Heart Disease in Men

The Copenhagen City Heart Study

Hans H. Wittrup; Anne Tybjærg-Hansen; Rolf Steffensen; Samir S. Deeb; John D. Brunzell; Gorm Jensen; Børge G. Nordestgaard

From the Department of Clinical Biochemistry (H.H.W., A.T.-H., B.G.N.), Herlev University Hospital, Herlev; the Copenhagen City Heart Study, Bispebjerg University Hospital (A.T.-H., G.J., B.G.N.), Copenhagen; and the Department of Medicine B (R.S.), Division of Cardiology, Rigshospitalet, National University Hospital, Copenhagen, Denmark; and the Departments of Genetics (S.S.D.) and Medicine (J.D.B.), University of Washington, Seattle.

Correspondence and reprint requests to Børge G. Nordestgaard, MD, DMSc, Department of Clinical Biochemistry, Glostrup University Hospital, Glostrup Ringvej, DK-2600 Glostrup, Denmark. E-mail bn{at}dcb-glostrup.dk

Abstract—The aim of this study was to test the hypothesis that the Asp9Asn substitution and the T(-93)G mutation in the promoter of the lipoprotein lipase gene affect plasma lipid levels and thereby the risk of ischemic heart disease (IHD). We genotyped 9033 men and women from a general population sample and 940 patients with IHD. The frequency of both the G allele and the Asn9 allele in the general population sample was 0.015 for both men and women. These 2 mutations appeared together in 95% of carriers. The average triglyceride-raising effect associated with double heterozygosity for the T(-93)G mutation and the Asp9Asn substitution was 0.28 mmol/L (P=0.004) and 0.16 mmol/L (P=0.10) in men and women, respectively. On logistic regression analysis allowing for age, the risk of IHD for double heterozygous men and women was increased 90% (95% confidence interval [CI], 20% to 200%) and 30% (95% CI, -40% to 170%), respectively, compared with noncarriers. When, in addition, other conventional cardiovascular risk factors were allowed for, the risk of IHD for double heterozygous men and women was increased 70% (95% CI, 0% to 190%) and 20% (95% CI, -50% to 180%), respectively. Of the overall risk of IHD in men in the general population, the fraction attributable to double heterozygosity was 3%, similar to the 5% attributable to diabetes mellitus. These results demonstrate that the Asp9Asn substitution is in linkage disequilibrium with the T(-93)G mutation and that the double-heterozygous carrier status is associated with elevated plasma triglycerides and an increased risk of IHD in men.

Key Words: atherosclerosis • coronary disease • genes • enzymes • lipids

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