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(Arteriosclerosis, Thrombosis, and Vascular Biology. 1999;19:2708.)
© 1999 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

A Frequent Mutation in the Lipoprotein Lipase Gene (D9N) Deteriorates the Biochemical and Clinical Phenotype of Familial Hypercholesterolemia

Marianne E. Wittekoek; Etelka Moll; Simon N. Pimstone; Mieke D. Trip; Peter J. Lansberg; Joep C. Defesche; Jasper J. van Doormaal; Michael R. Hayden; John J. P. Kastelein

From the Department of Vascular Medicine, Academic Medical Centre, Amsterdam (M.E.W., E.M., M.D.T., P.J.L., J.C.D., J.J.P.K.) and Atherosclerosis Lipids Outpatient Clinics, Thorax Centre, University Hospital Groningen (J.J.v.D.), the Netherlands; and Centre for Molecular Medicine and Therapeutics, UBC, Vancouver, Canada (S.N.P., M.R.H.).

Correspondence to John J.P. Kastelein, MD, PhD, Department of Vascular Medicine Academic Medical Centre, G1-114, Universtiy of Amsterdam, 1105 AZ, Amsterdam. E-mail JohnJPK{at}worldonline.nl

Abstract—The D9N substitution is a common mutation in the lipoprotein lipase (LPL) gene. This mutation has been associated with reduced levels of HDL cholesterol and elevated triglycerides (TG) in a wide variety of patients. We investigated the influence of this D9N mutation on lipid and lipoprotein levels and risk for cardiovascular disease (CVD) in patients with familial hypercholesterolemia (FH). A total of 2091 FH heterozygotes, all of Dutch extraction, were screened for the D9N mutation using standard polymerase chain reaction techniques, followed by specific enzyme digestion. A total of 94 FH subjects carrried the D9N mutation at a carrier frequency of 4.5%. Carriers of other common LPL mutations, such as the N291S and the S447X were excluded. Clinical data on 80 FH individuals carrying the D9N were available and were compared with a FH control group matched for age, sex, and body mass index (n=203). Analysis revealed significantly higher TG (P=0.01) and lower HDL-cholesterol levels (P=0.002). Dyslipidemia was more pronounced in D9N carriers with higher body mass index. Moreover, FH patients carrying this common LPL mutation were at higher risk for CVD, (odds ratio=2.8; 95% CI, 1.43 to 5.32; P=0.002). The common D9N LPL mutation leads to increased TG and decreased HDL plasma levels in patients with FH. These effects are most apparent in those FH heterozygotes with an increased body mass index. Furthermore, this mutation, present in 4.5% of Dutch FH heterozygotes, leads to increased risk for CVD.

Key Words: lipoprotein lipase gene • mutations • familial hypercholesterolemia • cardiovascular disease

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