(Circulation. 1997;95:2628-2635.)
© 1997 American Heart Association, Inc.
Articles |
Genetic Variant Showing a Positive Interaction With ß-Blocking Agents With a Beneficial Influence on Lipoprotein Lipase Activity, HDL Cholesterol, and Triglyceride Levels in Coronary Artery Disease Patients
The Ser447-Stop Substitution in the Lipoprotein Lipase Gene
the Department of Vascular Medicine (B.E.G., P.W.A.R., J.A.K., T.B., J.J.P.K.) and Department of Cardiology (K.I.L.), Academic Medical Center, Amsterdam, Netherlands; the Human Genetics Center (M.D.H., E.B.), University of Texas Health Science Center, Houston; the Department of Medical Genetics (E.G., M.R.H.), University of British Columbia, Vancouver, Canada; the Department of Biochemistry (H.J.), University of Rotterdam, Netherlands; and the Department of Cardiology (A.V.G.B.), University Hospital, Leiden, Netherlands.
Correspondence to John J.P. Kastelein, MD, PhD, Department of Vascular Medicine (G1-114), Academic Medical Center, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands. E-mail lansberg{at}uva.amc.nl
Background Lipoprotein lipase (LPL) is the rate-limiting enzyme in the lipolysis of triglyceride-rich lipoproteins, and the gene coding for LPL is therefore a candidate gene in atherogenesis. We previously demonstrated that two amino acid substitutions in LPL, the Asn291-Ser and the Asp9-Asn, are associated with elevated triglycerides and lower HDL cholesterol and are present with greater frequency in coronary artery disease (CAD) patients than in normolipidemic control subjects. Conversely, a third frequent mutation in this gene, the Ser447-Stop, is reported by some investigators to underlie higher HDL cholesterol levels and would represent a beneficial genetic variant in lipoprotein metabolism. We therefore sought conclusive evidence for these allegations by investigating the effects of the LPL Ser447-Stop mutation on LPL and hepatic lipase (HL) activity, HDL cholesterol, and triglycerides in a large group of CAD patients (n=820) with normal to mildly elevated total and LDL cholesterol levels.
Methods and Results Carriers of the Ser447-Stop allele (heterozygotes and homozygotes) had significantly higher postheparin LPL activity (P=.034), normal postheparin HL activity (P=.453), higher HDL cholesterol levels (P=.013), and lower triglyceride levels (P=.044) than noncarriers. The influence of the Ser447-Stop allele on LPL activity was pronounced in patients using ß-blockers (P=.042) and not significant in those not using them (P=.881), suggesting a gene-environment interaction between the Ser447-Stop mutation and ß-blockers.
Conclusions We conclude that the LPL Ser447-Stop mutation has a significant positive effect on LPL activity and HDL cholesterol and triglyceride levels and that certain subgroups of CAD patients carrying the Ser447-Stop mutation will have less adverse metabolic effects when placed on ß-blockers. The LPL Ser447-Stop mutation therefore should have a protective effect against the development of atherosclerosis and subsequent CAD.
Key Words: genetics • lipoproteins • coronary disease
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