Genetic variant showing a positive interaction with beta-blocking agents with a beneficial influence on lipoprotein lipase activity, HDL cholesterol, and triglyceride levels in coronary artery disease patients - The Ser(447)-Stop substitution in the lipoprotein lipase gene

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 Asn(291)-Ser and the Asp(9)-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 Ser(447)-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 Ser(447)-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 Ser(447)-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 Ser(447)-Stop allele on LPL activity was pronounced in patients using beta-blockers (P=.042) and not significant in those not using them (P=.881), suggesting a gene-environment interaction between the Ser(447)-Stop mutation and beta-blockers. Conclusions We conclude that the LPL Ser(447)-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 Ser(447)-Stop mutation will have less adverse metabolic effects when placed on beta-blockers. The LPL Ser(477)-Stop mutation therefore should have a protective effect against the development of atherosclerosis and subsequent CAD.