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 Ser447-stop substitution in the lipoprotein lipase gene. REGRESS Study Group.
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.


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 beta-blockers (P = .042) and not significant in those not using them (P = .881), suggesting a gene-environment interaction between the Ser447-Stop mutation and beta-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 beta-blockers. The LPL Ser447-Stop mutation therefore should have a protective effect against the development of atherosclerosis and subsequent CAD.
Groenemeijer
B E
BE
Department of Vascular Medicine, Academic Medical Center, Amsterdam, Netherlands.
Hallman
M D
MD
Reymer
P W
PW
Gagné
E
E
Kuivenhoven
J A
JA
Bruin
T
T
Jansen
H
H
Lie
K I
KI
Bruschke
A V
AV
Boerwinkle
E
E
Hayden
M R
MR
Kastelein
J J
JJ
D000319:Adrenergic beta-Antagonists / Q000627:therapeutic use*; D000483:Alleles; D008076:Cholesterol, HDL / Q000097:blood*; D003324:Coronary Artery Disease / Q000097:blood / Q000188:drug therapy* / Q000235:genetics; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D005787:Gene Frequency; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases; D008071:Lipoprotein Lipase / Q000097:blood* / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D017035:Pravastatin / Q000627:therapeutic use; D014280:Triglycerides / Q000097:blood*
D000319:Adrenergic beta-Antagonists; D008076:Cholesterol, HDL; D004791:Enzyme Inhibitors; D014280:Triglycerides; D006903:Hydroxymethylglutaryl CoA Reductases; D008071:Lipoprotein Lipase; D017035:Pravastatin