© 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
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
This article has been cited by other articles:
 |
|
 |
|
  R. Frikke-Schmidt, B. G. Nordestgaard, M. C. A. Stene, A. A. Sethi, A. T. Remaley, P. Schnohr, P. Grande, and A. Tybjaerg-Hansen Association of Loss-of-Function Mutations in the ABCA1 Gene With High-Density Lipoprotein Cholesterol Levels and Risk of Ischemic Heart Disease JAMA, June 4, 2008; 299(21): 2524 - 2532. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E.-C. Langberg, H. F Gu, S. Nordman, S. Efendic, and C.-G. Ostenson Genetic variation in receptor protein tyrosine phosphatase {sigma} is associated with type 2 diabetes in Swedish Caucasians Eur. J. Endocrinol., October 1, 2007; 157(4): 459 - 464. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Rip, M. C. Nierman, C. J. Ross, J. W. Jukema, M. R. Hayden, J. J.P. Kastelein, E. S.G. Stroes, and J. A. Kuivenhoven Lipoprotein Lipase S447X: A Naturally Occurring Gain-of-Function Mutation Arterioscler. Thromb. Vasc. Biol., June 1, 2006; 26(6): 1236 - 1245. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. H. Wittrup, R. V. Andersen, A. Tybjaerg-Hansen, G. B. Jensen, and B. G. Nordestgaard Combined Analysis of Six Lipoprotein Lipase Genetic Variants on Triglycerides, High-Density Lipoprotein, and Ischemic Heart Disease: Cross-Sectional, Prospective, and Case-Control Studies from the Copenhagen City Heart Study J. Clin. Endocrinol. Metab., April 1, 2006; 91(4): 1438 - 1445. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Rip, M. C. Nierman, N. J. Wareham, R. Luben, S. A. Bingham, N. E. Day, J. N.I. van Miert, B. A. Hutten, J. J.P. Kastelein, J. A. Kuivenhoven, et al. Serum Lipoprotein Lipase Concentration and Risk for Future Coronary Artery Disease: The EPIC-Norfolk Prospective Population Study Arterioscler. Thromb. Vasc. Biol., March 1, 2006; 26(3): 637 - 642. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Katzov, A. M. Bennet, P. Kehoe, B. Wiman, M. Gatz, K. Blennow, B. Lenhard, N. L. Pedersen, U. de Faire, and J. A. Prince A cladistic model of ACE sequence variation with implications for myocardial infarction, Alzheimer disease and obesity Hum. Mol. Genet., November 1, 2004; 13(21): 2647 - 2657. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Keavney, A. Palmer, S. Parish, S. Clark, L. Youngman, J. Danesh, C. McKenzie, M. Delepine, M. Lathrop, R. Peto, et al. Lipid-related genes and myocardial infarction in 4685 cases and 3460 controls: discrepancies between genotype, blood lipid concentrations, and coronary disease risk Int. J. Epidemiol., October 1, 2004; 33(5): 1002 - 1013. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. F. Gu, S. Efendic, S. Nordman, C.-G. Ostenson, K. Brismar, A. J. Brookes, and J. A. Prince Quantitative Trait Loci Near the Insulin-Degrading Enzyme (IDE) Gene Contribute to Variation in Plasma Insulin Levels Diabetes, August 1, 2004; 53(8): 2137 - 2142. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Merkel, R. H. Eckel, and I. J. Goldberg Lipoprotein lipase: genetics, lipid uptake, and regulation J. Lipid Res., December 1, 2002; 43(12): 1997 - 2006. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. L. Ruel, D. Gaudet, P. Perron, J. Bergeron, P. Julien, and B. Lamarche Characterization of LDL Particle Size Among Carriers of a Defective or a Null Mutation in the Lipoprotein Lipase Gene: The Quebec LIPD Study Arterioscler. Thromb. Vasc. Biol., July 1, 2002; 22(7): 1181 - 1186. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Schneider, J. Kreuzer, A. Hamann, P. P. Nawroth, and K. A. Dugi The Proline 12 Alanine Substitution in the Peroxisome Proliferator-Activated Receptor-{gamma}2 Gene Is Associated With Lower Lipoprotein Lipase Activity in Vivo Diabetes, March 1, 2002; 51(3): 867 - 870. [Abstract] [Full Text] [PDF]
|
|