This Article Full Text Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Zhang, H. Articles by Ma, Y. Search for Related Content PubMed PubMed Citation Articles by Zhang, H. Articles by Ma, Y.

(Arteriosclerosis, Thrombosis, and Vascular Biology. 1995;15:1695-1703.)
© 1995 American Heart Association, Inc.

Articles

Patients With ApoE3 Deficiency (E2/2, E3/2, and E4/2) Who Manifest With Hyperlipidemia Have Increased Frequency of an Asn 291Ser Mutation in the Human LPL Gene

Presented in part at the 66th Scientific Sessions of the American Heart Association, Atlanta, Ga, November 8-11, 1993, and published in abstract form (Circulation. 1993;88[suppl I]:I-179).

Hanfang Zhang; Paul W. A. Reymer; Ming-Sun Liu; Ian J. Forsythe; Bjorn E. Groenemeyer; Jiri Frohlich; John D. Brunzell; John J. P. Kastelein; Michael R. Hayden; Yuanhong Ma

From the Department of Medicine (H.Z., Y.M.), the Department of Medical Genetics (H.Z., M.-S.L., I.J.F., M.R.H), and the Academic Medical Center, Amsterdam, The Netherlands (P.W.A.R, B.E.G, J.J.P.K.); the Department of Pathology (J.F.), University of British Columbia, Vancouver, Canada; and the Department of Medicine, University of Washington, Seattle (J.D.B.).

Correspondence to Dr Yuanhong Ma, Department of Medicine, Rm 416-2125 East Mall, NCE Bldg, Vancouver, BC V6T 1Z4, Canada.

Abstract Approximately 1% to 2% of persons in the general population are homozygous for a lipoprotein receptor–binding defective form of apoE (apoE2/2). However, only a small percentage (2% to 5%) of all apoE2/2 homozygotes develop type III hyperlipoproteinemia. Interaction with other genetic and environmental factors are required for the expression of this lipid abnormality. We sought to investigate the possible role of LPL gene mutations in the development of hyperlipoproteinemia in apoE2/2 homozygotes and in apoE2 heterozygotes. As a first step, we performed DNA sequence analysis of all 10 LPL coding exons in 2 patients with the apoE2/2 genotype who had type III hyperlipoproteinemia and identified a single missense mutation (Asn 291Ser) in exon 6 of the LPL gene. The mutation was then found in 5 of 18 patients with type III hyperlipoproteinemia who had the apoE2/2 genotype (allele frequency=13.9%; P7.4x10^-5) and 6 of 22 hyperlipidemic E2 heterozygous patients with the apoE3/2 and E4/2 genotype (allele frequency=13.6%; P=2.2x10^-5). In contrast, this mutation was found in only 3 of 230 normolipidemic controls (allele frequency=0.7%). In vitro mutagenesis studies revealed that the Asn 291Ser mutant LPL had approximately 60% of LPL catalytic activity and approximately 70% of specific activity compared with wild-type LPL. The heparin-binding affinity of the mutant LPL was not impaired. Our data suggest that the Asn 291Ser substitution is likely to be a significant predisposing factor contributing to the expression of different forms of hyperlipidemia when associated with other genetic factors such as the presence of apoE2.

Key Words: hyperlipoproteinemia • lipoprotein lipase • missense mutations • apoE • gene-gene interaction

This article has been cited by other articles:

				Y. Hu, W. Liu, R. Huang, and X. Zhang A systematic review and meta-analysis of the relationship between lipoprotein lipase Asn291Ser variant and diseases J. Lipid Res., September 1, 2006; 47(9): 1908 - 1914. [Abstract] [Full Text] [PDF]

				Y. J. Kim, R. A. Williamson, K. Chen, J. L. Smith, J. C. Murray, and D. C. Merrill Lipoprotein Lipase Gene Mutations and the Genetic Susceptibility of Preeclampsia Hypertension, November 1, 2001; 38(5): 992 - 996. [Abstract] [Full Text] [PDF]

				E. J. G. Sijbrands, M. J. V. Hoffer, A. E. Meinders, L. M. Havekes, R. R. Frants, A. H. M. Smelt, and P. De Knijff Severe Hyperlipidemia in Apolipoprotein E2 Homozygotes Due to a Combined Effect of Hyperinsulinemia and an SstI Polymorphism Arterioscler Thromb Vasc Biol, November 1, 1999; 19(11): 2722 - 2729. [Abstract] [Full Text] [PDF]

				S. Cheng, M. A. Grow, C. Pallaud, W. Klitz, H. A. Erlich, S. Visvikis, J. J. Chen, C. R. Pullinger, M. J. Malloy, G. Siest, et al. A Multilocus Genotyping Assay for Candidate Markers of Cardiovascular Disease Risk Genome Res., October 1, 1999; 9(10): 936 - 949. [Abstract] [Full Text]

				N. Mero, L. Suurinkeroinen, M. Syvänne, P. Knudsen, H. Yki-Järvinen, and M.-R. Taskinen Delayed clearance of postprandial large TG-rich particles in normolipidemic carriers of LPL Asn291Ser gene variant J. Lipid Res., September 1, 1999; 40(9): 1663 - 1670. [Abstract] [Full Text]

				H. H. Wittrup, A. Tybjærg-Hansen, and B. G. Nordestgaard Lipoprotein Lipase Mutations, Plasma Lipids and Lipoproteins, and Risk of Ischemic Heart Disease : A Meta-Analysis Circulation, June 8, 1999; 99(22): 2901 - 2907. [Abstract] [Full Text] [PDF]

				P. J. Talmud, S. Hall, S. Holleran, R. Ramakrishnan, H. N. Ginsberg, and S. E. Humphries LPL promoter -93T/G transition influences fasting and postprandial plasma triglycerides response in African-Americans and Hispanics J. Lipid Res., June 1, 1998; 39(6): 1189 - 1196. [Abstract] [Full Text]

				H.E. Miettinen, H. Gylling, J. Tenhunen, J. Virtamo, M. Jauhiainen, J.K. Huttunen, I. Kantola, T.A. Miettinen, and K. Kontula Molecular Genetic Study of Finns With Hypoalphalipoproteinemia and Hyperalphalipoproteinemia : A Novel Gly230Arg Mutation (LCATFin) of Lecithin:Cholesterol Acyltransferase (LCAT) Accounts for 5% of Cases With Very Low Serum HDL Cholesterol Levels Arterioscler Thromb Vasc Biol, April 1, 1998; 18(4): 591 - 598. [Abstract] [Full Text] [PDF]

				M. E. Wittekoek, S. N. Pimstone, P. W. A. Reymer, L. Feuth, G.-J. Botma, J. C. Defesche, M. Prins, M. R. Hayden, and J. J. P. Kastelein A Common Mutation in the Lipoprotein Lipase Gene (N291S) Alters the Lipoprotein Phenotype and Risk for Cardiovascular Disease in Patients With Familial Hypercholesterolemia Circulation, March 3, 1998; 97(8): 729 - 735. [Abstract] [Full Text] [PDF]

				J. M. A. Boer, C. Ehnholm, H.-J. Menzel, L. M. Havekes, M. Rosseneu, D. S. J. O'Reilly, L. Tiret, and f. t. E. Group Interactions Between Lifestyle-Related Factors and the ApoE Polymorphism on Plasma Lipids and Apolipoproteins : The EARS Study Arterioscler Thromb Vasc Biol, September 1, 1997; 17(9): 1675 - 1681. [Abstract] [Full Text]

				B. E. Groenemeijer, M. D. Hallman, P. W.A. Reymer, E. Gagne, J. A. Kuivenhoven, T. Bruin, H. Jansen, K. I. Lie, A. V.G. Bruschke, E. Boerwinkle, et al. 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 Circulation, June 17, 1997; 95(12): 2628 - 2635. [Abstract] [Full Text]