Advertisement

Plasma levels of apolipoprotein E and risk of ischemic heart disease in the general population

  • Katrine L. Rasmussen
    Affiliations
    Department of Clinical Biochemistry, Rigshospitalet, Blegdamsvej 9, DK-2100 Copenhagen, Denmark

    Copenhagen University Hospital and Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3, DK-2200 Copenhagen, Denmark
    Search for articles by this author
  • Anne Tybjærg-Hansen
    Affiliations
    Department of Clinical Biochemistry, Rigshospitalet, Blegdamsvej 9, DK-2100 Copenhagen, Denmark

    The Copenhagen City Heart Study, Frederiksberg Hospital, Nordre Fasanvej 57, DK-2000 Frederiksberg, Denmark

    The Copenhagen General Population Study, Herlev and Gentofte Hospital, Herlev Ringvej 75, DK-2730 Herlev, Denmark

    Copenhagen University Hospital and Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3, DK-2200 Copenhagen, Denmark
    Search for articles by this author
  • Børge G. Nordestgaard
    Affiliations
    The Copenhagen City Heart Study, Frederiksberg Hospital, Nordre Fasanvej 57, DK-2000 Frederiksberg, Denmark

    The Copenhagen General Population Study, Herlev and Gentofte Hospital, Herlev Ringvej 75, DK-2730 Herlev, Denmark

    Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Herlev Ringvej 75, DK-2730 Herlev, Denmark

    Copenhagen University Hospital and Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3, DK-2200 Copenhagen, Denmark
    Search for articles by this author
  • Ruth Frikke-Schmidt
    Correspondence
    Corresponding author. Department of Clinical Biochemistry KB 3011, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, DK-2100 Copenhagen, Denmark.
    Affiliations
    Department of Clinical Biochemistry, Rigshospitalet, Blegdamsvej 9, DK-2100 Copenhagen, Denmark

    The Copenhagen General Population Study, Herlev and Gentofte Hospital, Herlev Ringvej 75, DK-2730 Herlev, Denmark

    Copenhagen University Hospital and Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3, DK-2200 Copenhagen, Denmark
    Search for articles by this author

      Highlights

      • High plasma apoE was associated with increased risk of IHD in men but not in women.
      • The associations were independent of APOE genotype.
      • The associations were attenuated after adjustment for triglycerides.
      • Triglyceride-rich lipoproteins may partly explain these associations.

      Abstract

      Background and aims

      Triglyceride-rich lipoproteins are causally associated with high risk of ischemic heart disease (IHD), and apolipoprotein E (apoE) has a central role in their plasma clearance. While both quantitative and qualitative changes of apoE are established causes of rare dyslipidemia syndromes, it remains unclear whether plasma levels of apoE are associated with risk of IHD in the general population.

      Methods

      We tested whether plasma levels of apoE at enrollment were associated with future risk of IHD and myocardial infarction (MI) in 91,695 individuals from the general population.

      Results

      Multifactorially adjusted hazard ratios (HRs) for highest versus lowest apoE tertile were 1.15 (1.04–1.27) for IHD and 1.16 (1.00–1.36) for MI in men, and 0.94 (0.84–1.05) and 1.04 (0.85–1.26) in women. These associations were attenuated by adjustments for triglyceride levels. Corresponding HRs for highest versus lowest apoE tertile in ε33 carriers were 1.18 (1.03–1.36) for IHD and 1.21 (0.98–1.49) for MI in men, and 0.91 (0.78–1.06) and 0.93 (0.71–1.21) in women. Thus, the present associations were independent of APOE genotype.

      Conclusion

      These findings suggest that high plasma levels of apoE are associated with IHD in men but not in women. Triglyceride-rich lipoproteins may partly explain these associations.

      Keywords

      Abbreviations:

      apoE (Apolipoprotein E), CI (95% confidence interval), CCHS (Copenhagen City Heart Study), CGPS (Copenhagen General Population Study), HDL (High density lipoprotein), HRs (Hazard ratios), ICD (International Classification of Diseases), IHD (Ischemic heart disease), LDL (Low density lipoprotein), LRP (LDL receptor related protein), MI (Myocardial infarction)
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Atherosclerosis
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Jorgensen A.B.
        • Frikke-Schmidt R.
        • Nordestgaard B.G.
        • Tybjaerg-Hansen A.
        Loss-of-function mutations in APOC3 and risk of ischemic vascular disease.
        N. Engl. J. Med. 2014; 371: 32-41https://doi.org/10.1056/NEJMoa1308027
        • Nordestgaard B.G.
        • Varbo A.
        Triglycerides and cardiovascular disease.
        Lancet. 2014; 384: 626-635https://doi.org/10.1016/S0140-6736(14)61177-6
        • Schaefer E.J.
        • Gregg R.E.
        • Ghiselli G.
        • et al.
        Familial apolipoprotein E deficiency.
        J. Clin. Invest. 1986; 78: 1206-1219https://doi.org/10.1172/JCI112704
        • Mak A.C.
        • Pullinger C.R.
        • Tang L.F.
        • et al.
        Effects of the absence of apolipoprotein e on lipoproteins, neurocognitive function, and retinal function.
        JAMA Neurol. 2014; 71: 1228-1236https://doi.org/10.1001/jamaneurol.2014.2011
        • Sing C.F.
        • Davignon J.
        Role of the apolipoprotein E polymorphism in determining normal plasma lipid and lipoprotein variation.
        Am. J. Hum. Genet. 1985; 37: 268-285
        • Mahley R.W.
        • Ji Z.S.
        Remnant lipoprotein metabolism: key pathways involving cell-surface heparan sulfate proteoglycans and apolipoprotein E.
        J. Lipid Res. 1999; 40: 1-16
        • Mahley R.W.
        • Rall Jr., S.C.
        Type III hyperlipoproteinemia (dysbetalipoproteinemia): the role of apolipoprotein E in normal and abnormal lipoprotein metabolism.
        in: Scriver C.R. Beaudet A.L. Sly W.S. Valle D. The Metabolic and Molecular Bases of Inherited Disease. eighth ed. McGraw-Hill, New York, NY2001: 2835-2862
        • Mooijaart S.P.
        • Berbee J.F.
        • van H.D.
        • et al.
        ApoE plasma levels and risk of cardiovascular mortality in old age.
        PLoS Med. 2006; 3: e176https://doi.org/10.1371/journal.pmed.0030176
        • Schiele F.
        • De B.D.
        • Vincent-Viry M.
        • et al.
        Apolipoprotein E serum concentration and polymorphism in six European countries: the ApoEurope Project.
        Atherosclerosis. 2000; 152: 475-488https://doi.org/10.1016/S0021-9150(99)00501-8
        • Vincent-Viry M.
        • Schiele F.
        • Gueguen R.
        • Bohnet K.
        • Visvikis S.
        • Siest G.
        Biological variations and genetic reference values for apolipoprotein E serum concentrations: results from the STANISLAS cohort study.
        Clin. Chem. 1998; 44: 957-965
        • Simon R.
        • Girod M.
        • Fonbonne C.
        • et al.
        Total ApoE and ApoE4 isoform assays in an Alzheimer's disease case-control study by targeted mass spectrometry (n=669): a pilot assay for methionine-containing proteotypic peptides.
        Mol. Cell Proteomics. 2012; 11: 1389-1403https://doi.org/10.1074/mcp.M112.018861
        • Soares H.D.
        • Potter W.Z.
        • Pickering E.
        • et al.
        Plasma biomarkers associated with the apolipoprotein E genotype and Alzheimer disease.
        Arch. Neurol. 2012; 69: 1310-1317https://doi.org/10.1001/archneurol.2012.1070
        • Scacchi R.
        • Gambina G.
        • Ruggeri M.
        • et al.
        Plasma levels of apolipoprotein E and genetic markers in elderly patients with Alzheimer's disease.
        Neurosci. Lett. 1999; 259: 33-36https://doi.org/10.1016/S0304-3940(98)00889-1
        • Slooter A.J.
        • de K.P.
        • Hofman A.
        • et al.
        Serum apolipoprotein E level is not increased in Alzheimer's disease: the Rotterdam study.
        Neurosci. Lett. 1998; 248: 21-24https://doi.org/10.1016/S0304-3940(98)00339-5
        • Rasmussen K.L.
        • Tybjaerg-Hansen A.
        • Nordestgaard B.G.
        • Frikke-Schmidt R.
        Plasma levels of apolipoprotein E and risk of dementia in the general population.
        Ann. Neurol. 2015; 77: 301-311https://doi.org/10.1002/ana.24326
        • Utermann G.
        • Hees M.
        • Steinmetz A.
        Polymorphism of apolipoprotein E and occurrence of dysbetalipoproteinaemia in man.
        Nature. 1977; 269: 604-607https://doi.org/10.1038/269604a0
        • Frikke-Schmidt R.
        • Nordestgaard B.G.
        • Agerholm-Larsen B.
        • Schnohr P.
        • Tybjaerg-Hansen A.
        Context-dependent and invariant associations between lipids, lipoproteins, and apolipoproteins and apolipoprotein E genotype.
        J. Lipid Res. 2000; 41: 1812-1822
        • Frikke-Schmidt R.
        • Tybjaerg-Hansen A.
        • Steffensen R.
        • Jensen G.
        • Nordestgaard B.G.
        Apolipoprotein E genotype: epsilon32 women are protected while epsilon43 and epsilon44 men are susceptible to ischemic heart disease: the Copenhagen City Heart Study.
        J. Am. Coll. Cardiol. 2000; 35: 1192-1199https://doi.org/10.1016/S0735-1097(00)00520-9
        • Dallongeville J.
        • Lussier-Cacan S.
        • Davignon J.
        Modulation of plasma triglyceride levels by apoE phenotype: a meta-analysis.
        J. Lipid Res. 1992; 33: 447-454
        • Bennet A.M.
        • Di A.E.
        • Ye Z.
        • et al.
        Association of apolipoprotein E genotypes with lipid levels and coronary risk.
        JAMA. 2007; 298: 1300-1311https://doi.org/10.1001/jama.298.11.1300
        • Frikke-Schmidt R.
        • Nordestgaard B.G.
        • Stene M.C.
        • et al.
        Association of loss-of-function mutations in the ABCA1 gene with high-density lipoprotein cholesterol levels and risk of ischemic heart disease.
        JAMA. 2008; 299: 2524-2532https://doi.org/10.1001/jama.299.21.2524
        • Zacho J.
        • Tybjaerg-Hansen A.
        • Jensen J.S.
        • Grande P.
        • Sillesen H.
        • Nordestgaard B.G.
        Genetically elevated C-reactive protein and ischemic vascular disease.
        N. Engl. J. Med. 2008; 359: 1897-1908https://doi.org/10.1056/NEJMoa0707402
        • Kamstrup P.R.
        • Tybjaerg-Hansen A.
        • Steffensen R.
        • Nordestgaard B.G.
        Genetically elevated lipoprotein(a) and increased risk of myocardial infarction.
        JAMA. 2009; 301: 2331-2339https://doi.org/10.1001/jama.2009.801
        • Friedewald W.T.
        • Levy R.I.
        • Fredrickson D.S.
        Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge.
        Clin. Chem. 1972; 18: 499-502
        • Weverling-Rijnsburger A.W.
        • Jonkers I.J.
        • van E.E.
        • Gussekloo J.
        • Westendorp R.G.
        High-density vs low-density lipoprotein cholesterol as the risk factor for coronary artery disease and stroke in old age.
        Arch. Intern Med. 2003; 163: 1549-1554https://doi.org/10.1001/archinte.163.13.1549
        • Weverling-Rijnsburger A.W.
        • Blauw G.J.
        • Lagaay A.M.
        • Knook D.L.
        • Meinders A.E.
        • Westendorp R.G.
        Total cholesterol and risk of mortality in the oldest old.
        Lancet. 1997; 350: 1119-1123https://doi.org/10.1016/S0140-6736(97)04430-9
        • Shepherd J.
        • Blauw G.J.
        • Murphy M.B.
        • et al.
        Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial.
        Lancet. 2002; 360: 1623-1630https://doi.org/10.1016/S0140-6736(02)11600-X
        • Packard C.J.
        • Ford I.
        • Robertson M.
        • et al.
        Plasma lipoproteins and apolipoproteins as predictors of cardiovascular risk and treatment benefit in the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER).
        Circulation. 2005; 112: 3058-3065https://doi.org/10.1161/CIRCULATIONAHA.104.526848
        • Corsetti J.P.
        • Gansevoort R.T.
        • Bakker S.J.
        • Navis G.
        • Sparks C.E.
        • Dullaart R.P.
        Apolipoprotein E predicts incident cardiovascular disease risk in women but not in men with concurrently high levels of high-density lipoprotein cholesterol and C-reactive protein.
        Metabolism. 2012; 61: 996-1002https://doi.org/10.1016/j.metabol.2011.11.010
        • Corsetti J.P.
        • Bakker S.J.
        • Sparks C.E.
        • Dullaart R.P.
        Apolipoprotein A-II influences apolipoprotein E-linked cardiovascular disease risk in women with high levels of HDL cholesterol and C-reactive protein.
        PLoS One. 2012; 7: e39110https://doi.org/10.1371/journal.pone.0039110
        • Havel R.J.
        • Kane J.P.
        Introduction: structure and metabolism of plasma lipoproteins.
        in: Scriver C.R. Beaudet A.L. Sly W.S. Valle D. The Metabolic and Molecular Bases of Inherited Disease. eighth ed. McGraw-Hill, New York, NY2001: 2705-2716
        • Huang Y.
        • Liu X.Q.
        • Rall Jr., S.C.
        • et al.
        Overexpression and accumulation of apolipoprotein E as a cause of hypertriglyceridemia.
        J. Biol. Chem. 1998; 273: 26388-26393https://doi.org/10.1074/jbc.273.41.26388
        • Brewer Jr., H.B.
        • Zech L.A.
        • Gregg R.E.
        Schwartz, Schaefer EJ. NIH conference. Type III hyperlipoproteinemia: diagnosis, molecular defects, pathology, and treatment.
        Ann. Intern Med. 1983; 98: 623-640
        • Dong L.M.
        • Parkin S.
        • Trakhanov S.D.
        • et al.
        Novel mechanism for defective receptor binding of apolipoprotein E2 in type III hyperlipoproteinemia.
        Nat. Struct. Biol. 1996; 3: 718-722https://doi.org/10.1038/nsb0896-718
        • Williams K.J.
        • Chen K.
        Recent insights into factors affecting remnant lipoprotein uptake.
        Curr. Opin. Lipidol. 2010; 21: 218-228https://doi.org/10.1097/MOL.0b013e328338cabc
        • Olsson U.
        • Camejo G.
        • Hurt-Camejo E.
        • Elfsber K.
        • Wiklund O.
        • Bondjers G.
        Possible functional interactions of apolipoprotein B-100 segments that associate with cell proteoglycans and the ApoB/E receptor.
        Arterioscler. Thromb. Vasc. Biol. 1997; 17: 149-155https://doi.org/10.1161/01.ATV.17.1.149
        • Mahley R.W.
        • Weisgraber K.H.
        • Huang Y.
        Apolipoprotein E: structure determines function, from atherosclerosis to Alzheimer's disease to AIDS.
        J. Lipid Res. 2009; 50https://doi.org/10.1194/jlr.R800069-JLR200
        • Verghese P.B.
        • Castellano J.M.
        • Holtzman D.M.
        Apolipoprotein E in Alzheimer's disease and other neurological disorders.
        Lancet Neurol. 2011; 10: 241-252https://doi.org/10.1016/S1474-4422(10)70325-2
        • Cramer P.E.
        • Cirrito J.R.
        • Wesson D.W.
        • et al.
        ApoE-directed therapeutics rapidly clear beta-amyloid and reverse deficits in AD mouse models.
        Science. 2012; 335: 1503-1506https://doi.org/10.1126/science.1217697