Apolipoprotein E polymorphism in men and women from a Spanish population: allele frequencies and influence on plasma lipids and apolipoproteins


      The apolipoprotein (apo) E phenotype and its influence on plasma lipid and apolipoprotein levels were determined in men and women from a working population of Madrid, Spain. The relative frequencies of alleles ε2, ε3 and ε4 for the study population (n=614) were 0.080, 0.842 and 0.078, respectively. In men, apo E polymorphism was associated with variations in plasma triglyceride and very low-density lipoprotein (VLDL) lipid levels. It was associated with the proportion of apo C-II in VLDL, and explained 5.5% of the variability in the latter parameter. In women apo E polymorphism was associated with the concentrations of plasma cholesterol and low-density lipoprotein (LDL) and high-density lipoprotein (HDL) related variables. The allelic effects were examined taking allele ε3 homozygosity as reference. In men, allele ε2 significantly increased VLDL triglyceride and VLDL cholesterol concentrations, and this was accompanied by an increase of the apo C-II content in these particles. Allele ε4 did not show any significant influence on men's lipoproteins. In women, allele ε2 lowered LDL cholesterol and apo B levels, while allele ε4 increased LDL cholesterol and decreased the concentrations of HDL cholesterol, HDL phospholipid and apo A-I. These effects were essentially maintained after excluding postmenopausal women and oral contraceptive users from the analysis. In conclusion: (1) the population of Madrid, similar to other Mediterranean populations, exhibits an underexpression of apo E4 compared to the average prevalence in Caucasians, (2) gender interacts with the effects of apo E polymorphism: in women, it influenced LDL and HDL levels, whereas in men it preferentially affected VLDL, and (3) allele ε2 decreased LDL levels in women, while it increased both VLDL lipid levels and apo C-II content in men, but, in contrast to allele ε4, it did not show an impact on HDL in either sex.


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        • Weisgraber K.H.
        Apolipoprotein E: structure-function relationships.
        Adv Protein Chem. 1994; 45: 249-302
        • Mahley R.W.
        Apolipoprotein E: cholesterol transport protein with expanding role in cell biology.
        Science. 1988; 240: 622-630
        • Davignon J.
        • Gregg R.E.
        • Sing C.F.
        Apolipoprotein E polymorphism and atherosclerosis.
        Arteriosclerosis. 1988; 8: 1-21
        • Siest G.
        • Pillot T.
        • Régis-Bailly A.
        • Leininger-Muller B.
        • Steinmetz J.
        • Galteau M.-M.
        • et al.
        Apolipoprotein E: an important gene and protein to follow in laboratory medicine.
        Clin Chem. 1995; 41: 1068-1086
        • Dallongeville J.
        • Lussier-Cacan S.
        • Davignon J.
        Modulation of plasma triglyceride levels by apo E phenotype: a meta-analysis.
        J Lipid Res. 1992; 33: 447-454
        • Wilson P.W.F.
        • Schaefer E.J.
        • Larson M.G.
        • Ordovás J.M.
        Apolipoprotein E alleles and risk of coronary disease. A meta-analysis.
        Arterioscler Thromb Vasc Biol. 1996; 16: 1250-1255
        • Wilson P.W.F.
        • Myers R.H.
        • Larson M.G.
        • Ordovás J.M.
        • Wolf P.A.
        • Schaefer E.J.
        Apolipoprotein E alleles, dyslipidemia, and coronary heart disease. The Framingham Offspring Study.
        J Am Med Assoc. 1994; 272: 1666-1671
        • Ehnholm C.
        • Mahley R.W.
        • Chappell D.A.
        • Weisgraber K.H.
        • Ludwig E.
        • Witztum J.L.
        Role of apolipoprotein E in the lipolytic conversion of very low-density lipoproteins to low-density lipoproteins in type III hyperlipoproteinemia.
        Proc Natl Acad Sci USA. 1984; 81: 5566-5570
        • Demant T.
        • Bedford D.
        • Packard C.J.
        • Shepherd J.
        Influence of apolipoprotein E polymorphism on apolipoprotein B-100 metabolism in normolipidemic subjects.
        J Clin Invest. 1991; 88: 1490-1501
        • Turner P.R.
        • Cortese C.
        • Wootton R.
        • Marenah C.
        • Miller N.E.
        • Lewis B.
        Plasma apolipoprotein B metabolism in familial type III dysbetalipoproteinaemia.
        Eur J Clin Invest. 1985; 15: 100-112
        • 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. McGraw-Hill, New York1995: 1953-1980
        • Hodis H.N.
        • Mack W.J.
        Triglyceride-rich lipoproteins and the progression of coronary artery disease.
        Curr Opin Lipidol. 1995; 6: 209-214
        • Davignon J.
        • Cohn J.S.
        Triglycerides: a risk factor for coronary heart disease.
        Atherosclerosis. 1996; 124: S57-S64
        • Wang C.-S.
        • McConathy W.J.
        • Kloer H.U.
        • Alaupovic P.
        Modulation of lipoprotein lipase activity by apolipoproteins. Effect of apolipoprotein C-III.
        J Clin Invest. 1985; 75: 384-390
        • Ginsberg H.N.
        • Le N.-A.
        • Goldberg I.J.
        • Gibson J.C.
        • Rubinstein A.
        • Wang-Iverson P.
        • et al.
        Apolipoprotein B metabolism in subjects with deficiency of apolipoproteins C-III and A-I. Evidence that apolipoprotein C-III inhibits catabolism of triglyceride-rich lipoproteins by lipoprotein lipase in vivo.
        J Clin Invest. 1986; 78: 1287-1295
        • Windler E.
        • Kovanen P.T.
        • Chao Y.-S.
        • Brown M.S.
        • Havel R.J.
        • Goldstein J.L.
        The estradiol-stimulated lipoprotein receptor of rat liver. A binding site that mediates the uptake of rat lipoproteins containing apoproteins B and E.
        J Biol Chem. 1980; 255: 10464-10471
        • Sehayek E.
        • Eisenberg S.
        Mechanism of inhibition by apolipoprotein C of apolipoprotein E-dependent cellular metabolism of human triglyceride-rich lipoproteins through the low-density lipoprotein receptor pathway.
        J Biol Chem. 1991; 266: 18259-18267
        • Kowal R.C.
        • Herz J.
        • Weisgraber K.H.
        • Mahley R.W.
        • Brown M.S.
        • Goldstein J.L.
        Opposing effects of apolipoproteins E and C on lipoprotein binding to low-density lipoprotein receptor-related protein.
        J Biol Chem. 1990; 265: 10771-10779
        • Weisgraber K.H.
        • Mahley R.W.
        • Kowal R.C.
        • Herz J.
        • Goldstein J.L.
        • Brown M.S.
        Apolipoprotein C-I modulates the interaction of apolipoprotein E with β-migrating very low-density lipoproteins (β-VLDL) and inhibits binding of β-VLDL to low-density lipoprotein receptor-related protein.
        J Biol Chem. 1990; 265: 22453-22459
        • Le N.-A.
        • Gibson J.C.
        • Ginsberg H.N.
        Independent regulation of plasma apolipoprotein C-II and C-III concentrations in very low-density and high-density lipoproteins: implications for the regulation of the catabolism of these lipoproteins.
        J Lipid Res. 1988; 29: 669-677
        • de Knijff P.
        • Havekes L.M.
        Apolipoprotein E as a risk factor for coronary heart disease: a genetic and molecular biology approach.
        Curr Opin Lipidol. 1996; 7: 59-63
        • Tiret L.
        • de Knijff P.
        • Menzel H.-J.
        • Ehnholm C.
        • Nicaud V.
        • Havekes L.M.
        Apo E polymorphism and predisposition to coronary heart disease in youths of different European populations. The EARS study.
        Arterioscler Thromb. 1994; 14: 1617-1624
        • Luc G.
        • Bard J.-M.
        • Arveiler D.
        • Evans A.
        • Cambou J.-P.
        • Bingham A.
        • et al.
        Impact of apolipoprotein E polymorphism on lipoproteins and risk of myocardial infarction. The ECTIM study.
        Arterioscler Thromb. 1994; 14: 1412-1419
        • Corbo R.M.
        • Scacchi R.
        • Mureddu L.
        • Mulas G.
        • Alfano G.
        Apolipoprotein E polymorphism in Italy investigated in native plasma by a simple polyacrylamide gel isoelectric focusing technique. Comparison with frequency data of other European populations.
        Ann Hum Genet. 1995; 59: 197-209
        • James R.W.
        • Boemi M.
        • Giansanti R.
        • Fumelli P.
        • Pometta D.
        Underexpression of the apolipoprotein E4 isoform in an Italian population.
        Arterioscler Thromb. 1993; 13: 1456-1459
        • Muros M.
        • Rodrı́guez-Ferrer C.
        Apolipoprotein E polymorphism influence on lipids, apolipoproteins and Lp(a) in a Spanish population underexpressing apo E4.
        Atherosclerosis. 1996; 121: 13-21
        • Sans S.
        • Kesteloot H.
        • Kromhout D.
        The burden of cardiovascular diseases mortality in Europe. Task Force of the European Society of Cardiology on cardiovascular mortality and morbidity statistics in Europe.
        Eur Heart J. 1997; 18: 1231-1248
        • Villar Álvarez F.
        • Banegas Banegas J.R.
        • Rodrı́guez Artalejo F.
        • del Rey Calero J.
        Mortalidad cardiovascular en España y sus comunidades autónomas (1975–1992).
        Med Clin (Barc). 1998; 110: 321-327
        • Rodrı́guez Artalejo F.
        • Banegas J.R.
        • Garcı́a Colmenero C.
        • del Rey Calero J.
        Lower consumption of wine and fish as a possible explanation for higher ischaemic heart disease mortality in Spain's Mediterranean region.
        Int J Epidemiol. 1996; 25: 1196-1201
        • Gómez-Coronado D.
        • Sáez G.T.
        • Lasunción M.A.
        • Herrera E.
        Different hydrolytic efficiencies of adipose tissue lipoprotein lipase on very low-density lipoprotein subfractions separated by heparin-Sepharose chromatography.
        Biochim Biophys Acta. 1993; 1167: 70-78
        • Ordovás J.M.
        • Litwack-Klein L.
        • Wilson P.W.F.
        • Schaefer M.M.
        • Schaefer E.J.
        Apolipoprotein E isoform phenotyping methodology and population frequency with identification of apoE1 and apoE5 isoforms.
        J Lipid Res. 1987; 28: 371-380
        • Emi M.
        • Wu L.L.
        • Robertson M.A.
        • Myers R.L.
        • Hegele R.A.
        • Williams R.R.
        • et al.
        Genotyping and sequence analysis of apolipoprotein E isoforms.
        Genomics. 1988; 3: 373-379
        • Cariolou M.A.
        • Kokkofitou A.
        • Manoli P.
        • Christou S.
        • Karagrigoriou A.
        • Middleton L.
        Underexpression of apolipoprotein E2 and E4 alleles in the Greek Cypriot population of Cyprus.
        Genet Epidemiol. 1995; 12: 489-497
        • Fiol C.
        • Argimón J.M.
        • Hurtado I.
        • Machuca I.
        • Pintó X.
        • Castiñeiras M.J.
        • et al.
        Estudio poblacional de la distribución del fenotipo de la apolipoproteı́na E.
        Clin Invest Arterioscler. 1991; 3: 130-134
        • Kaprio J.
        • Ferrell R.E.
        • Kottke B.A.
        • Kamboh M.I.
        • Sing C.F.
        Effects of polymorphisms in apolipoproteins E, A-IV, and H on quantitative traits related to risk for cardiovascular disease.
        Arterioscler Thromb. 1991; 11: 1330-1348
        • Schaefer E.J.
        • Lamon-Fava S.
        • Johnson S.
        • Ordovás J.M.
        • Schaefer M.M.
        • Castelli W.P.
        • et al.
        Effects of gender and menopausal status on the association of apolipoprotein E phenotype with plasma lipoprotein levels. Results from the Framingham offspring study.
        Arterioscler Thromb. 1994; 14: 1105-1113
        • Kamboh M.I.
        • Aston C.E.
        • Hamman R.F.
        The relationship of APOE polymorphism and cholesterol levels in normoglycemic and diabetic subjects in a biethnic population from the San Luis Valley, Colorado.
        Atherosclerosis. 1995; 112: 145-159
        • Hanis C.L.
        • Hewett-Emmett D.
        • Douglas T.C.
        • Bertin T.K.
        • Schull W.J.
        Effects of the apolipoprotein E polymorphism on levels of lipids, lipoproteins, and apolipoproteins among Mexican-Americans in Starr County, Texas.
        Arterioscler Thromb. 1991; 11: 362-370
        • Ritter M.M.
        • Gewitsch J.
        • Richter W.O.
        • Geiss H.C.
        • Wildner M.W.
        • Schwandt P.
        Apolipoprotein E polymorphism has no independent effect on plasma levels of lipoprotein(a).
        Atherosclerosis. 1997; 131: 243-248
        • Mahley R.W.
        • Palaoglu K.E.
        • Atak Z.
        • Dawson-Pepin J.
        • Langlois A.-M.
        • Cheung V.
        • et al.
        Turkish heart study: lipids, lipoproteins, and apolipoproteins.
        J Lipid Res. 1995; 36: 839-859
        • Cohn J.S.
        • Giroux L.-M.
        • Fortin L.-J.
        • Davignon J.
        Prevalence of double pre-beta lipoproteinemia in hyperlipidemic patients is influenced by gender, menopausal status, and apo E phenotype.
        Arterioscler Thromb Vasc Biol. 1997; 17: 2630-2637
        • Matsuoka N.
        • Shirai K.
        • Johnson J.D.
        • Kashyap M.L.
        • Srivastava L.S.
        • Yamamura T.
        • et al.
        Effects of apolipoprotein C-II (apo C-II) on the lipolysis of very low-density lipoproteins from apo C-II deficient patients.
        Metabolism. 1981; 30: 818-824
        • Jackson R.L.
        • Tajima S.
        • Yamamura T.
        • Yokoyama S.
        • Yamamoto A.
        Comparison of apolipoprotein C-II-deficient triacylglycerol-rich lipoproteins and trioleoylglycerol/phosphatidylcholine-stabilized particles as substrates for lipoprotein lipase.
        Biochim Biophys Acta. 1986; 875: 211-219
        • Windler E.
        • Chao Y.-S.
        • Havel R.J.
        Regulation of the hepatic uptake of triglyceride-rich lipoproteins in the rat. Opposing effects of homologous apolipoprotein E and individual C apoproteins.
        J Biol Chem. 1980; 255: 8303-8307
        • Windler E.
        • Havel R.J.
        Inhibitory effects of C apolipoproteins from rats and humans on the uptake of triglyceride-rich lipoproteins and their remnants by the perfused rat liver.
        J Lipid Res. 1985; 26: 556-565