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Association between the Ala379Val variant of the lipoprotein associated phospholipase A2 and risk of myocardial infarction in the north and south of Europe

  • A.M. Abuzeid
    Affiliations
    Division of Cardiovascular Genetics, Department of Medicine, British Heart Foundation Laboratories, Rayne Building, Royal Free and University College Medical School, 5 University St, London WC1E 6JJ, UK
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  • E. Hawe
    Affiliations
    Division of Cardiovascular Genetics, Department of Medicine, British Heart Foundation Laboratories, Rayne Building, Royal Free and University College Medical School, 5 University St, London WC1E 6JJ, UK
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  • S.E. Humphries
    Affiliations
    Division of Cardiovascular Genetics, Department of Medicine, British Heart Foundation Laboratories, Rayne Building, Royal Free and University College Medical School, 5 University St, London WC1E 6JJ, UK
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  • Philippa J. Talmud
    Correspondence
    Corresponding author. Tel.: +44-207-679-6968; fax: +44-207-679-6212
    Affiliations
    Division of Cardiovascular Genetics, Department of Medicine, British Heart Foundation Laboratories, Rayne Building, Royal Free and University College Medical School, 5 University St, London WC1E 6JJ, UK
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  • The HIFMECH Study Group
    1
  • Author Footnotes
    1 See acknowledgements for list of members.

      Abstract

      Lipoprotein-associated phospholipase A2 (Lp-PLA2) has been identified as a coronary heart disease (CHD) risk predictor. Both its anti-inflammatory role by hydrolysing platelet activating factor, and pro-inflammatory generation of atherogenic mediators may influence CHD risk. We investigated the association of the activity-reducing A379V variant with risk of myocardial infarction (MI) in a large European case-control study, which compared 527 post-MI men with 566 age-matched controls from north and south Europe. Overall, the frequency of the V379 allele was 0.24 (95%CI 0.21–0.26), with no evidence for differences between centres. Homozygosity for the V379 allele was associated with lower risk of MI, (Odds Ratio (OR) 0.56, 95%CI 0.32–0.98), maintained after adjustment for lifestyle factors and levels of inflammatory risk factors (C-reactive protein, fibrinogen, IL-6) (OR 0.46, 0.22–0.93). There was no evidence of heterogeneity of effect between the centres in the north and south of Europe (P-value for interaction=0.80). Since homozygosity for V379 occurs in only 5–6% of subjects, this genotype is not a major determinant of population genetic risk of CHD, but the association of this genotype with low levels of Lp-PLA2, strongly support the pro-inflammatory causative, and not consequential, role of Lp-PLA2 in CHD.

      Keywords

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      References

        • Ross R.
        Atherosclerosis-an inflammatory disease.
        New Engl. J. Med. 1999; 340: 115-126
        • Stafforini D.M.
        • Satoh K.
        • Atkinson D.L.
        • et al.
        Platelet-activating factor acetylhydrolase deficiency. A missense mutation near the active site of an anti-inflammatory phospholipase.
        J. Clin. Invest. 1996; 97: 2784-2791
        • Macphee C.H.
        Lipoprotein-associated phospholipase A2: a potential new risk factor for coronary artery disease and a therapeutic target.
        Curr. Opin. Pharmacol. 2001; 1: 121-125
        • Kuijpers T.W.
        • van den Berg J.M.
        • Tool A.T.
        • Roos D.
        The impact of platelet-activating factor (PAF)-like mediators on the functional activity of neutrophils: anti-inflammatory effects of human PAF-acetylhydrolase.
        Clin. Exp. Immunol. 2001; 123: 412-420
        • Tjoelker L.W.
        • Stafforini D.M.
        Platelet-activating factor acetylhydrolases in health and disease.
        Biochim. Biophys. Acta. 2000; 1488: 102-123
        • Caslake M.J.
        • Packard C.J.
        • Suckling K.E.
        • Holmes S.D.
        • Chamberlain P.
        • Macphee C.H.
        Lipoprotein-associated phospholipase A(2), platelet-activating factor acetylhydrolase: a potential new risk factor for coronary artery disease.
        Atherosclerosis. 2000; 150: 413-419
        • Hakkinen T.
        • Luoma J.S.
        • Hiltunen M.O.
        • et al.
        Lipoprotein-associated phospholipase A(2), platelet-activating factor acetylhydrolase, is expressed by macrophages in human and rabbit atherosclerotic lesions.
        Arterioscler. Thromb. Vasc. Biol. 1999; 19: 2909-2917
        • Carpenter K.L.
        • Dennis I.F.
        • Challis I.R.
        • et al.
        Inhibition of lipoprotein-associated phospholipase A2 diminishes the death-inducing effects of oxidised LDL on human monocyte-macrophages.
        FEBS Lett. 2001; 505: 357-363
        • Yamada Y.
        • Yoshida H.
        • Ichihara S.
        • Imaizumi T.
        • Satoh K.
        • Yokota M.
        Correlations between plasma platelet-activating factor acetylhydrolase (PAF-AH) activity and PAF-AH genotype, age, and atherosclerosis in a Japanese population.
        Atherosclerosis. 2000; 150: 209-216
        • Unno N.
        • Nakamura T.
        • Kaneko H.
        • et al.
        Plasma platelet-activating factor acetylhydrolase deficiency is associated with atherosclerotic occlusive disease in japan.
        J. Vasc. Surg. 2000; 32: 263-267
        • Kruse S.
        • Mao X.Q.
        • Heinzmann A.
        • et al.
        The Ile198Thr and Ala379Val variants of plasmatic PAF-acetylhydrolase impair catalytical activities and are associated with atopy and asthma.
        Am. J. Hum. Genet. 2000; 66: 1522-1530
      1. Hamsten A, Margaglione M, Silveira A, et al. Differences in lifestyle, clinical characteristics and plasma lipid traits among healthy subjects and myocardial infarction survivors from the north and south of Europe (HIFMECH study), Atherosclerosis 2002; submitted for publication.

        • Juhan-Vague I.
        • Morange P.E.
        • Aubert H.
        • et al.
        Plasma thrombin-activatable fibrinolysis inhibitor antigen concentration and genotype in relation to myocardial infarction in the north and south of Europe.
        Arterioscler. Thromb. Vasc. Biol. 2002; 22: 867-873
        • Miller S.A.
        • Dykes D.D.
        • Polesky H.F.
        A simple salting out procedure for extracting DNA from human nucleated cells.
        Nucleic Acid Res. 1988; 16: 1215
        • Day I.N.
        • Humphries S.E.
        • Richards S.
        • Norton D.
        • Reid M.
        High-throughput genotyping using horizontal polyacrylamide gels with wells arranged for microplate array diagonal gel electrophoresis (MADGE).
        Biotechniques. 1995; 19: 830-835
        • Macphee C.H.
        • Moores K.E.
        • Boyd H.F.
        • et al.
        Lipoprotein-associated phospholipase A2, platelet-activating factor acetylhydrolase, generates two bioactive products during the oxidation of low-density lipoprotein: use of a novel inhibitor.
        Biochem. J. 1999; 338: 479-487
        • Packard C.J.
        • O'Reilly D.S.J.
        • Caslake M.J.
        • et al.
        Lipoprotein-associatedphopsholipase A2 as an independent predictor of coronary heart disease.
        New Engl. J. Med. 2000; 343: 1148-1155
        • Blake G.J.
        • Dada N.
        • Fox J.C.
        • Manson J.E.
        • Ridker P.M.
        A prospective evaluation of lipoprotein-associated phospholipase A(2) levels and the risk of future cardiovascular events in women.
        J. Am. Coll. Cardiol. 2001; 38: 1302-1306
        • Memon R.A.
        • Fuller J.
        • Moser A.H.
        • Feingold K.R.
        • Grunfeld C.
        In vivo regulation of plasma platelet-activating factor acetylhydrolase during the acute phase response.
        Am. J. Physiol. 1999; 277: R94-103
        • Howard K.M.
        • Olson M.S.
        The expression and localization of plasma platelet-activating factor acetylhydrolase in endotoxemic rats.
        J. Biol. Chem. 2000; 275: 19891-19896
        • Memon R.A.
        • Staprans I.
        • Noor M.
        • et al.
        Infection and inflammation induce LDL oxidation in vivo.
        Arterioscler. Thromb. Vasc. Biol. 2000; 20: 1536-1542
        • Benson G.M.
        • Grimsditch D.
        • Milliner K.
        • et al.
        Anti-atherosclerotic effect of SB-244323, a lipoprotein associated phospholipase A2 inhibitor, in WHHL rabbits.
        Atherosclerosis. 2000; 151: 166
      2. Yudkin JS, Juhan-Vague I, Hawe E, et al., on behalf of the HIFMECH Study Group. The insulin resistance syndrome and inflammatory markers in relation to myocardial infarction in north and south Europe (HIFMECH Study), Arterioscler Thromb Vasc Biol 2002; submitted for publication.

        • Tjoelker L.W.
        • Eberhardt C.
        • Unger J.
        • et al.
        Plasma platelet-activating factor acetylhydrolase is a secreted phospholipase A2 with a catalytic triad.
        J. Biol. Chem. 1995; 270: 25481-25487
        • McCall M.R.
        • La Belle M.
        • Forte T.M.
        • Krauss R.M.
        • Takanami Y.
        • Tribble D.L.
        Dissociable and nondissociable forms of platelet-activating factor acetylhydrolase in human plasma LDL: implications for LDL oxidative susceptibility.
        Biochim. Biophys. Acta. 1999; 1437: 23-36
        • Tsimihodimos V.
        • Karabina S.A.
        • Tambaki A.P.
        • et al.
        Atorvastatin preferentially reduces LDL-associated platelet-activating factor acetylhydrolase activity in dyslipidemias of type IIA and type IIB.
        Arterioscler. Thromb. Vasc. Biol. 2002; 22: 306-311