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The I4399M variant of apolipoprotein(a) is associated with increased oxidized phospholipids on apolipoprotein B-100 particles

      Abstract

      Objectives

      The LPA I4399M (rs3798220) single nucleotide polymorphism (SNP) is associated with increased plasma levels of Lp(a) and advanced coronary artery disease (CAD). We hypothesized that carriers of the Met allele of the I4399M SNP would also have elevated levels of oxidized phospholipids (OxPL) on apoB (OxPL/apoB) particles.

      Methods and results

      Plasma levels of Lp(a) and OxPL/apoB were measured in non-carriers (TT genotype, n = 116) and carriers (CT/CC genotype, n = 58) of the I4399M SNP. Carriers had significantly higher Lp(a) levels [median (interquartile range, IQR)] [43 (9–57) mg/dl vs. 5.5 (2–20) mg/dl, p < 0.0001] and smaller apolipoprotein(a) isoforms than non-carriers (number of kringle IV repeats: 18(17–20) vs. 22(18–25), p = 0.002). Median (IQR) OxPL/apoB levels were significantly higher in carriers than non-carriers [8019 (6254–31,785) relative light units (RLU) vs. 2168 (1303–5869), p < 0.0001]. Patients with small apolipoprotein(a) isoforms had the highest OxPL/apoB levels. The number of kringle IV repeats was inversely related to Lp(a) (r = −0.43, p < 0.001) and OxPL/apoB (r = −0.36, p < 0.0001) levels.

      Conclusion

      The CT and CC genotypes of the I4399M SNP in the LPA gene are associated with elevated OxPL/apoB levels, which primarily represent OxPL on Lp(a). The concomitant increase of OxPL/apoB levels in the setting of small apolipoprotein(a) isoforms may potentiate the atherogenic effect on CAD of elevated Lp(a) levels in carriers of the I4399M SNP.

      Keywords

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      References

        • Tsimikas S.
        • Brilakis E.S.
        • Miller E.R.
        • et al.
        Oxidized phospholipids, Lp(a) lipoprotein, and coronary artery disease.
        N Engl J Med. 2005; 353: 46-57
        • Anuurad E.
        • Boffa M.B.
        • Koschinsky M.L.
        • Berglund L.
        Lipoprotein(a): a unique risk factor for cardiovascular disease.
        Clin Lab Med. 2006; 26: 751-772
        • Boerwinkle E.
        • Leffert C.C.
        • Lin J.
        • Lackner C.
        • Chiesa G.
        • Hobbs H.H.
        Apolipoprotein(a) gene accounts for greater than 90% of the variation in plasma lipoprotein(a) concentrations.
        J Clin Invest. 1992; 90: 52-60
        • Kiechl S.
        • Willeit J.
        • Mayr M.
        • et al.
        Oxidized phospholipids, lipoprotein(a), lipoprotein-associated phospholipase A2 activity, and 10-year cardiovascular outcomes: prospective results from the Bruneck Study.
        Arterioscler Thromb Vasc Biol. 2007; 27: 1788-1795
        • Tsimikas S.
        • Kiechl S.
        • Willeit J.
        • et al.
        Oxidized phospholipids predict the presence and progression of carotid and femoral atherosclerosis and symptomatic cardiovascular disease: five-year prospective results from the Bruneck study.
        J Am Coll Cardiol. 2006; 47: 2219-2228
        • Tsimikas S.
        • Mallat Z.
        • Talmud P.J.
        • et al.
        Elevated oxidized phospholipids on apolipoprotein B-100 particles are associated with future cardiovascular events in the EPIC-Norfolk Study: potentiation of risk with lipoprotein-associated (Lp-PLA2) and secretory phospholipase A2 (sPLA2) activity.
        Circulation. 2008; ([AHA abstract November 2008])
        • Tsimikas S.
        • Clopton P.
        • Brilakis E.S.
        • et al.
        Relationship of oxidized phospholipids on apolipoprotein B-100 particles to race/ethnicity, apolipoprotein(a) isoform size, and cardiovascular risk factors: results from the Dallas Heart Study.
        Circulation. 2009; 119: 1711-1719
        • Luke M.M.
        • Kane J.P.
        • Liu D.M.
        • et al.
        A polymorphism in the protease-like domain of apolipoprotein(a) is associated with severe coronary artery disease.
        Arterioscler Thromb Vasc Biol. 2007; 27: 2030-2036
        • Bergmark C.
        • Dewan A.
        • Orsoni A.
        • et al.
        A novel function of lipoprotein [a] as a preferential carrier of oxidized phospholipids in human plasma.
        J Lipid Res. 2008; 49: 2230-2239
        • Tsimikas S.
        • Witztum J.L.
        The role of oxidized phospholipids in mediating lipoprotein(a) atherogenicity.
        Curr Opin Lipidol. 2008; 19: 369-377
        • Chasman D.I.
        • Shiffman D.
        • Zee R.Y.L.
        • et al.
        Polymorphism in the apolipoprotein(a) gene, plasma lipoprotein(a), cardiovascular disease, and low-dose aspirin therapy.
        Atherosclerosis. 2009; 203: 371-376
        • Tsimikas S.
        • Lau H.K.
        • Han K.R.
        • et al.
        Percutaneous coronary intervention results in acute increases in oxidized phospholipids and lipoprotein(a): short-term and long-term immunologic responses to oxidized low-density lipoprotein.
        Circulation. 2004; 109: 3164-3170
        • Tsimikas S.
        • Witztum J.L.
        • Miller E.R.
        • et al.
        High-dose atorvastatin reduces total plasma levels of oxidized phospholipids and immune complexes present on apolipoprotein B-100 in patients with acute coronary syndromes in the MIRACL trial.
        Circulation. 2004; 110: 1406-1412
        • Choi S.H.
        • Chae A.
        • Miller E.
        • et al.
        Relationship between biomarkers of oxidized low-density lipoprotein, statin therapy, quantitative coronary angiography, and atheroma: volume observations from the REVERSAL (Reversal of Atherosclerosis with Aggressive Lipid Lowering) study.
        J Am Coll Cardiol. 2008; 52: 24-32
        • Kraft H.G.
        • Lingenhel A.
        • Kochl S.
        • et al.
        Apolipoprotein(a) kringle IV repeat number predicts risk for coronary heart disease.
        Arterioscler Thromb Vasc Biol. 1996; 16: 713-719
        • Utermann G.
        Genetic architecture and evolution of the lipoprotein(a) trait.
        Curr Opin Lipidol. 1999; 10: 133-141
        • Hobbs H.H.
        • White A.L.
        Lipoprotein(a): intrigues and insights.
        Curr Opin Lipidol. 1999; 10: 225-236
        • Kostner G.M.
        • Wo X.
        • Frank S.
        • Kostner K.
        • Zimmermann R.
        • Steyrer E.
        Metabolism of Lp(a): assembly and excretion.
        Clin Genet. 1997; 52: 347-354
        • Cain W.J.
        • Millar J.S.
        • Himebauch A.S.
        • et al.
        Lipoprotein [a] is cleared from the plasma primarily by the liver in a process mediated by apolipoprotein [a].
        J Lipid Res. 2005; 46: 2681-2691
        • Paultre F.
        • Pearson T.A.
        • Weil H.F.
        • et al.
        High levels of Lp(a) with a small apo(a) isoform are associated with coronary artery disease in African American and white men.
        Arterioscler Thromb Vasc Biol. 2000; 20: 2619-2624
        • Ober C.
        • Nord A.S.
        • Thompson E.E.
        • et al.
        Genome-wide association study of plasma lipoprotein(a) levels identifies multiple genes on chromosome 6q.
        J Lipid Res. 2009; 50: 798-806
        • Tregouet D.A.
        • Konig I.R.
        • Erdmann J.
        • et al.
        Genome-wide haplotype association study identifies the SLC22A3-LPAL2-LPA gene cluster as a risk locus for coronary artery disease.
        Nat Genet. 2009; 41: 283-285
        • Ogorelkova M.
        • Kraft H.G.
        • Ehnholm C.
        • Utermann G.
        Single nucleotide polymorphisms in exons of the apo(a) kringles IV types 6 to 10 domain affect Lp(a) plasma concentrations and have different patterns in Africans and Caucasians.
        Hum Mol Genet. 2001; 10: 815-824
        • Valenti K.
        • Aveynier E.
        • Leaute S.
        • Laporte F.
        • Hadjian A.J.
        Contribution of apolipoprotein(a) size, pentanucleotide TTTTA repeat and C/T(+93) polymorphisms of the apo(a) gene to regulation of lipoprotein(a) plasma levels in a population of young European Caucasians.
        Atherosclerosis. 1999; 147: 17-24
        • Kraft H.G.
        • Windegger M.
        • Menzel H.J.
        • Utermann G.
        Significant impact of the +93 C/T polymorphism in the apolipoprotein(a) gene on Lp(a) concentrations in Africans but not in Caucasians: confounding effect of linkage disequilibrium.
        Hum Mol Genet. 1998; 7: 257-264
        • Gargalovic P.S.
        • Imura M.
        • Zhang B.
        • et al.
        Identification of inflammatory gene modules based on variations of human endothelial cell responses to oxidized lipids.
        Proc Natl Acad Sci USA. 2006; 103: 12741-12746
        • Navab M.
        • Ananthramaiah G.M.
        • Reddy S.T.
        • et al.
        Thematic review series: the pathogenesis of atherosclerosis. The oxidation hypothesis of atherogenesis: the role of oxidized phospholipids and HDL.
        J Lipid Res. 2004; 45: 993-1007
        • Berliner J.A.
        • Leitinger N.
        • Tsimikas S.
        The role of oxidized phospholipids in atherosclerosis.
        J Lipid Res. 2009; 50: S207-S212
        • Palinski W.
        • Hörkkö S.
        • Miller E.
        • et al.
        Cloning of monoclonal autoantibodies to epitopes of oxidized lipoproteins from apolipoprotein E-deficient mice. Demonstration of epitopes of oxidized low density lipoprotein in human plasma.
        J Clin Invest. 1996; 98: 800-814
        • Hõrkkõ S.
        • Bird D.A.
        • Miller E.
        • et al.
        Monoclonal autoantibodies specific for oxidized phospholipids or oxidized phospholipid–protein adducts inhibit macrophage uptake of oxidized low-density lipoproteins.
        J Clin Invest. 1999; 103: 117-128
        • Shaw P.X.
        • Hörkkö S.
        • Chang M.K.
        • et al.
        Natural antibodies with the T15 idiotype may act in atherosclerosis, apoptotic clearance, and protective immunity.
        J Clin Invest. 2000; 105: 1731-1740
        • Friedman P.
        • Hörkkö S.
        • Steinberg D.
        • Witztum J.L.
        • Dennis E.A.
        Correlation of antiphospholipid antibody recognition with the structure of synthetic oxidized phospholipids: importance of Schiff base formation and Aldol condensation.
        J Biol Chem. 2001; 277: 7010-7020
        • Tsimikas S.
        • Bergmark C.
        • Beyer R.W.
        • et al.
        Temporal increases in plasma markers of oxidized low-density lipoprotein strongly reflect the presence of acute coronary syndromes.
        J Am Coll Cardiol. 2003; 41: 360-370
        • Rodenburg J.
        • Vissers M.N.
        • Wiegman A.
        • et al.
        Oxidized low-density lipoprotein in children with familial hypercholesterolemia and unaffected siblings: effect of pravastatin.
        J Am Coll Cardiol. 2006; 47: 1803-1810
        • Imai Y.
        • Kuba K.
        • Neely G.G.
        • et al.
        Identification of oxidative stress and Toll-like receptor 4 signaling as a key pathway of acute lung injury.
        Cell. 2008; 133: 235-249
        • Chang M.K.
        • Binder C.J.
        • Miller Y.I.
        • et al.
        Apoptotic cells with oxidation-specific epitopes are immunogenic and proinflammatory.
        J Exp Med. 2004; 200: 1359-1370
        • Edelstein C.
        • Philips B.
        • Pfaffinger D.
        • Scanu A.M.
        The oxidized phospholipids linked to human apolipoprotein(a) do not derive from circulating low-density lipoproteins and are probably of cellular origin.
        FASEB J. 2009; 23: 950-956
        • Edelstein C.
        • Pfaffinger D.
        • Hinman J.
        • et al.
        Lysine–phosphatidylcholine adducts in kringle V impart unique immunological and potential pro-inflammatory properties to human apolipoprotein(a).
        J Biol Chem. 2003; 278: 52841-52847
        • Kronenberg F.
        • Lhotta K.
        • Konig P.
        • Margreiter R.
        • Dieplinger H.
        • Utermann G.
        Apolipoprotein(a) isoform-specific changes of lipoprotein(a) after kidney transplantation.
        Eur J Hum Genet. 2003; 11: 693-699
        • Shiffman D.
        • O’Meara E.S.
        • Bare L.A.
        • et al.
        Association of gene variants with incident myocardial infarction in the Cardiovascular Health Study.
        Arterioscler Thromb Vasc Biol. 2008; 28: 173-179
        • Lanktree M.B.
        • Rajakumar C.
        • Brunt J.H.
        • Koschinsky M.L.
        • Connelly P.W.
        • Hegele R.A.
        Determination of lipoprotein(a) kringle repeat number from genomic DNA: copy number variation genotyping using qPCR.
        J Lipid Res. 2009; 50: 768-772
        • Kamstrup P.R.
        • Tybjaerg-Hansen A.
        • Steffensen R.
        • Nordestgaard B.G.
        Genetically elevated lipoprotein(a) and increased risk of myocardial infarction.
        JAMA. 2009; 301: 2331-2339