Single variants can explain the association between coronary heart disease and haplotypes in the apolipoprotein(a) locus



      LPA encodes apolipoprotein(a), and a CCTC haplotype in the LPA locus is associated with CHD. The 4399Met variant (rs3798220) of LPA has a risk estimate for CHD similar to that of the CCTC haplotype. We asked whether co-incidence with the 4399Met variant explained the association of the haplotype with CHD.


      We stratified by the 4399Met variant and another LPA SNP (rs10455872) associated with CHD and tested the association between CHD and 4 SNPs that define two haplotypes associated with CHD: CCTC and CTTG.


      For CCTC, in the presence of the rs3798220 risk allele the OR was 1.68 (95% CI: 1.05–2.68, P = 0.03) versus 0.30 (95% CI: 0.06–1.59, P = 0.16) with the non-risk allele. For CTTG, in the presence of the rs10455872 risk allele the OR was 1.57 (95% CI: 1.15–2.13, P = 0.004) versus 1.04 (95% CI: 0.79–1.35, P = 0.77) with the non-risk allele.


      The rs3798220 and rs10455872 SNPs explain the association of the CCTC and CTTG haplotypes with CHD.


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


        • Bennet A.
        • Di Angelantonio E.
        • Erqou S.
        • et al.
        Lipoprotein(a) levels and risk of future coronary heart disease: large-scale prospective data.
        Arch Intern Med. 2008; 168: 598-608
        • Kamstrup P.R.
        • Benn M.
        • Tybaerg-Hansen A.
        • Nordestgaard B.G.
        Extreme lipoprotein(a) levels and risk of myocardial infarction in the general population: the Copenhagen City Heart Study.
        Circulation. 2008; 117: 176-184
        • Erqou S.
        • Kaptoge S.
        • Perry P.L.
        • et al.
        Lipoprotein(a) concentration and the risk of coronary heart disease, stroke, and nonvascular mortality.
        JAMA. 2009; 302: 412-423
        • Valentine R.J.
        • Grayburn P.A.
        • Vega G.L.
        • Grundy S.M.
        Lp(a) lipoprotein is an independent, discriminating risk factor for premature peripheral atherosclerosis among white men.
        Arch Intern Med. 1994; 154: 801-806
        • Cheng S.W.
        • Ting A.C.
        • Wong J.
        Lipoprotein (a) and its relationship to risk factors and severity of atherosclerotic peripheral vascular disease.
        Eur J Vasc Endovasc Surg. 1997; 14: 17-23
        • Molgaard J.
        • Klausen I.C.
        • Lassvik C.
        • et al.
        Significant association between low-molecular-weight apolipoprotein(a) isoforms and intermittent claudication.
        Arterioscler Thromb. 1992; 12: 895-901
        • Catalano M.
        • Cortelazzo A.
        • Yilmaz Y.
        • et al.
        The LPA gene C93T polymorphism influences plasma lipoprotein(a) levels and is independently associated with susceptibility to peripheral arterial disease.
        Clin Chim Acta. 2008; 387: 109-112
        • Boerwinkle E.
        • Leffert C.C.
        • Lin J.
        • et al.
        Apolipoprotein(a) gene accounts for greater than 90% of the variation in plasma lipoprotein(a) concentrations.
        J Clin Invest. 1992; 90: 52-60
        • Kraft H.G.
        • Köchl S.
        • Menzel H.J.
        • Sandholzer C.
        • Utermann G.
        The apolipoprotein (a) gene: a transcribed hypervariable locus controlling plasma lipoprotein (a) concentration.
        Hum Genet. 1992; 90: 220-230
        • Trégouët D.A.
        • König 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
        • 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
        • Shiffman D.
        • Kane J.P.
        • Louie J.Z.
        • et al.
        Analysis of 17,576 potentially functional SNPs in three case-control studies of myocardial infarction.
        PLoS ONE. 2008; 3: e2895
        • 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
        • Chasman D.I.
        • Shiffman D.
        • Zee R.Y.
        • et al.
        Polymorphism in the apolipoprotein(a) gene, plasma lipoprotein(a), cardiovascular disease, and low-dose aspirin therapy.
        Atherosclerosis. 2009; 203: 3716
        • Clarke R.
        • Peden J.F.
        • Hopewell J.C.
        • et al.
        Genetic variants associated with Lp(a) lipoprotein level and coronary disease.
        N Engl J Med. 2009; 361: 2518-2528
        • Shiffman D.
        • Chasman D.I.
        • Ballantyne C.M.
        • et al.
        Coronary heart disease risk, aspirin use, and apolipoprotein(a) 4399Met allele in the Atherosclerosis Risk in Communities (ARIC) study.
        Thromb Haemost. 2009; 102: 179-180
        • Schaid D.J.
        • Rowland C.M.
        • Tines D.E.
        • Jacobsen R.M.
        • Poland G.A.
        Score tests for association between traits and haplotypes when linkage phase is ambiguous.
        Am J Hum Genet. 2002; 70: 425-434
        • Lake S.
        • Lyon H.
        • Silverman E.
        • et al.
        Estimation and tests of haplotype-environment interaction when linkage phase is ambiguous.
        Hum Hered. 2003; 44: 56-65
        • Gavish D.
        • Azrolan N.
        • Breslow J.L.
        Plasma Lp(a) concentration is inversely correlated with the ratio of Kringle IV/Kringle V encoding domains in the apo(a) gene.
        J Clin Invest. 1989; 84: 2021-2027
        • Peros E.
        • Geroldi D.
        • D’Angelo A.
        • et al.
        Apolipoprotein(a) phenotypes are reliable biomarkers for familial aggregation of coronary heart disease.
        Int J Mol Med. 2004; 13: 243-247
        • McLean J.W.
        • Tomlinson J.E.
        • Kuang W.J.
        • et al.
        cDNA sequence of human apolipoprotein(a) is homologous to plasminogen.
        Nature. 1987; 330: 132-137
        • Marcovina S.M.
        • Koschinsky M.L.
        Evaluation of lipoprotein(a) as a prothrombotic factor: progress from bench to bedside.
        Curr Opin Lipidol. 2003; 14: 361-366