Advertisement

Associations of the apolipoprotein A1/C3/A4/A5 gene cluster with triglyceride and HDL cholesterol levels in women with type 2 diabetes

  • Lu Qi
    Correspondence
    Corresponding author. Tel.: +1 617 432 4116; fax: +1 617 432 2435.
    Affiliations
    Department of Nutrition, Harvard School of Public Health, 665 Huntington Ave, Boston, MA 02115, United States

    Channing Laboratory, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, United States
    Search for articles by this author
  • Simin Liu
    Affiliations
    Department of Epidemiology, UCLA School of Public Health, Los Angeles, CA, United States
    Search for articles by this author
  • Nader Rifai
    Affiliations
    Department of Laboratory Medicine, Children's Hospital and Harvard Medical School, Boston, MA, United States
    Search for articles by this author
  • David Hunter
    Affiliations
    Department of Nutrition, Harvard School of Public Health, 665 Huntington Ave, Boston, MA 02115, United States

    Department of Epidemiology, Harvard School of Public Health, Boston, MA, United States

    Channing Laboratory, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, United States
    Search for articles by this author
  • Frank B. Hu
    Affiliations
    Department of Nutrition, Harvard School of Public Health, 665 Huntington Ave, Boston, MA 02115, United States

    Department of Epidemiology, Harvard School of Public Health, Boston, MA, United States

    Channing Laboratory, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, United States
    Search for articles by this author

      Abstract

      The apolipoprotein gene cluster (APOA1/C3/A4/A5) was recently associated with triglycerides (TG) and high-density lipoprotein cholesterol (HDL-C) in non-diabetic population. Little is known whether the variations in these genes affect lipid homeostasis in patients with type 2 diabetes. We examined the associations of 10 polymorphisms at APOA1/C3/A4/A5 gene cluster with blood lipids among 902 diabetic women. A linkage disequilibrium (LD) breakdown was observed between APOA5 and other genes. APOA5 S19W was associated with significantly higher fasting TG levels (P = 0.001). Two common haplotypes encompassing four APOA5 polymorphisms (SNP1, SNP2, S19W, and SNP3) were associated with 35.6 mg/dL (haplotype 2212, APOA5*2, P = 0.016) and 57.8 mg/dL (haplotype 1121, APOA5*3, P = 0.0002) higher fasting TG levels compared with the most common (haplotype 1111, APOA5*1), respectively. Adjustment for age, BMI, and other covariates did not appreciably change such associations. In addition, APOC3 promoter polymorphism −455T/C showed significant associations with fasting TG levels (P = 0.006), whereas APOA4 +347T/A showed significant associations with lower levels of HDL-C (P = 0.017). Our results indicate that the variability in APOA1/C3/A4/A5 gene cluster may affect TG and HDL levels in women with type 2 diabetes.

      Keywords

      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

      Reference

        • Beckman J.A.
        • Creager M.A.
        • Libby P.
        Diabetes and atherosclerosis: epidemiology, pathophysiology, and management.
        JAMA. 2002; 287: 2570-2581
        • Szapary P.O.
        • Rader D.J.
        The triglyceride-high-density lipoprotein axis: an important target of therapy?.
        Am Heart J. 2004; 148: 211-221
        • Friedlander Y.
        • Kark J.D.
        • Stein Y.
        Biological and environmental sources of variation in plasma lipids and lipoproteins: the Jerusalem Lipid Research Clinic.
        Hum Hered. 1986; 36: 143-153
        • Wang Q.F.
        • Liu X.
        • O’Connell J.
        • et al.
        Haplotypes in the APOA1-C3-A4-A5 gene cluster affect plasma lipids in both humans and baboons.
        Hum Mol Genet. 2004; 13: 1049-1056
        • Talmud P.J.
        • Hawe E.
        • Martin S.
        • et al.
        Relative contribution of variation within the APOC3/A4/A5 gene cluster in determining plasma triglycerides.
        Hum Mol Genet. 2002; 11: 3039-3046
        • Shoulders C.C.
        • Harry P.J.
        • Lagrost L.
        • et al.
        Variation at the apo AI/CIII/AIV gene complex is associated with elevated plasma levels of apo CIII.
        Atherosclerosis. 1991; 87: 239-247
        • Ginsberg H.N.
        • Le N.A.
        • Goldberg I.J.
        • et al.
        Apolipoprotein B metabolism in subjects with deficiency of apolipoproteins CIII and AI. Evidence that apolipoprotein CIII inhibits catabolism of triglyceride-rich lipoproteins by lipoprotein lipase in vivo.
        J Clin Invest. 1986; 78: 1287-1295
        • Pennacchio L.A.
        • Rubin E.M.
        Apolipoprotein A5, a newly identified gene that affects plasma triglyceride levels in humans and mice.
        Arterioscler Thromb Vasc Biol. 2003; 23: 529-534
        • Shioji K.
        • Mannami T.
        • Kokubo Y.
        • et al.
        An association analysis between ApoA1 polymorphisms and the high-density lipoprotein (HDL) cholesterol level and myocardial infarction (MI) in Japanese.
        J Hum Genet. 2004; 49: 433-439
        • Ordovas J.M.
        • Corella D.
        • Cupples L.A.
        • et al.
        Polyunsaturated fatty acids modulate the effects of the APOA1 G-A polymorphism on HDL-cholesterol concentrations in a sex-specific manner: the Framingham Study.
        Am J Clin Nutr. 2002; 75: 38-46
        • Xu C.F.
        • Talmud P.
        • Schuster H.
        • et al.
        Association between genetic variation at the APO AI-CIII-AIV gene cluster and familial combined hyperlipidemia.
        Clin Genet. 1994; 46: 385-397
        • Dammerman M.
        • Sandkuijl L.A.
        • Halaas J.L.
        • Chung W.
        • Breslow J.L.
        An apolipoprotein CIII haplotype protective against hypertriglyceridemia is specified by promoter and 3′ untranslated region polymorphisms.
        Proc Natl Acad Sci USA. 1993; 90: 4562-4566
        • Pennacchio L.A.
        • Olivier M.
        • Hubacek J.A.
        • et al.
        Two independent apolipoprotein A5 haplotypes influence human plasma triglyceride levels.
        Hum Mol Genet. 2002; 11: 3031-3038
      1. Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care 1997;20:1183–97.

        • Tregouet D.A.
        • Escolano S.
        • Tiret L.
        • Mallet A.
        • Golmard J.L.
        A new algorithm for haplotype-based association analysis: the Stochastic-EM algorithm.
        Ann Hum Genet. 2004; 68: 165-177
        • Olivier M.
        • Wang X.
        • Cole R.
        • et al.
        Haplotype analysis of the apolipoprotein gene cluster on human chromosome 11.
        Genomics. 2004; 83: 912-923
        • Lai C.Q.
        • Demissie S.
        • Cupples L.A.
        • et al.
        Influence of the APOA5 locus on plasma triglyceride, lipoprotein subclasses, and CVD risk in the Framingham Heart Study.
        J Lipid Res. 2004; 45: 2096-2105
        • Pennacchio L.A.
        • Olivier M.
        • Hubacek J.A.
        • et al.
        An apolipoprotein influencing triglycerides in humans and mice revealed by comparative sequencing.
        Science. 2001; 294: 169-173
        • Schaap F.G.
        • Rensen P.C.
        • Voshol P.J.
        • et al.
        ApoAV reduces plasma triglycerides by inhibiting very low density lipoprotein-triglyceride (VLDL-TG) production and stimulating lipoprotein lipase-mediated VLDL-TG hydrolysis.
        J Biol Chem. 2004; 279: 27941-27947
        • Merkel M.
        • Loeffler B.
        • Kluger M.
        • et al.
        Apolipoprotein AV accelerates plasma hydrolysis of triglyceride-rich lipoproteins by interaction with proteoglycan bound lipoprotein lipase.
        J Biol Chem. 2005; 280: 21553-21560
        • O’Brien P.J.
        • Alborn W.E.
        • Sloan J.H.
        • et al.
        The novel apolipoprotein A5 is present in human serum, is associated with VLDL, HDL, and chylomicrons, and circulates at very low concentrations compared with other apolipoproteins.
        Clin Chem. 2005; 51: 351-359
        • Lai C.Q.
        • Parnell L.D.
        • Ordovas J.M.
        The APOA1/C3/A4/A5 gene cluster, lipid metabolism and cardiovascular disease risk.
        Curr Opin Lipidol. 2005; 16: 153-166
        • Olivieri O.
        • Bassi A.
        • Stranieri C.
        • et al.
        Apolipoprotein C-III, metabolic syndrome, and risk of coronary artery disease.
        J Lipid Res. 2003; 44: 2374-2381
        • Baroukh N.
        • Bauge E.
        • Akiyama J.
        • et al.
        Analysis of apolipoprotein A5, c3, and plasma triglyceride concentrations in genetically engineered mice.
        Arterioscler Thromb Vasc Biol. 2004; 24: 1297-1302
        • Utermann G.
        • Beisiegel U.
        Apolipoprotein A-IV: a protein occurring in human mesenteric lymph chylomicrons and free in plasma. Isolation and quantification.
        Eur J Biochem. 1979; 99: 333-343
        • Lohse P.
        • Kindt M.R.
        • Rader D.J.
        • Brewer Jr, H.B.
        Three genetic variants of human plasma apolipoprotein A-IV. apoA-IV-1(Thr347–Ser), apoA-IV-0(Lys167–Glu, ln360–His), and apoA-IV-3(Glu165–Lys).
        J Biol Chem. 1991; 266: 13513-13518
        • von Eckardstein A.
        • Funke H.
        • Schulte M.
        • et al.
        Nonsynonymous polymorphic sites in the apolipoprotein (apo) A-IV gene are associated with changes in the concentration of apo B- and apo A-I-containing lipoproteins in a normal population.
        Am J Hum Genet. 1992; 50: 1115-1128
        • Wong W.M.
        • Hawe E.
        • Li L.K.
        • et al.
        Apolipoprotein AIV gene variant S347 is associated with increased risk of coronary heart disease and lower plasma apolipoprotein AIV levels.
        Circ Res. 2003; 92: 969-975