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Plasma lipid transfer proteins and cardiovascular disease. The Framingham Heart Study

  • Sander J. Robins
    Correspondence
    Corresponding author. Framingham Heart Study, 73 Mt. Wayte Ave, Framingham, MA 01702-5803, USA. Tel.: +1 508 935 3452, +1 508 905 5990 (cell); fax: +1 508 820 0340.
    Affiliations
    Framingham Heart Study and Boston University School of Medicine, Boston, MA, USA
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  • Author Footnotes
    1 Tel.: +1 508 935 3469; fax: +1 508 820 0340.
    Asya Lyass
    Footnotes
    1 Tel.: +1 508 935 3469; fax: +1 508 820 0340.
    Affiliations
    Department of Mathematics and Statistics, Boston University, Boston, MA, USA
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  • Author Footnotes
    2 Tel.: +1 212 280 2983; fax: +1 212 280 2968.
    Robert W. Brocia
    Footnotes
    2 Tel.: +1 212 280 2983; fax: +1 212 280 2968.
    Affiliations
    Roar Biomedical, Inc., Audubon Biomedical Center, 3960 Broadway, New York, NY 10032, USA
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  • Author Footnotes
    3 Tel.: +1 617 638 7728; fax: +1 617 353 4767.
    Joseph M. Massaro
    Footnotes
    3 Tel.: +1 617 638 7728; fax: +1 617 353 4767.
    Affiliations
    Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA
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  • Author Footnotes
    4 Tel.: +1 617 638 8090; fax: +1 617 638 8076.
    Ramachandran S. Vasan
    Footnotes
    4 Tel.: +1 617 638 8090; fax: +1 617 638 8076.
    Affiliations
    Section of Preventive Medicine and Cardiology, Boston University School of Medicine, Boston, MA, USA
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  • Author Footnotes
    1 Tel.: +1 508 935 3469; fax: +1 508 820 0340.
    2 Tel.: +1 212 280 2983; fax: +1 212 280 2968.
    3 Tel.: +1 617 638 7728; fax: +1 617 353 4767.
    4 Tel.: +1 617 638 8090; fax: +1 617 638 8076.

      Abstract

      Objective

      Cholesteryl ester transfer protein (CETP) and phospholipid transfer protein (PLTP) are two genetically-related plasma proteins involved in the exchange of cholesteryl esters and phospholipids between high-density lipoproteins (HDL) and other lipoproteins. Although low CETP and high PLTP activity both result in higher concentrations of plasma HDL-cholesterol (HDL-C), there is no evidence that either of these changes is associated with a decrease in cardiovascular disease (CVD) in a general population.

      Methods

      Plasma CETP and PLTP activities, measured by homogenous fluorometric assays using synthetic donor particle substrates, were related to the incidence of a first CVD event in Framingham Heart Study Offspring participants without CVD (n = 2679, mean age 59 y, 56% women) attending the 6th examination cycle (1995–98). Because of an effect modification by sex for both CETP and PLTP, analyzes were stratified by sex.

      Results

      During follow-up (mean 10.4 years) 187 participants experienced a first CVD event. In sex-specific Cox models, both CETP and PLTP as continuous and as binary variables were associated with significantly increased CVD in men, but not women. In men compared to a referent group with CETP ≥ median and PLTP < median, the multivariable-adjusted hazard ratio (HR) for new CVD events was significantly greater with either the combination of high CETP and high PLTP (HR 2.27, 95% CI 1.23–4.20); low CETP and low PLTP (HR 2.23, 95% CI 1.19–4.17); or low CETP and high PLTP (HR 2.85, 95% CI 1.53–5.31). In contrast, in women the multivariable-adjusted HR for new CVD events was non-significant and virtually equal to “1.0” with all combinations of high and low CETP or PLTP values.

      Conclusions

      Lower plasma CETP or higher PLTP activity was each associated with a significantly increased risk of CVD. Inexplicably, the increase in CVD associated with both lipid transfer proteins was confined to men.

      Highlights

      • Population-wide (Framingham Study) plasma levels of both CETP and PLTP activities.
      • Low CETP and high PLTP levels each independently predicted CVD events.
      • Combination of low CETP and high PLTP resulted in higher CVD risk than either alone.
      • However, both low CETP and high PLTP predicted CVD only in men (and not women).
      • The unusual sex-specific risk was not anticipated and is currently unexplained.

      Keywords

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      Linked Article

      • Phospholipid transfer protein, an emerging cardiometabolic risk marker: Is it time to intervene?
        AtherosclerosisVol. 228Issue 1
        • Preview
          The global epidemic of cardiometabolic disorders provides a convincing rationale for our continuous drive to explore novel biomarkers and therapeutic targets in order to better classify those subjects at increased risk of cardiovascular disease (CVD), and to preserve their vascular health. It is well appreciated that various abnormalities in lipid metabolism are causally implicated in the development of atherosclerotic vascular disease. Human plasma contains two lipid transfer proteins, cholesteryl ester transfer protein (CETP) and phospholipid transfer protein (PLTP), which play pivotal but distinct roles in lipoprotein metabolism [1,2].
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