In humans, cholesteryl ester, triglycerides and phospholipids can be exchanged between circulating lipoprotein particles thanks to proteins that are active in the plasma. The plasma also displays a cholesterol esterification activity associated with lecithin acyl cholesterol transferase (LCAT), a glycoprotein thought to play a role in the HDL-mediated transport of cholesterol. Interestingly, the activation of LCAT needs the apolipoprotein AI, which is associated with the HDL particles (Frank and Marcel, 2000). Three arginine residues on apoAl have been shown to be critical for LCAT activation by apoAI and conversely, mutations in the apoAI gene induced a severe decrease in LCAT activity (Roosbeek et al.,
2001). LCAT deficiency is usually associated with low plasma HDL levels, which thus addresses the potential role of this enzyme in the development of coronary heart disease (Peelman et al., 1999). For example, a p.Pro143Leu mutation has been identified in 5.79% of Chinese patients suffering from coronary heart disease (Zhang et al., 2004).
A lipotransfer protein, the cholesterol ester transfer protein (CETP) promotes the exchange of cholesterol from HDL particles to triglyceride-rich particles (TRL) and of triacylglycerol from TRL to HDL. Since HDL can be roughly considered as responsible for transferring to the liver endogenously synthesized cholesterol, the CETP activity would modify the ratio between LDL cholesterol and HDL cholesterol. For example, in a recent study undertaken in a population from diverse origins, an association was demonstrated between the g.—629>C allele and a 30% decrease in CETP mass (Thompson et al., 2003). In another study, such a decrease in mass has been shown to result in changes in the size of HDL particles with a marked increase in the large alpha-1 HDL particles and decrease in the small pre-beta-1 particles, features that have been clearly associated with lower risk for coronary heart disease (Asztalos et al., 2000,
2002). Interestingly, in a recent study on a large cohort of German patients, the patients bearing the g.—629>C allele were significantly more sensitive to statin therapy and those homozygous for this allele displayed a cardiovascular mortality reduced by half (Blankenberg et al., 2003). The Taq1B polymorphism in the CETP gene has also been extensively studied. This polymorphism generates three genotypes, namely B1/B1 (frequency about 0.33), B1/B2 (approx. 0.5) and B2/B2 (approx 0.17). This latter genotype seems to be associated with a lower CETP activity and therefore a reduction in CVD risk, an effect certainly due to a significantly higher plasma HDL (Brousseau et al., 2002). Nevertheless, other recent studies do not support this finding and conclude that the Taq1 B polymorphism does not predict cardiovascular events and does not discriminate those who will and those who will not benefit from statin treatment (de Grooth et al., 2004).
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