Lipid Pathway

Elevated cholesterol and other dyslipidemias are major risk factors for atherosclerotic diseases and CVDs. Several polymorphisms in lipid pathways (Fig. 2), involving apolipopro-teins A-I and IV, B, E, C-II and III, cholesteryl ester transfer protein (CETP), and others have been associated with cardiovascular conditions. The following section describes apolipoprotein E (ApoE) and CETP polymorphisms.

Apolipoprotein E (ApoE)

The gene that is most comprehensively studied in this pathway is that encoding ApoE on chromosome 19. ApoE is synthesized in the liver and intestine and is found in association with triglyceride-rich lipoproteins. Polymorphism in the APOE gene determines the greatest fraction (around 5%) of the population variance in low-density lipoprotein (LDL) cholesterol of the known gene variants related to lipoprotein metabolism. In humans, there are three common alleles, designated E2, E3, E4, that give rise to three homozygous—22,33,44—and three heterozygous genotypes—32,42,34. Corbo et al. (96) found that the E3 allele was the most frequent in all human populations tested and that its frequency was always negatively correlated with that of E4. The E4 allele is also one of the few polymorphisms that has repeatedly been shown to be a good predictor of CVD/myocardial infarction (97-99) and is thus potentially an important genetic marker for risk stratification. The most likely explanation for the increased risk associated with the E4 allele is that these individuals have a preponderance of small dense LDLs, which are prone to oxidation.

The APOE gene variants also differ with respect to response to statin therapy: Individuals with an E4 allele tend to have a lesser response, and those with the E2 allele a

Figure 2 Genetic polymorphisms in the lipid pathway.

greater response to statins. Importantly, in the 4S study, the risk of death or a major coronary event in survivors of myocardial infarction was related to the APOE genotype. The E4 allele carriers had nearly a twofold increased risk of dying in the follow-up period, compared with other patients. Also, E4 allele-bearing patients on statins benefited more than those without the E4 allele (100). APOE genotypes that have been shown to influence plasma cholesterol level had, however, no effect on the hypolipidemic efficacy of colesti-pol (101). Reports of response to fibrates in relation to the APOE gene variation are conflicting (102,103). With regard to HMG Co-A reductase, there have been no reports of variants of the gene itself that influence the efficacy of the treatment.

Cholesterol Ester Transfer Protein (CETP)

CETP is involved in reverse cholesterol transport, and several polymorphisms with a functional impact on plasma high-density lipoprotein (HDL) cholesterol and triglycerides have been identified (104). CETP mediates the transfer of neutral lipids between lipoproteins and plays a central role in HDL metabolism. The B2 allele of the TaqlB polymorphism of the CETP gene located on chromosome 16, a silent base change in the nucleotide 277 of the first intron, is associated with decreased CETP activity and increased HDL concentration (105,106). Kuivenhoven et al. (105) reported a significant genotype-dependent association of the CETP TaqIB polymorphism with the progression of coronary atherosclerosis in the placebo group, as compared with the treatment group: carriers of the B1B1 genotype had the highest CETP and the lowest HDL concentrations and the fastest progression of atherosclerosis. Ordovas et al. (106) found the CETP activity to be decreased in B2 allele carriers. In addition to the TaqlB polymorphism, several other CETP SNPs have also been associated with interindividual variation in CETP plasma and HDL cholesterol levels and the risk of CVD (107-109).

Interestingly, polymorphisms in the CETP gene have been shown to influence the effectiveness of hypolipidemic drugs and dietary intervention. In the REGRESS study, statin therapy slowed the progression of coronary atherosclerosis in the B1B1 CETP TaqlB carriers but not in the B2B2 carriers (105). However, in the WOSCOPS trial this association was not observed. Nevertheless, the B1B1 CETP TaqlB homozygotes have also been shown to serve as a marker of lipoprotein response to dietary intervention (110,111). These results suggest that polymorphisms in the CETP gene could influence the effects of therapy (diet or statins) in the general population.

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