Cholesteryl ester transfer protein (CETP) plays a major role in modifying lipoprotein particles by mediating the transfer of cholesteryl esters from high-density lipoprotein (HDL) particles to apolipoprotein B-containing lipoproteins in exchange for triglycerides (TG) [1]. The CETP gene encompasses 16 exons, on chromosome 16q12-16q21; several CETP polymorphisms have been identified including I405V and TaqIB which are associated with reduced CETP mass and increased HDL cholesterol (HDL-C) [2]. I405V results in a single amino acid change at codon 405 in exon 14; in several studies, the I405V allele was associated with lower CETP levels [2]. TaqIB has been shown to be a silent base change affecting the 277th nucleotide in the first intron of the gene [3]. The B2 allele (absence of the TaqI restriction site) at this polymorphic site has been associated in normolipemic subjects with increased HDL-C levels and decreased CETP activity and levels [4].

HMG-CoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase inhibitors (statins) are the main drugs used to reduce plasma low density lipoprotein cholesterol (LDL-C) levels. Also, statins can be administrated to subjects with high triglyceride (TG) and low HDL-C levels (a dyslipidaemic combination which often coexists) [5, 6]. There is considerable variation in the response to statin treatment [7]. Although most subjects derive a 30% to 50% reduction in LDL-C cholesterol with statin therapy, there is wide variation in the dose response. Environmental and genetic factors may contribute to this variability. In line with our previous work [8], we assessed whether 2 common polymorphisms of CETP (I405V and TaqIB) influence the lipid response after treatment with atorvastatin.

We evaluated whether the common CETP TaqIB or I405V gene polymorphism was associated with differentiation of the plasma lipid profile and involvement of the atorvastatin effectiveness on lipid lowering. Our results show that TaqIB polymorphism modulated the effectiveness of atorvastatin reduction on lipid values, especially on HDL-C and TG (to a lesser degree). Also, in the Low HDL group the effectiveness of reduction of total cholesterol and TG varied according to TaqIB polymorphism. In the High HDL group the % reduction of LDL-C varied according to I405V polymorphism.

The gene frequencies for the TaqIB and I405V polymorphisms in our study cohort were similar to those reported in other Caucasian [3, 12, 13] and dyslipidaemic populations [14]. For example, the population in the Regression Growth Evaluation Statin Study (REGRESS) had similar TaqIB allele frequencies with our population (B1: 59% vs 58.9% and B2: 41% vs 41.1%, respectively) [15]. In another study involving Greek dyslipidaemic individuals, the V allele frequency was 33% and in Greeks with coronary artery disease 32% [8, 16], all similar to the present study (34.5%).

Concerning the baseline lipid profile, the VV and B2B2 genotypes have been reported to present with higher HDL-C levels [2, 8]. Similarly, in the present study, the B2B2 genotypes, as well as the B2 allele, were associated with higher HDL-C levels. The IV (rather than the VV) genotype and V allele was associated with higher HDL-C levels. However, no such association was found for the VV genotype which could be attributed to the low number of subjects with this genotype.

Despite the proven efficacy of statins as a primary and secondary prevention for cardiovascular disease, a significant proportion of patients do not achieve LDL-C goals [17]. This could be due to the interindividual variability in the response to statin treatment [18]. In the REGRESS study, pravastatin reduced total cholesterol, LDL-C, and TG levels and increased HDL-C to a similar extent in all 3 TaqIB genotypes [15]. However, in animals study de Haan et al. [19] reported that atorvastatin increased HDL-C by reducing hepatic CETP expression in E3L.CETP mice (APOE*3-Leiden mice crossbred with mice expressing human CETP). This fact supported the hypothesis that CETP gene polymorphisms could play an important role in the lipid lowering effectiveness of atorvastatin. Also, van Venrooij et al., who evaluated the cohort (n=217) from Diabetes Atorvastatin Lipid Intervention (DALI) study (frequency of B1 allele similar to our study 57.1%), reported that in carriers with the B1B1 genotype, HDL-C levels increased, whereas in B2B2 carriers, atorvastatin had no effect on HDL-C [20]. Poduri et al. [21] found association with reduced LDL-C lowering by atorvastatin and gene polymorphisms involved in lipid metabolism (including CETP gene) in an Indian population. They compared the wild-allele homozygote genotype vs variant allele carrying heterozygote and homozygote genotypes and found that variant allele-carrying genotype of TaqIB showed greater increase in HDL-C concentrations following atorvastatin therapy and variant allele carrying I405V showed lower reduction in total cholesterol levels. Contrary to our findings, patients involved in their study had coronary artery disease, were mostly men and had median total cholesterol of 204(35) mg/dl and HDL-C of 35(9) mg/dl, while subjects in our study were dyslipidaemic, 30% were women and had total cholesterol 286(69) mg/dl and HDL-C 44(20) mg/dl. Furthermore, Mohrschladt et al. did not find any differences between TaqIB and statin treatment [22]. In a previous study of ours, the TaqIB had no influence on response to treatment with simvastatin opposite to I405V polymorphism, where I allele carriers responded better [8]. In the present study, carriers of B1 allele increased HDL-C levels after atorvastatin therapy, while the carriers of B2 alleles decreased the HDL-C levels. One explanation is that carriers of the B2 allele had higher HDL-C levels at baseline [42(19) mg/dl vs 48(19) mg/dl, respectively]. In the Low HDL group the B2 carriers responded better to statin therapy (greater reduction of total cholesterol and TGs). Moreover, in the High HDL-C group the II genotype was associated with greater % reduction of LDL-C and B1B1 genotype with lower reduction of HDL-C after atorvastatin treatment. Possible explanation for this discrepancy may be that another statin was used (atorvastatin instead of simvastatin). Overall, subjects with low HDL-C levels at baseline seem to benefit to a greater extent than those with high HDL-C levels at baseline after atorvastatin treatment. The HDL-C level was significantly increased (+12.9%) and TGs were significantly decreased (-38%) in group with low HDL-C compared with -8.3% and -15.2%, respectively in the group with high HDL-C. The different response to hypolipidaemic drugs according the HDL-C baseline levels was suggested by our research group since 1995 [7, 23, 24]. At that time, this was only a clinical observation. However, the response to statin treatment is not solely influenced by a single gene polymorphism. Furthermore, the pharmacogenetic studies on association between genes and lipid lowering response to statins are limited [25]. Many factors could contribute to an individual’s response such as side effects, gender, age, body mass index, diet, environmental, CETP mass and activity (CETP genotypes may influence both by approximately 5% to 10%) [26], as well as gene-gene interaction. Gene assessment also has cost and time implications which are disadvantages in routine clinical practice. Nevertheless, these disadvantages may become less relevant as technology develops.

The results favour the hypothesis that CETP polymorphisms modify the effect of statin treatment and may help to identify subjects who will benefit more from statin therapy. Thus, the prospective identification of subjects who have a diminished or increased response to statins, may improve the risk-to-benefit ratio of statin therapy. However, this is a small study. To clarify the genes contribution to the statin lipid lowering effect more studies involving higher number of individuals are required.