Cholesteryl Ester Transfer Protein Gene Research Articles

Cholesteryl Ester Transfer Protein and ATP-Binding Cassette Transporter A1 Genotype Alter the Atorvastatin and Simvastatin Efficacy

We compared the efficacy of atorvastatin with simvastatin according to cholesteryl ester transfer protein (CETP) and adenosine triphosphate-binding cassette transporter A1 (ABCA1) genes. Patients treated with atorvastatin (n = 254) or simvastatin (n = 332) were genotyped for CETP (TaqIB and I405V) and ABCA1 (R219K) genetic variants. For genotype B1B2, atorvastatin compared with simvastatin treatment resulted in a greater decrease in total cholesterol (35.4% vs 31.6%, P = .035) and a lower increase in high-density lipoprotein cholesterol (2% vs 8%, P = .05). For genotype B2B2, atorvastatin compared with simvastatin treatment resulted in a lower decrease in low-density lipoprotein cholesterol (31.85 vs 42%, P = .029). For genotypes RR and KK, atorvastatin compared with simvastatin treatment resulted in a greater decrease of triglycerides (27% vs 17% and 35% vs 15%, respectively; P = .02 for all comparisons). The TaqIB and R219K (opposite to I405V) gene polymorphisms seem to modify the response to lipid-lowering therapy with simvastatin or atorvastatin treatment.

Advances in Exercise, Fitness, and Performance Genomics in 2011

This review of the exercise genomics literature emphasizes the highest quality articles published in 2011. Given this emphasis on the best publications, only a small number of published articles are reviewed. One study found that physical activity levels were significantly lower in patients with mitochondrial DNA mutations compared with controls. A two-stage fine-mapping follow-up of a previous linkage peak found strong associations between sequence variation in the activin A receptor, type-1B (ACVRIB) gene and knee extensor strength, with rs2854464 emerging as the most promising candidate polymorphism. The association of higher muscular strength with the rs2854464 A allele was confirmed in two separate cohorts. A study using a combination of transcriptomic and genomic data identified a comprehensive map of the transcriptomic features important for aerobic exercise training-induced improvements in maximal oxygen consumption, but no genetic variants derived from candidate transcripts were associated with trainability. A large-scale de novo meta-analysis confirmed that the effect of sequence variation in the fat mass and obesity-associated (FTO) gene on the risk of obesity differs between sedentary and physically active adults. Evidence for gene-physical activity interactions on type 2 diabetes risk was found in two separate studies. A large study of women found that physical activity modified the effect of polymorphisms in the lipoprotein lipase (LPL), hepatic lipase (LIPC), and cholesteryl ester transfer protein (CETP) genes, identified in previous genome-wide association study reports, on HDL cholesterol. We conclude that a strong exercise genomics corpus of evidence would not only translate into powerful genomic predictors but also have a major effect on exercise biology and exercise behavior research.

Lipid and Apoprotein Composition of HDL in Partial or Complete CETP Deficiency

Hyperalphalipoproteinemia, as observed in patients who are either homozygous or heterozygous for cholesteryl ester transfer protein (CETP) deficiency, has been shown to be associated with striking changes in apolipoprotein size distribution, namely, of high-density lipoprotein (HDL) and HDL-like particles. We compared the effect of varying degrees of CETP activity on the HDL apolipoprotein profile in Caucasian CETP-deficient subjects and following pharmacological decrease in CETP activity, using Size Exclusion Chromatography followed by Reverse Phase Protein Array (SEC RPA). The main HDL-associated apolipoproteins (Apo), i.e. ApoA-I, ApoA-II, ApoC-I, and ApoC-III, co-eluted with the HDL peak. The presence of a HDL-like peak migrating between the ApoB-LDL and ApoA-I-HDL was identified in a Caucasian patient with homozygosity for a point mutation in exon 2 of the CETP gene (c.109 C > T) resulting in a premature termination codon (R37X) and complete CETP deficiency. This HDL-like peak was not observed either in healthy volunteers treated with the CETP modulator dalcetrapib, patients heterozygous for the same mutation, or in patients heterozygous with G165X mutations. SEC RPA offers the possibility to investigate the distribution of a large number of apolipoproteins simultaneously under non-denaturing separation in normal and dyslipidemic subjects. This is only limited by the availability of antibodies against specific apolipoproteins to be investigated.

Multiple gene polymorphisms predisposing to the prothrombotic state in an adolescent with acute myocardial infarction

Acute myocardial infarction with ST-segment elevation (STEMI) is rare in adolescents and its pathogenesis is unclear. Growing evidence shows an association between the prothrombotic state and acute STEMI. Prothrombotic genetic factors may be involved in the pathogenesis of STEMI. We present a case of an adolescent with acute STEMI who had multiple prothrombotic gene polymorphisms: in the beta fibrinogen, methylenetetrahydrofolate reductase and cholesteryl ester transfer protein genes, as well as genotypes in plasminogen activator inhibitor-1 and human platelet antigen type-1. He had normal coronary arteries with catheterinduced spasm and was treated with a calcium antagonist and aspirin.

Cholesteryl Ester Transfer Protein (CETP) Polymorphisms Affect mRNA Splicing, HDL Levels, and Sex-Dependent Cardiovascular Risk

Polymorphisms in and around the Cholesteryl Ester Transfer Protein (CETP) gene have been associated with HDL levels, risk for coronary artery disease (CAD), and response to therapy. The mechanism of action of these polymorphisms has yet to be defined. We used mRNA allelic expression and splice isoform measurements in human liver tissues to identify the genetic variants affecting CETP levels. Allelic CETP mRNA expression ratios in 56 human livers were strongly associated with several variants 2.5–7 kb upstream of the transcription start site (e.g., rs247616 p = 6.4×10−5, allele frequency 33%). In addition, a common alternatively spliced CETP isoform lacking exon 9 (Δ9), has been shown to prevent CETP secretion in a dominant-negative manner. The Δ 9 expression ranged from 10 to 48% of total CETP mRNA in 94 livers. Increased formation of this isoform was exclusively associated with an exon 9 polymorphism rs5883-C>T (p = 6.8×10−10) and intron 8 polymorphism rs9930761-T>C (5.6×10−8) (in high linkage disequilibrium with allele frequencies 6–7%). rs9930761 changes a key splicing branch point nucleotide in intron 8, while rs5883 alters an exonic splicing enhancer sequence in exon 9.The effect of these polymorphisms was evaluated in two clinical studies. In the Whitehall II study of 4745 subjects, both rs247616 and rs5883T/rs9930761C were independently associated with increased HDL-C levels in males with similar effect size (rs247616 p = 9.6×10−28 and rs5883 p = 8.6×10−10, adjusted for rs247616). In an independent multiethnic US cohort of hypertensive subjects with CAD (INVEST-GENE), rs5883T/rs9930761C alone were significantly associated with increased incidence of MI, stroke, and all-cause mortality in males (rs5883: OR 2.36 (CI 1.29–4.30), p = 0.005, n = 866). These variants did not reach significance in females in either study. Similar to earlier results linking low CETP activity with poor outcomes in males, our results suggest genetic, sex-dependent CETP splicing effects on cardiovascular risk by a mechanism independent of circulating HDL-C levels.

Cholesteryl ester transfer protein TaqIB polymorphism and its association with serum lipid levels and longevity in Chinese Bama Zhuang population.

BackgroundTaqIB polymorphism in the cholesteryl ester transfer protein (CETP) gene has been reported to be associated with serum high-density lipoprotein cholesterol (HDL-C) levels and longevity in several populations, but controversial results also arose probably due to racial/ethnic diversity. Bama is a remote and mountainous county located in the northwest of Guangxi, People's Republic of China, which has been well known for its longevity for centuries. The current study was to investigate the possible association of CETP TaqIB polymorphism with serum lipid levels and longevity in the Bama Zhuang population.MethodsThe CETP TaqIB genotypes were determined by polymerase chain reaction and restriction fragment length polymorphism in 523 long-lived inhabitants (long-lived group, LG; aged 90-107 years) and 498 healthy controls without longevity family history (non-long-lived group, non-LG; aged 40-69 years) residing in Bama County.ResultsThe levels of total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) were higher but TG, HDL-C/LDL-C ratio and the prevalence of dyslipidemia were lower in LG than in non-LG (P < 0.001 for all). There were no differences in the allelic and genotypic frequencies between the two groups (P > 0.05). Serum HDL-C levels and HDL-C/LDL-C ratio in LG were different among the genotypes (P < 0.01 for each), the subjects with B2B2 and B1B2 genotyes had higher HDL-C levels and HDL-C/LDL-C ratio than the subjects with B1B1genotye, whereas the levels of TC and HDL-C in non-LG were different among/between the genotypes (P < 0.01 for each), the B2 allele carriers had lower TC and higher HDL-C levels than the B2 allele noncarriers. Serum TG and HDL-C levels and HDL-C/LDL-C ratio were correlated with genotypes in LG, whereas serum TC and HDL-C levels were associated with genotypes in non-LG (P < 0.05-0.001).ConclusionsThe association of CETP TaqIB polymorphism and serum lipid profiles is different between LG and non-LG in the Chinese Bama Zhuang population. CETP TaqIB polymorphism might be one of the longevity-related genetic factors in this population.

Effect of Genetic Variants Related to Lipid Metabolism as Risk Factors for Cholelithiasis After Bariatric Surgery in Brazilian Population

The manifestation of cholelithiasis after bariatric surgery may depend on genetic factors related to lipid metabolism, including apolipoprotein E (APOE) and cholesteryl ester transfer protein (CETP) gene polymorphisms. We investigated the association between APOE HhaI and CETP TaqIB polymorphisms [PCR-RFLP] and occurrence of cholelithiasis over up to 8months of follow-up after gastroplasty to Roux-en-Y gastric bypass in 220 patients distributed in Group 1 (G1) 114 with cholelithiasis postoperatively and Group 2 (G2) 106 without cholelithiasis, including biochemical and anthropometric profiles analyses. In our series, the allelic and genotypic distributions of CETP TaqIB and APOE HhaI polymorphisms were similar in both groups (P > 0.05). The subgroup analysis evidenced that 54% of the patients from G1, APOE*4 allele carriers compared with APOE*3/3 carriers, presented altered low-density lipoprotein cholesterol (LDL cholesterol) serum levels (P = 0.022) before bariatric surgery. The B1 allele for CETP was associated to more quickly elevation of HDL cholesterol levels just in individuals without cholelitiasis (P < 0.0001). The multivariate logistic regression analysis demonstrates correlation between APOE*4 allele, higher total cholesterol (TC) serum levels and prediposition to cholelitiasis in preoperative period. However, the presence of postoperative cholelithiasis was not associated with altered lipid profile. The CETP TaqIB and APOE HhaI polymorphisms do not seem to have association with gallstones in the late postoperative bariatric surgery, considering that these genetic variants do not differ subgroups of patients who are eligible to routine prophylactic cholecystectomy, at least in Brazilian population.

The CETP I405V polymorphism is associated with an increased risk of Alzheimer's disease.

The cholesteryl ester transfer protein (CETP) gene plays an essential role in regulating cholesterol homeostasis and is a candidate susceptibility gene for late-onset Alzheimer's disease (AD). Recent finding suggests that the CETP I405V polymorphism (rs5882) is associated with a slower rate of memory decline and a lower risk of incident dementia. Using data from two ongoing epidemiologic clinical-pathologic cohort studies of aging and dementia in the United States, the Religious Order Study and the Memory and Aging Project, we evaluated the association of the CETP I405V polymorphism (rs5882) with cognitive decline and risk of incident AD in more than 1300 participants of European ancestry. Our results suggest that the CETP I405V polymorphism was associated with a faster rather than a slower rate of decline in cognition over time, and an increased risk of incident AD. This finding is consistent with data showing that the CETP I405V is associated with increased neuritic plaque density at autopsy.

Novel mutations of cholesteryl ester transfer protein (CETP) gene in Japanese hyperalphalipoproteinemic subjects

BackgroundThe half of hyperalphalipoproteinemia (HALP) in Japan is caused by CETP gene mutations. Other than two prevalent mutations (D442G and Intron 14 splicing donor site +1G>A), some rare CETP mutations are found in Japanese HALP subjects. MethodsCETP gene analysis of genomic DNA from subjects was performed by restriction fragment length polymorphism (RFLP) and sequencing analysis. Mutations which were suspected to cause a splicing defect or a protein secretion defect were investigated in COS-1 cells transfected with a CETP minigene construct or a cDNA expression vector. ResultsEach of three subjects was identified as a carrier of CETP gene mutation of a compound heterozygote of c.653_654delGGinsAAAC and Intron 14 splicing donor site +1G>A, a heterozygote of c.658G>A or a homozygote of L261R. The c.658G>A mutation was located at the last nucleotide of exon 7, and it was confirmed to cause splicing abnormality revealed by the CETP minigene analysis. The L261R CETP was not secreted to conditioned media of the cells. ConclusionsThree novel CETP gene mutations are responsible for HALP by CETP deficiency. It is predicted that there are more rare CETP gene mutations in Japanese, and these multiple rare mutations alone or a combination with each of prevalent mutations is responsible for mild-to-moderate or marked HALP, respectively.

Interaction between Cholesteryl Ester Transfer Protein and Hepatic Lipase Encoding Genes and the Risk of Type 2 Diabetes: Results from the Telde Study

Background and AimDiabetic dyslipidaemia is common in type 2 diabetes (T2D) and insulin resistance and often precedes the onset of T2D. The Taq1B polymorphism in CETP (B1 and B2 alleles) (rs708272) and the G-250A polymorphism in LIPC (rs2070895) are associated with changes in enzyme activity and lipid concentrations. Our aim was to assess the effects of both polymorphisms on the risk of T2D.Methods and ResultsIn a case-control study from the population-based Telde cohort, both polymorphisms were analysed by PCR-based methods. Subjects were classified, according to an oral glucose tolerance test, into diabetic (N = 115) and pre-diabetic (N = 116); 226 subjects with normal glucose tolerance, matched for age and gender, were included as controls. Chi-square (comparison between groups) and logistic regression (identification of independent effects) were used for analysis. The B1B1 Taq1B CETP genotype frequency increased with worsening glucose metabolism (42.5%, 46.1% and 54.3% in control, IGR and diabetic group; p = 0.042). This polymorphism was independently associated with an increased risk of diabetes (OR: 1.828; IC 95%: 1.12–2.99; p = 0.016), even after adjusting by confounding variables, whereas the LIPC polymorphism was not. Regarding the interaction between both polymorphisms, in the B1B1 genotype carriers, the absence of the minor (A) allele of the LIPC polymorphism increased the risk of having diabetes.ConclusionThe presence of the B1B1 Taq1B CETP genotype contributes to the presence of diabetes, independently of age, sex, BMI and waist. However, among carriers of B1B1, the presence of GG genotype of the -250 LIPC polymorphism increases this risk further.

Apolipoprotein A–I stimulates cholesteryl ester transfer protein and apolipoprotein E secretion from lipid-loaded macrophages; the role of NF-κB and PKA signaling pathways

Cholesteryl ester transfer protein (CETP) and apolipoprotein E (apoE) are secreted by macrophages. Apolipoprotein A–I (apoA–I) is a potent inducer of apoE secretion from lipid-loaded macrophages, but its effect on CETP is not known. We aimed to identify the signaling pathways involved in apoA–I and HDL-mediated regulation of CETP and apoE secretion from lipid-loaded macrophages. THP-1 macrophages were loaded with lipids by incubation with human copper-oxidized LDL. The cells were subsequently exposed to human purified apoA–I or HDL 3 with/without inhibitors of NF-κB (TPCK) or PKA (H89). CETP and apoE in the cultured cells and media were quantified by real-time PCR and Western blot. Results showed that in lipid-loaded macrophages: (i) CETP and apoE gene expression and secretion were increased in the presence of apoA–I, and further increased by inhibition of NF-kB with TPCK; (ii) CETP and apoE gene expression and secretion were reduced by the inhibition of PKA with H89; (iii) PKA-gamma subunit was activated by oxidized LDL and moreover by apoA–I. We also showed that: (i) siRNA-mediated CETP gene silencing diminished apoE secretion from both non-loaded and lipid-loaded macrophages; (ii) addition of apoA–I partially restored apoE secretion from lipid-loaded macrophages with the silenced CETP gene. In conclusion, our data suggest a new mechanism by which apoA–I stimulates CETP secretion, in addition to apoE, from lipid loaded macrophages, a process involving NF-κB inhibition and/or PKA pathway activation.

CETP polymorphisms associate with brain structure, atrophy rate, and Alzheimer's disease risk in an APOE-dependent manner.

Two alleles in cholesteryl ester transfer protein (CETP) gene polymorphisms have been disputably linked to enhanced cognition and decreased risk of Alzheimer's disease (AD): the V and A alleles of I405V and C-629A. This study investigates whether these polymorphisms affect brain structure in 188 elderly controls and 318AD or mild cognitive impairment (MCI) subjects from the Alzheimer's Disease Neuroimaging Initiative cohort. Nominally signficant associations were dependent on APOE ε4 carrier status. In APOE ε4 carriers, the V and A alleles, both of which decrease CETP and increase HDL, associated with greater baseline cortical thickness and less 12-month atrophy in the medial temporal lobe. Conversely, in APOE ε4 non-carriers, the I allele, which increases CETP and decreases HDL, associated with greater baseline thickness, less atrophy and lower risk of dementia. These results suggest CETP may contribute to the genetic variability of brain structure and dementia susceptibility in an APOE-dependent manner.

− 629C/A polymorphism in the cholesteryl ester transfer protein (CETP) gene and metabolic syndrome disorder

− 629C/A polymorphism in the cholesteryl ester transfer protein (CETP) gene and metabolic syndrome disorder

Synthetic LXR agonist inhibits the development of atherosclerosis in New Zealand White rabbits

The nuclear receptors Liver X receptors, LXRα and LXRβ, regulate cholesterol and triglyceride metabolism. We and others have previously reported that synthetic LXR agonists reduced atherosclerosis in models of mouse with no detectable plasma cholesteryl ester transfer protein (CETP) activity, which plays an important role in reverse cholesterol transport. In the present study, we investigated the effect of LXR activation in rabbits to elucidate the influence of CETP activity. First, we cloned rabbit LXRs cDNA. The data indicated that rabbit LXRα was mostly highly expressed in the liver, whereas LXRβ expression was ubiquitous. Next, we investigated the effect of LXR agonist on lipid levels. Treatment with LXR agonist T0901317 increased plasma CETP activity and consequently elevated LDL, but no change in HDL. High cholesterol (HC) diet-feeding, which is thought to provide oxysterols as the natural agonists, could also increase expression of CETP and other LXR target genes. Finally, we tested T0901317 in the atherosclerosis intervention study. Chronic administration of T0901317 significantly reduced atherosclerosis in HC diet-fed rabbits despite less favorable lipid profiles, i.e. increases of plasma triglycerides and no change of HDL. T0901317 induced ATP-binding cassette transporters ABCA1 and ABCG1 and suppressed inflammatory genes expression in the aorta, suggesting that direct actions of LXR agonist on vascular gene expression are likely to contribute to the antiatherogenic effect. The present work strongly supports the idea that LXR agonists could be beneficial as therapeutic agents for treatment of atherosclerosis.

Cholesteryl Ester Transfer Protein Taq1B (g.5454G>A) Gene Polymorphism in Primary Combined Hyperlipidemia in the Egyptian Population

Objective: To study the relationship between Taq1B polymorphism of the cholesteryl ester transfer protein (CETP) gene and lipid profile in the Egyptian population. A base substitution from G (B1) to A (B2) in intron 1 of the gene leads to 1 of 3 variants, B1B1, B1B2, or B2B2, at the Taq1B site (5454G>A) (Mutalyzer 2.0 B-6). Materials and Methods: Lipid profile parameters and CETP Taq1B polymorphisms were studied in 30 patients with primary combined hyperlipidemia and in 28 control subjects. The lipid profile was measured. Polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) were used to study Taq1B polymorphisms. Results: The B2B2 genotype was significantly lower in the patient group (13.3%) than it was in the control group (35.7%). No significant difference was found in allelic distribution between groups. In the patient group, the B2B2 genotype showed a higher serum high-density lipoprotein cholesterol (HDL-C) and lower total cholesterol (TC)/HDL ratio than B1B1 and B1B2. In the control group, triglycerides (TGs), TC/HDL ratio, and low-density lipoprotein (LDL) levels were lower in the B2B2 genotype than other genotypes. Conclusion: There was a suggested association between Taq1B polymorphism of the CETP gene and lipid profile changes, with the B2B2 genotype being protective against hyperlipidemia and atherosclerosis. * CETP : cholesteryl ester transfer protein PCR : polymerase chain reaction RFLP : restriction fragment length polymorphism HDL-C : high-density lipoprotein cholesterol TC : total cholesterol LDL : low-density lipoprotein CHD : coronary heart disease VLDL : very-low-density lipoprotein AST : aspartate transaminase ALT : alanine transaminase TSH : thyroid-stimulating hormone TG : triglyceride dATP : deoxyadenosine triphosphate cDTP : deoxycytidine triphosphate dGTP : deoxyguanosine triphosphate dTTP : deoxythymidine triphosphate ANOVA : analysis of variance CVD : cardiovascular disease

Cholesteryl ester transfer protein and hepatic lipase gene polymorphisms: Effects on hepatic mRNA levels, plasma lipids and carotid atherosclerosis

ObjectiveHDL modifying effects of cholesteryl ester transfer protein (CETP) and hepatic lipase (LIPC) depend in part on each other. We studied associations of CETP-Taq1B and -514C>T-LIPC polymorphisms with hepatic mRNA levels, and their combined effects on plasma lipids and carotid atherosclerosis. MethodsWe genotyped the CETP-Taq1B and the -514C>T-LIPC polymorphisms in 67 obese women in whom hepatic CETP and LIPC transcript levels were determined as well as in 1549 participants of the Salzburg Atherosclerosis Prevention Program in Subjects at High Individual Risk (SAPHIR). Carotid atherosclerosis was assessed by intima-media thickness and extent of plaques (B-score) of the carotid arteries. ResultsIn obese women, CETP-Taq1B and -514C>T-LIPC variant alleles were associated with reduced hepatic levels of CETP and LIPC mRNA, respectively. The CETP and LIPC polymorphisms accounted for 12.9 and 14.4% of the variability in respective transcripts. In the SAPHIR population, CETP-Taq1B showed independent effects on LDL diameter, HDL and LDL cholesterol, apolipoproteins AI and B and cholesterol/HDL cholesterol, while -514C>T-LIPC revealed independent effects on HDL cholesterol and apolipoprotein AI. The two polymorphisms displayed interactions at the level of HDL cholesterol. Compared to subjects carrying wild-type alleles at both loci, subjects homozygous for the CETP wild-type allele, but heterozygous for the LIPC polymorphism and subjects heterozygous for the CETP polymorphism, but homozygous for the LIPC wild-type allele showed an increased risk of carotid atherosclerosis (both P<0.05). ConclusionsCETP and LIPC polymorphisms influence the respective hepatic transcript levels, demonstrate interactions on HDL cholesterol and suggest that imbalances between CETP and LIPC activities may modulate the risk of carotid atherosclerosis.

The role of common variants of the cholesteryl ester transfer protein gene in left main coronary artery disease

BackgroundThe cholesteryl ester transfer protein (CETP) has a central role in the lipid metabolism and therefore may alter the susceptibility to atherosclerosis.MethodsThe DNA of 471 subjects [133 subjects with angiographically documented left main coronary artery disease (LMCAD), 241 subjects with more peripheral coronary artery disease (MPCAD) and 97 subjects self reported healthy (Controls)] was analyzed for the frequency of TaqIB and I405V polymorphisms in the gene coding CETP.ResultsThere is no significant difference in CETP allele frequency or genotype distribution among LMCAD and MPCAD patients although there is statistical difference between LMCAD and Controls (p = 0.001). Specifically, patients with LMCAD and B1B1 genotype of TaqIB polymorphism were more frequent present compared to Controls (33.8% vs 22.9%, respectively). The frequency of B2B2 genotype was 3 times lower in the LMCAD group compared to Controls (10.5% vs 30.2%, respectively). In the LMCAD group the frequency of B1 allele compared to Controls was higher (62% vs 46%, respectively, p = 0.001). The relationship between TaqIB gene polymorphism and the LMCAD was independent of lipid profile, with the exception of apolipoprotein A.ConclusionsThese findings indicate that the TaqIB polymorphism may have potential importance in screening individuals at high risk for developing CAD. However, this polymorphism cannot distinguish between LMCAD and MPCAD. Further prospective investigations in larger populations are required to confirm these findings.

Clinical Implications of Pharmacogenetic Variation on the Effects of Statins

The last decade has seen an increase in the trend of HMG-CoA reductase inhibitor (statin) usage in the Western world, which does not come as a surprise noting that the latest American Heart Association heart and stroke statistics indicate an alarming prevalence of 80 million Americans (one in three) with one or more forms of diagnosed cardiovascular disease (CVD). Meta-analysis of several large-scale, randomized clinical trials has demonstrated statins to be efficacious in significantly reducing CVD-associated mortality in both primary and secondary prevention. Despite their proven efficacy, statins have also gained attention with respect to adverse drug reactions (ADRs) of muscle myopathy, derangements in hepatic function and even ADRs classified as psychiatric in nature. The depletion of cholesterol within the myocyte cell wall and/or the depletion of key intermediates within the cholesterol synthesis pathway are hypothesized as possible mechanisms of statin-associated ADRs. However, pharmacogenetic variability may also be a risk factor for ADRs and can include, for example, enzymes, transporters, cell membrane receptors, intracellular receptors or components of ion channels that contribute to the pharmacokinetics or pharmacodynamics of response to a particular drug. The cytochrome P450 (CYP) enzymatic pathways that comprise the polymorphic genes, CYP2D6, CYP3A4 and CYP3A5, and also a hepatic transporter, solute carrier organic anion transporter (SLCO1B1), which is a single nucleotide polymorphism discovered to be associated with statin-induced myopathy through a genome-wide association study, are discussed with respect to their effect on altering the pharmacokinetic profile of statin metabolism. Variants of the Apolipoprotein E (APO-E) gene, polymorphisms in the cholesteryl ester transfer protein (CETP) gene, the HMG-CoA reductase gene and other proteins are discussed with respect to altering the pharmacodynamic profile of statins. Pharmacogenetics and its application in medicine to individualize drug therapy has been previously shown to be clinically and economically beneficial through quality-adjusted life-year assessment. Therefore, polymorphisms affecting the pharmacokinetic and pharmacodynamic profiles of statins, which are widely used in therapy, with their potential application in the personalized prescribing of statin therapy, need further research. In this review, we update the recent literature with respect to genetic polymorphisms that may influence the pharmacokinetics and pharmacodynamics of statin therapy, and consider the relevance of these findings to the efficacy of treatment, prevention of ADRs and what this may mean for patient tolerance and compliance.

Association of a Functional Polymorphism in the Cholesteryl Ester Transfer Protein (CETP) Gene With Memory Decline and Incidence of Dementia

Association of a Functional Polymorphism in the Cholesteryl Ester Transfer Protein (CETP) Gene With Memory Decline and Incidence of Dementia

Cholesteryl Ester Transfer Protein Gene and Effectiveness of Lipid Lowering of Atorvastatin

Cholesteryl ester transfer protein (CETP) plays a key role in lipid metabolism. Thus, variations in the CETP gene may be clinically relevant. Newly started atorvastatin users (n=212) were genotyped for CETP genetic variants (TaqIB and I405V). Homozygotes for B1 allele of TaqIB polymorphism had lower plasma high density lipoprotein cholesterol (HDL-C) compared with B1B2 or B2B2 genotypes (p=0.03, for each). Homozygotes for I allele of I405V polymorphism had lower plasma HDL-C compared with IV or VV genotypes (p=0.001, for each). In the whole population, the B1 carriers increased HDL-C levels by 4% after atorvastatin treatment, compared with B2 carriers, where a 4% decrease occurred (p=0.03). Also homozygotes for B1 allele decreased triglyceride levels to a lesser, though not significant, degree compared to B1B2 or B2B2 genotypes. CETP TaqIB or I405V polymorphisms seem to modify the lipid lowering response to atorvastatin treatment. This knowledge may help design more effective hypolipidaemic treatment.