Cholesteryl Ester Transfer Protein Genotype Research Articles

The Association between HDL-C and Subclinical Atherosclerosis Depends on CETP Plasma Concentration: Insights from the IMPROVE Study.

The impact of cholesteryl ester transfer protein (CETP) on atherosclerosis is highly debated. This study aimed to investigate the associations between plasma CETP or CETP genotypes and carotid intima-media thickness (cIMT) and the influence of high-density lipoprotein cholesterol (HDL-C) on these associations. Plasma CETP and HDL-C concentrations were measured in 552 subjects free of any pharmacological treatment from the IMPROVE cohort, which includes 3711 European subjects at high cardiovascular risk. CETP single-nucleotide polymorphisms (SNPs) and cIMT measures (cIMTmax; cIMTmean–max of bifurcations, common and internal carotids; plaque-free common carotid [PF CC]-IMTmean) were available for the full cohort. In drug-free subjects, plasma CETP correlated with HDL-C levels (r = 0.19, p < 0.0001), but not with cIMT variables. When stratified according to HDL-C quartiles, CETP positively correlated with cIMTmax and cIMTmean–max, but not with PF CC-IMTmean, in the top HDL-C quartile only. Positive associations between the CETP concentration and cIMTmax or cIMTmean–max were found in the top HDL-C quartile, whereas HDL-C levels were negatively correlated with cIMTmax and cIMTmean–max when the CETP concentration was below the median (HDL-C × CETP interaction, p = 0.001 and p = 0.003 for cIMTmax and cIMTmean–max, respectively). In the full cohort, three CETP SNPs (rs34760410, rs12920974, rs12708968) were positively associated with cIMTmax. rs12444708 exhibited a significant interaction with HDL-C levels in the prediction of cIMTmax. In conclusion, a significant interplay was found between plasma CETP and/or CETP genotype and HDL-C in the prediction of carotid plaque thickness, as indexed by cIMTmax. This suggests that the association of HDL-C with carotid atherosclerosis is CETP-dependent.

CETP genetic variant rs1800777 (allele A) is associated with abnormally low HDL-C levels and increased risk of AKI during sepsis

High-density cholesterol (HDL-C) levels are influenced by genetic variation in several genes. Low levels of HDL-C have been associated with increased risk of acute kidney injury (AKI). We investigated whether genetic polymorphisms in ten genes known to regulate HDL-C levels are associated with both HDL-C levels and AKI development during sepsis. Two cohorts were retrospectively analyzed: Derivation Cohort (202 patients with sepsis enrolled at the Emergency Department from 2011 to 2014 in Vancouver, Canada); Validation Cohort (604 septic shock patients enrolled into the Vasopressin in Septic Shock Trial (VASST)). Associations between HDL-related genetic polymorphisms and both HDL-C levels, and risk for clinically significant sepsis-associated AKI (AKI KDIGO stages 2 and 3) were evaluated. In the Derivation Cohort, one genetic variant in the Cholesteryl Ester Transfer Protein (CETP) gene, rs1800777 (allele A), was strongly associated with lower HDL-C levels (17.4 mg/dL vs. 32.9 mg/dL, P = 0.002), greater CETP mass (3.43 µg/mL vs. 1.32 µg/mL, P = 0.034), and increased risk of clinically significant sepsis-associated AKI (OR: 8.28, p = 0.013). Moreover, the same allele was a predictor of sepsis-associated AKI in the Validation Cohort (OR: 2.38, p = 0.020). Our findings suggest that CETP modulates HDL-C levels in sepsis. CETP genotype may identify patients at high-risk of sepsis-associated AKI.

Beneficial effect of CETP gene polymorphism in combination with a Mediterranean diet influencing lipid metabolism in metabolic syndrome patients: CORDIOPREV study

The cholesteryl ester transfer protein (CETP) gene has been implicated in high-density lipoprotein (HDL-C) metabolism. However, little is known about the impact of this gene on metabolic syndrome (MetS) patients and its interaction with diet. Here, we evaluate whether the consumption of a Mediterranean diet, compared with a Low-fat diet, interacts with the rs3764261 SNP at the CETP locus to modify lipid metabolism in MetS patients. Plasma lipid concentrations and rs3764261 genotypes were determined in 424 MetS subjects participating in the CORDIOPREV clinical trial (NCT00924937). Gene-diet interactions were analyzed after a year of dietary intervention (Mediterranean diet (35% fat, 22% MUFA) vs Low-fat diet (28% fat, 12% MUFA)). We found significant gene-diet interactions between rs3764261 SNP and the dietary pattern for HDL-C (P=0.006) and triglyceride concentrations (P=0.040). Specifically, after 12 months of Mediterranean diet intervention, subjects who were carriers of the minor T allele (TT+TG) displayed higher plasma HDL-C concentrations (P=0.021) and lower triglycerides (P=0.020) compared with those who were homozygous for the major allele (GG). In contrast, in the Low-fat intervention group, no significant differences were found between CETP genotypes after 12 months of dietary treatment. Our data support the notion that the consumption of a Mediterranean diet may play a contributing role in triggering lipid metabolism by interacting with the rs3764261 SNP at CETP gene locus in MetS patients. Due to the complex nature of gene-environment interactions, dietary adjustment in MetS patients may require a personalized approach.

Cholesteryl ester transfer protein genotype modifies the effect of apolipoprotein ε4 on memory decline in older adults

Apolipoprotein ε4 (ApoE4) is a strong genetic risk factor for sporadic Alzheimer's disease and memory decline in older adults. A single-nucleotide polymorphism in the cholesteryl ester transfer protein (CETP) gene (isoleucine to valine; V405) is associated with slower memory decline and a lower risk of Alzheimer's disease. As both genes regulate cholesterol, we hypothesized that the favorable CETPV405 allele may buffer the effect of ApoE4 on memory decline in older adults. Using linear regression, we examined the interactive effect of ApoE4 by CETPV405 on memory decline among 909 community-dwelling, nondemented, older adults (≥70 years) from the Einstein Aging Study. Episodic memory was measured using the picture version of the Free and Cued Selective Reminding Test with immediate recall (pFCSRT+IR). There was a significant ApoE × CETP interaction on decline in pFCSRT+IR scores (p = 0.01). ApoE4 carriers experienced faster decline than noncarriers among CETPI405I homozygotes (p = 0.007) and in CETPI405V heterozygotes (p = 0.015) but not in CETPV405V homozygotes (p = 0.614). Results suggest that the CETPV405 allele buffers ApoE4-associated memory decline in a gene dose-dependent manner.

Functional and association studies of the cholesteryl ester transfer protein (CETP) gene in a Wannan Black pig model.

Some polymorphisms of the human CETP gene are causally and significantly associated with serum lipids levels; however, the information regarding this gene in pigs is sparse. To evaluate the effects of CETP on blood lipid traits and fat deposition in pig, porcine CETP tissue expression patterns were observed by quantitative real-time polymerase chain reaction (qPCR) first. High expression was detected in liver, spleen, gluteus medius (GM) muscle and backfat. A de novo polymorphism (AF333037:g.795C>T) in the intron 1 region of porcine CETP was identified. This polymorphism was further genotyped by direct sequencing of the PCR products of 390 Wannan Black pigs, a Chinese native breed population. Association analyses at 45 and 300days of age revealed highly significant associations between CETP genotypes and serum lipid traits. Furthermore, this polymorphism was proved to be associated with differences in liver CETP mRNA levels: pigs at 300days of age with the TT genotype had higher levels than did those with other genotypes (P=0.021). Additionally, analysis at 300days of age showed that GM CETP mRNA expression correlated positively with serum lipids levels as well as with carcass backfat thickness and intramuscular fat content in GM. These results indicate that CETP is involved in serum, adipose and muscle lipid metabolism in pigs. The mechanisms underlying such relationships and their functional implications are worthy of further research.

CETP genotype and changes in lipid levels in response to weight-loss diet intervention in the POUNDS LOST and DIRECT randomized trials

Little is known about whether cholesteryl ester transfer protein (CETP) genetic variation may modify the effect of weight-loss diets varying in fat content on changes in lipid levels. We analyzed the interaction between the CETP variant rs3764261 and dietary interventions on changes in lipid levels among 732 overweight/obese adults from a 2 year randomized weight-loss trial [Preventing Overweight Using Novel Dietary Strategies (POUNDS LOST)], and replicated the findings in 171 overweight/obese adults from an independent 2 year weight-loss trial [Dietary Intervention Randomized Controlled Trial (DIRECT)]. In the POUNDS LOST, participants with the CETP rs3764261 CC genotype on the high-fat diet had larger increases in HDL cholesterol (P = 0.001) and decreases in triglycerides (P = 0.007) than those on the low-fat diet at 6 months, while no significant difference between these two diets was observed among participants carrying other genotypes. The gene-diet interactions on changes in HDL-cholesterol and tri-glyc-erides were replicated in the DIRECT (pooled P for interaction ≤ 0.01). Similar results on trajectory of changes in HDL cholesterol and triglycerides over the 2 year intervention were observed in both trials. Our study provides replicable evidence that individuals with the CETP rs3764261 CC genotype might derive greater effects on raising HDL cholesterol and lowering triglycerides by choosing a low-carbohydrate/high-fat weight-loss diet instead of a low-fat diet.

Abstract 19836: Lipid Metabolism is Modified by the Interaction Between Cholesteryl Ester Transfer Protein Gene Polymorphism and Mediterranean Diet in Patients in Secondary Prevention for Cardiovascular Disease

Introduction: Cholesteryl ester transfer protein (CETP) gene has been implicated in lipid metabolism. However, little is known about the impact of this gene on coronary heart disease (CHD) patients and its interaction with diet. Hypothesis: To evaluate whether the chronic consumption of a Mediterranean diet enriched in olive oil, compared with a Low fat diet, interacts with the rs3764261 SNP at CETP locus in order to modify lipid metabolism among MetS patients from the CORDIOPREV clinical trial Methods: Plasma lipid concentrations and rs3764261 genotypes were determined in 424 MetS subjects participating in the CORDIOPREV clinical trial. Gene-diet interactions were analyzed after a year of dietary intervention (Mediterranean diet (35% fat, 22% MUFA) vs Low fat diet (28% fat, 12% MUFA)) Results: We found significant gene-diet interactions between rs3764261 SNP and the dietary pattern for HDL-C ( P=0.006 ) and triglyceride concentrations ( P=0.040 ). Specifically, after 12 months of Mediterranean diet intervention, subjects who were carriers of the minor T allele (TT+TG) displayed higher plasma HDL-C concentrations ( P=0.021 ) and lower triglycerides ( P=0.020 ) compared with homozygous for the major allele (GG). In contrast, in the Low fat intervention group no significant differences were found between CETP genotypes after 12 months of dietary treatment. Conclusions: Our data support the notion that a chronic consumption of a Mediterranean diet may play a contributing role in triggering lipid metabolism by interacting with the rs3764261 SNP at CETP gene locus in MetS patients

Association of cholesteryl ester transfer protein genotypes with paraoxonase-1 activity, lipid profile and oxidative stress in type2 diabetes mellitus: A study in San Luis, Argentina.

Aims/IntroductionDiabetic dyslipidemia is common in type 2 diabetes. The TaqIB polymorphism in cholesteryl ester transfer protein (CETP; B1 and B2 alleles; rs708272) is associated with changes in enzyme activity and lipid concentrations. The aim of the present study was to assess associations of CETP genotypes with lipoprotein profile, oxidant/anti-oxidant status and the plasma activity of paraoxonase-1 (PON-1) in a population of diabetic patients living in San Luis, Argentina.Materials and MethodsFor oxidative stress status parameters, thiobarbituric acid-reactive substances (TBARS) and nitric oxide (NO) levels, and catalase and PON-1 activity were assessed in 40 patients with type 2 diabetes mellitus and 30 healthy participants. CETP polymorphism was analyzed by polymerase chain reaction-based methods.ResultsType 2 diabetes mellitus had significantly higher concentrations of oxidative stress parameters: TBARS (P < 0.0001) and catalase activity (P < 0.0001). PON-1 activity and NO levels were significantly lower in diabetics (P = 0.0002 and P = 0.0008, respectively). The CETP genotypes distribution among study groups was not significantly different. The B2 carriers of the TaqIB CETP polymorphism are associated with higher high-density lipoprotein cholesterol levels and PON-1 activity in control and type 2 diabetes mellitus patients. Linear regression analysis showed that there was a significant and positive correlation between the changes of PON-1 activity and high-density lipoprotein cholesterol levels in non-B1B1 (B2 carriers) in controls (r = 0.83, P < 0.0001) and diabetic patients (r = 0.39, P = 0.0003).ConclusionsThe results of the current study show that type 2 diabetes mellitus is characterized by intense oxidative stress, and that the alterations observed in the lipoprotein profile and PON-1 activity might be related to the higher CETP activity in diabetic patients as a consequence of insulin resistance.

Cholesteryl Ester Transfer Protein Polymorphisms, Statin Use, and Their Impact on Cholesterol Levels and Cardiovascular Events

The association of nonfunctional variants of the cholesteryl ester transfer protein (CETP) with efficacy of statins has been a subject of debate. We evaluated whether three functional CETP variants influence statin efficacy. The effect of CETP genotype on achieved levels of high-density lipoprotein cholesterol (HDLc), low-density lipoprotein cholesterol (LDLc), and total cholesterol during statin treatment was estimated by meta-analysis of the linear regression outcomes of three studies (11,021 individuals). The effect of these single-nucleotide polymorphisms (SNPs) on statin response in protecting against myocardial infarction (MI) was estimated by meta-analysis of statin × SNP interaction terms from logistic regression in five studies (16,570 individuals). The enhancer SNP rs3764261 significantly increased HDLc by 0.02 mmol/l per T allele (P = 6 × 10(-5)) and reduced protection against MI by statins (interaction odds ratio (OR) = 1.19 per T allele; P = 0.04). Focusing on functional CETP variants, we showed that in carriers of the rs3764261 T variant, HDLc increased more during statin treatment, and protection against MI by statins appeared to be reduced as compared with those in noncarriers.

Common variation in Cholesteryl Ester Transfer Protein: Relationship of first major adverse cardiovascular events with the apolipoprotein B/apolipoprotein A-I ratio and the total cholesterol/high-density lipoprotein cholesterol ratio

The preference of the apolipoprotein (apo) B/apoA-I ratio over the total cholesterol/HDL cholesterol (TC/HDL-C) ratio in cardiovascular risk prediction is disputed. Cholesteryl ester transfer protein (CETP) is instrumental in lipoprotein remodelling and affects the cholesterol content in pro- and antiatherogenic lipoproteins relative to their major apolipoproteins. We tested the influence of common CETP variations on the strength of associations of a first major adverse cardiovascular event (MACE) with the apoB/apoA-I ratio compared with the TC/HDL-C ratio. A prospective case-cohort study was performed (PREVEND cohort; no previous cardiovascular disease and no use of lipid-lowering drugs initially). Fasting serum TC/HDL-C, apoB/apoA-I, triglycerides, and common CETP variations (TaqIB [rs708272] and -629C>A [rs1800775] polymorphisms) were measured at baseline. The composite end point was incident MACE. A total of 532 of 6780 subjects experienced a first MACE during 10.8 years follow-up. The age- and sex-adjusted hazard ratio was 1.31 (95 % confidence interval 1.23-1.41) for the apoB/apoA-I ratio and 1.22 (95% confidence interval 1.26-1.39) for the TC/HDL-C ratio (both P < .001). These relationships were essentially similar within each TaqIB and -629C>A CETP genotype group. No interactions of the apoB/apoA-I ratio and the TC/HDL-C ratio with the TaqIB and the -629C>A CETP variations on incident MACE were observed (P > .20 for all). The relationship of first MACE with the TC/HDL-C and the apoB/apoA-I ratio is notto an important extent dependent on common CETP variations. CETP variations are unlikely to affectthe strength of the relationship of first MACE with the apoB/apoA-I ratio compared with the TC/HDL-C ratio.

Genetic Inhibition of CETP, Ischemic Vascular Disease and Mortality, and Possible Adverse Effects

This study tested whether genetic variation in the CETP gene is consistent with a protective effect of cholesteryl ester transfer protein (CETP) inhibition on risk of ischemic events and on total mortality, without the adverse effects reported for torcetrapib. Torcetrapib, an inhibitor of CETP, increased risk of death and ischemic cardiovascular disease of those randomized to the drug, despite improving the lipid profile. The Copenhagen City Heart Study is a prospective cohort study of 10,261 individuals, aged 20 to 93 years, who were followed for up to 34 years (1976 to 2010). Of these, 2,087 developed ischemic heart disease, 1,064 developed ischemic cerebrovascular disease, and 3,807 died during follow-up. We selected 2 common genetic variants in CETP previously associated with reductions in CETP activity, thus mimicking the effect of pharmacological CETP inhibition. In individuals carrying 4 versus 0 high-density lipoprotein cholesterol-increasing alleles, there was an increase in levels of high-density lipoprotein cholesterol of up to 14% (0.2 mmol/l), and concomitant decreases in triglycerides, low-density lipoprotein cholesterol, and non-high-density lipoprotein cholesterol of, respectively, 6% (0.1 mmol/l), 3% (0.1 mmol/l), and 4% (0.2 mmol/l) (p for trend 0.004 to <0.001). Corresponding hazard ratios were 0.76 (95% confidence interval [CI]: 0.68 to 0.85) for any ischemic vascular event, 0.74 (95% CI: 0.65 to 0.85) for ischemic heart disease, 0.65 (95% CI: 0.54 to 0.79) for myocardial infarction, 0.77 (95% CI: 0.65 to 0.93) for ischemic cerebrovascular disease, 0.71 (95% CI: 0.58 to 0.88) for ischemic stroke, and 0.88 (95% CI: 0.80 to 0.97) for total mortality. CETP genotypes did not associate with variation in markers of possible side effects previously reported for torcetrapib. Genetic CETP inhibition associates with reductions in risk of ischemic heart disease, myocardial infarction, ischemic cerebrovascular disease, and ischemic stroke, with a corresponding antiatherogenic lipid profile, and with increased longevity, without adverse effects.

P3‐124: HDL cholesterol levels mediate association of CETP genotype with mortality

A single-nucleotide polymorphism (SNP) in the cholesteryl ester transfer protein (CETP) gene at codon 405 (isoleucine to valine V405; rs5882) has been associated with exceptional longevity in cross-sectional data and with a reduced risk of AD in some cohort studies. This SNP is associated with lower levels of circulating CETP protein and corresponding elevations in HDL levels. The goal of this study was to examine the association of this CETP SNP with all-cause mortality and to examine the mediating role of HDL cholesterol level. Analyses were based on follow-up data from the Einstein Aging Study, a longitudinal study of aging and cognition of 70+ year old initially community-dwelling residents of the Bronx, NY (USA). Mortality was ascertained through US National Death Index and informant reports. Linear mixed models were used to assess the stability of HDL levels across time in individuals and the association of CETP genotype with HDL over time. Cox models using age as the time scale estimated hazard ratios (HR) for all-cause mortality associated with CETP genotype and HDL cholesterol. In 1140 study participants, valine homozygosity was associated with lower mortality compared to II (HR 0.63, 95% CI [0.47, 0.85], P=0.002) and also compared to IV (HR 0.69 [0.51–0.92], P=0.01). 627 of these participants had HDL measurements at one or more clinic visits, of this group, 89 have died. In mixed linear models, VV genotype was associated with higher HDL cholesterol than II (difference 4.24[0.94, 7.54] mg/dl, P=0.01) but the difference in HDL levels between VV and heterozygous participants was non-significant (VV > IV, difference 1.00[-2.09, 4.08] mg/dl, P=0.53). Higher HDL was strongly associated with lower mortality (HR 0.963[0.946, 0.980]/mg/dl, P<.0001). Inclusion of mean HDL in survival models attenuated the association of CETP genotype with mortality (VV vs. II HR 0.69[0.37, 1.30], P=0.25, VV vs. IV HR 0.78[0.42, 1.43], P=0.42). Inclusion of race, education, and sex did not materially affect results in any model. CETP rs5882 is associated with reduced rates of all-cause mortality. Attenuation of this association by HDL levels suggests that the effect of genotype may be partially mediated through HDL, and suggest that additional mechanisms must be involved. Similar effects may pertain to AD.

Gene polymorphisms of CETP and apolipoprotein E in elderly subjects with cognitive impairment

Abstract The association of cholesteryl ester transfer protein (CETP) and apolipoprotein E (APOE) gene polymorphisms with mild cognitive impairment (MCI) is under debate. Our aim was to evaluate the relationship between APOE and CETP genotypes with healthy ageing. We analysed 267 elderly subjects (55 to 80+ years), 163 with MCI and 104 healthy, and 50 healthy control subjects (35 to 55 years) from a Romanian population. Biochemical parameters and thyroid hormones were assayed in plasma. APOE and CETP TaqIB gene polymorphisms were determined. Elderly subjects had higher frequency of ɛ3/ɛ2 genotype (14.6% vs. 4%, P&lt;0.001) than controls. Elderly subjects with MCI had lower high density lipoproteins (HDL) cholesterol (P=0.031), apoA-I (P=0.018), T3 (P=0.002), T4 (P=0.028) and TSH (P=0.001) hormone levels, higher systolic blood pressure (P=0.005), lower frequency of CETP B2 allele than the age-matched subjects. Healthy elderly subjects had CETP B2 allele associated with higher plasma apoA-I (P=0.021), lower circulating collagen (P=0.001) levels, and an increased frequency of the combined APOE ɛ2- CETP B2 genotype (18.3%) relative to MCI elderly subjects (7.6%, P=0.011). Healthy elderly subjects are characterized by higher HDL cholesterol, apoA-I levels and higher frequency of the combined APOE ɛ2 and CETP B2 alleles, indicating this pattern as representative for healthy ageing.

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.

Point: The Relationship between Cholesteryl Ester Transfer Protein and Cardiovascular Risk

There is overwhelming epidemiologic evidence that increased concentrations of LDL cholesterol (LDL-C)2) and low concentrations of HDL cholesterol (HDL-C) are independently associated with increased cardiovascular risk. Furthermore, the risk associated with low HDL-C concentrations persists even when LDL-C has been reduced to concentrations <1.8 mmol/L (<70 mg/dL) by treatment with statins (1). It is logical, therefore, to investigate strategies designed to redistribute cholesterol away from atherogenic LDL particles in favor of potentially protective HDL particles. One such approach is to inhibit the cholesteryl ester transfer protein (CETP), a protein in human plasma that transfers cholesterol from the HDL to non-HDL fractions (2). CETP activity is prominent in humans, nonhuman primates, and rabbits (2). In contrast, there is little or no CETP activity in the plasma of most other species, including rodents (2). In general, species with CETP activity in plasma are susceptible to the development of atherosclerosis, whereas those lacking the protein tend to be naturally resistant. Furthermore, inhibiting CETP in rabbits markedly reduces the development of atherosclerosis, regardless of whether the CETP inhibition is achieved by genetic manipulation (3), by vaccination against CETP (4), or by chemical inhibitors of CETP (5). ### CETP POLYMORPHISMS AND SUSCEPTIBILITY TO ATHEROSCLEROSIS IN HUMANS Several polymorphisms of the human CETP (cholesteryl ester transfer protein, plasma) gene have been reported (2). Although many of these studies have demonstrated associations between CETP single-nucleotide polymorphisms and small changes in plasma CETP and HDL concentrations, the relationship between these polymorphisms and susceptibility to atherosclerosis is variable (2). A recent metaanalysis of 92 studies involving 113 833 participants (6) concluded, however, that those CETP genotypes associated with inhibition of CETP activity show an inverse association with coronary risk and that the magnitude of the reduction of coronary events was consistent with the reductions in risk for equivalent increases in HDL-C concentration as predicted from …

Increased Coronary Heart Disease Risk Determined by High High-Density Lipoprotein Cholesterol and C-Reactive Protein: Modulation by Variation in the CETP Gene

Epidemiological evidence strongly favors the notion that the risk of cardiovascular disease (CVD) is inversely related to the plasma high-density lipoprotein (HDL) cholesterol concentration.1 Low HDL cholesterol is still predictive of high CVD risk in subjects with low LDL cholesterol,2 as well as during statin treatment.3 These observational data and other studies, which show that HDL particles contain a large number of antioxidative, antiinflammatory, and antiproliferative proteins, underlie the generally held view that HDL particles have atheroprotective properties.1–5 However, evidence is accumulating supporting the concept that high HDL cholesterol levels do not always predict reduced CVD risk. The Incremental Decrease in End Points through Aggressive Lipid Lowering (IDEAL) trial and the European Prospective Investigation into Cancer and Nutrition (EPIC)-Norfolk case-control study revealed that (recurrent) CVD risk is not decreased in subjects with the highest HDL cholesterol and the greatest mean HDL particle size.6 More recently, a high HDL cholesterol, high C-reactive protein (CRP) subgroup of individuals at increased risk for a first cardiovascular event was identified in the community-dwelling Prevention of Renal and Vascular End-Stage Disease (PREVEND) cohort using the “outcome event mapping approach,” a graphical exploratory data analysis tool that has been originally developed by Corsetti et al.7 Applying this analytic method to the Thrombogenic Factors and Recurrent Coronary Events (THROMBO) postinfarction cohort, the presence of a subgroup …

Cholesteryl Ester Transfer Protein (CETP) Genotype and Reduced CETP Levels Associated With Decreased Prevalence of Hypertension

To clarify whether reduced cholesteryl ester transfer protein (CETP) activity carries inherent blood pressure risks and to infer whether the increased blood pressure and elevated mortality associated with torcetrapib are idiosyncratic or characteristic of this class of drugs. We examined the associations among CETP genotype, phenotype, and blood pressure in a cohort of 521 older adults (who have complete data for the variables required in our primary analysis) enrolled between November 1, 1998, and June 30, 2003, in our ongoing studies of genes associated with longevity, including a cohort with a high prevalence of a genotype coding for a reduced activity variant of CETP and low levels of CETP. The prevalence of hypertension was actually lower among homozygotes for the variant CETP (48% vs 60% among those with wild-type and 65% among heterozygotes; P=.03). Low levels of CETP were associated with reduced prevalence of hypertension (65% in highest tertile, 59% in middle tertile, and 55% in lowest tertile; P=.04) and lower systolic blood pressure (140.8, 138.1, 136.2 mm Hg, respectively; P=.03). Reduced levels of CETP are associated with lower, not higher, blood pressure. The adverse results with torcetrapib, if mediated through blood pressure, are likely to represent effects of this specific drug, rather than a result of lower CETP levels.

Association of a Functional Polymorphism in the Cholesteryl Ester Transfer Protein (&lt;emph type="ital"&gt;CETP&lt;/emph&gt;) Gene With Memory Decline and Incidence of Dementia

Polymorphisms in the cholesteryl ester transfer protein (CETP) gene have been associated with exceptional longevity and lower cardiovascular risk, but associations with memory decline and dementia risk are unclear. To test the hypothesis that a single-nucleotide polymorphism (SNP) at CETP codon 405 (isoleucine to valine V405; SNP rs5882) is associated with a lower rate of memory decline and lower risk of incident dementia, including Alzheimer disease (AD). Prospective cohort study comprising 608 community-dwelling adults without dementia aged 70 years or older from the Einstein Aging Study with CETP genotype available. Fifteen participants with prevalent dementia were excluded, and 70 without follow-up--63 lost to follow-up and 7 new to the study--were excluded from the Cox proportional hazards model, which included 523 participants in the analysis. Standardized neuropsychological and neurological measures were administered annually from 1994-2009. Linear mixed-effects models adjusted for sex, education, race, medical comorbidities, and apolipoprotein (APOE) epsilon4 examined associations of V405 genotype with longitudinal performance on cognitive tests of episodic memory (Free and Cued Selective Reminding Test [FCSRT], possible scores of 0-48), attention (Digit Span), and psychomotor speed (Digit Symbol Substitution). The V405 genotype was the main predictor of incident dementia or AD in similarly adjusted Cox proportional hazards models with age as the time scale. Memory decline and incident dementia. Valine allele frequency was 43.5%. A total of 40 cases of incident dementia occurred during follow-up (mean [(SD], 4.3 [3.1] years). Compared with isoleucine homozygotes, valine homozygotes had significantly slower memory decline on the FCSRT (0.43 points per year of age for isoleucine; 95% confidence interval [CI], -0.58 to -0.29 vs 0.21 points per year of age for valine; 95% CI, -0.39 to -0.04; difference in linear age slope, 0.22; 95% CI, 0.02 to 0.41; P = .03) and no significant differences on the Digit Span or Digit Symbol Substitution tests. Valine homozygotes also had lower risk of dementia (hazard ratio, 0.28; 95% CI, 0.10-0.85; P = .02) and AD (hazard ratio, 0.31; 95% CI, 0.10-0.95; P = .04). This preliminary report suggests that CETP V405 valine homozygosity is associated with slower memory decline and lower incident dementia and AD risk.

Incorrect CME Quiz Question in: Association of Cholesteryl Ester Transfer Protein Genotypes With CETP Mass and Activity, Lipid Levels, and Coronary Risk

Incorrect CME Quiz Question in: Association of Cholesteryl Ester Transfer Protein Genotypes With CETP Mass and Activity, Lipid Levels, and Coronary Risk

Association of Cholesteryl Ester Transfer Protein Genotypes With CETP Mass and Activity, Lipid Levels, and Coronary Risk

The importance of the cholesteryl ester transfer protein (CETP) pathway in coronary disease is uncertain. Study of CETP genotypes can help better understand the relevance of this pathway to lipid metabolism and disease risk. To assess associations of CETP genotypes with CETP phenotypes, lipid levels, and coronary risk. Studies published between January 1970 and January 2008 were identified through computer-based and manual searches using MEDLINE, EMBASE, BIOSIS, Science Citation Index, and the Chinese National Knowledge Infrastructure Database. Previously unreported studies were sought through correspondence with investigators. Relevant studies related principally to 3 common (TaqIB [rs708272], I405V [rs5882], and -629C>A [rs1800775]) and 3 uncommon (D442G [rs2303790], -631C>A [rs1800776], and R451Q [rs1800777]) CETP polymorphisms. Information on CETP genotypes, CETP phenotypes, lipid levels, coronary disease, and study characteristics was abstracted from publications, supplied by investigators, or both. Ninety-two studies had data on CETP phenotypes, lipid levels, or both in 113,833 healthy participants, and 46 studies had data on 27,196 coronary cases and 55,338 controls. For each A allele inherited, individuals with the TaqIB polymorphism had lower mean CETP mass (-9.7%; 95% confidence interval [CI], -11.7% to -7.8%), lower mean CETP activity (-8.6%; 95% CI, -13.0% to -4.1%), higher mean high-density lipoprotein cholesterol (HDL-C) concentrations (4.5%; 95% CI, 3.8%-5.2%), and higher mean apolipoprotein A-I concentrations (2.4%; 95% CI, 1.6%-3.2%). The pattern of findings was very similar with the I405V and -629C>A polymorphisms. The combined per-allele odds ratios (ORs) for coronary disease were 0.95 (95% CI, 0.92-0.99) for TaqIB, 0.94 (95% CI, 0.89-1.00) for I405V, and 0.95 (95% CI, 0.91-1.00) for -629C>A. Three CETP genotypes that are associated with moderate inhibition of CETP activity (and, therefore, modestly higher HDL-C levels) show weakly inverse associations with coronary risk. The ORs for coronary disease were compatible with the expected reductions in risk for equivalent increases in HDL-C concentration in available prospective studies.