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Cholesteryl Ester Transfer Protein (CETP) polymorphisms affect mRNA splicing, HDL levels, and sex-dependent cardiovascular risk.

ABSTRACT: 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 (?9), has been shown to prevent CETP secretion in a dominant-negative manner. The ? 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.

SUBMITTER: Papp AC

PROVIDER: S-EPMC3293889 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Cholesteryl Ester Transfer Protein (CETP) polymorphisms affect mRNA splicing, HDL levels, and sex-dependent cardiovascular risk.

Papp Audrey C AC Pinsonneault Julia K JK Wang Danxin D Newman Leslie C LC Gong Yan Y Johnson Julie A JA Pepine Carl J CJ Kumari Meena M Hingorani Aroon D AD Talmud Philippa J PJ Shah Sonia S Humphries Steve E SE Sadee Wolfgang W

PloS one 20120305 3

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 ...[more]

PMID: 22403620

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Project description:In almost 30 years since the introduction of HMG-CoA reductase inhibitors (statins), no other class of lipid modulators has entered the market. Elevation of high-density lipoprotein-cholesterol (HDL-C) via inhibiting cholesteryl ester transfer protein (CETP) is an attractive strategy for reducing the risk of cardiovascular events in high-risk patients. Transfer of triglyceride and cholesteryl ester (CE) between lipoproteins is mediated by CETP; thus inhibition of this pathway can increase the concentration of HDL-C. Torcetrapib was the first CETP inhibitor evaluated in phase III clinical trials. Because of off-target effects, torcetrapib raised blood pressure and increased the concentration of serum aldosterone, leading to higher cardiovascular events and mortality. Torcetrapib showed positive effects on cardiovascular risk especially in patients with a greater increase in HDL-C and apolipoprotein A-1 (apoA-1) levels. The phase III clinical trial of dalcetrapib, the second CETP inhibitor that has entered clinical development, was terminated because of ineffectiveness. Dalcetrapib is a CETP modulator that elevated HDL-C levels but did not reduce the concentration of low-density lipoprotein cholesterol (LDL-C). Both heterotypic and homotypic CE transfer between lipoproteins are mediated by some CETP inhibitors, including torcetrapib, anacetrapib, and evacetrapib, while dalcetrapib only affects the heterotypic CE transfer. Dalcetrapib has a chemical structure that is distinct from other CETP inhibitors, with a smaller molecular weight and a lack of trifluoride moieties. Moreover, dalcetrapib is a pro-drug that must be hydrolyzed to a pharmacologically active thiol form. Two other CETP inhibitors, anacetrapib and evacetrapib, are currently undergoing evaluation in phase III clinical trials. Both molecules have shown beneficial effects by increasing HDL-C and decreasing LDL-C concentration. The success of anacetrapib and evacetrapib remains to be confirmed upon the completion of phase III clinical trials in 2017 and 2015, respectively. Generally, the concentration of HDL-C has been considered a biomarker for the activity of CETP inhibitors. However, it is not clear whether a fundamental relationship exists between HDL-C levels and the risk of coronary artery diseases. The most crucial role for HDL is cholesterol efflux capacity in which HDL can reverse transport cholesterol from foam cells in atherosclerotic plaques. In view of the heterogeneity in HDL particle size, charge, and composition, the mere concentration of HDL-C may not be a good surrogate marker for HDL functionality. Recent clinical studies have reported that increased HDL functionality inversely correlates with the development of atherosclerotic plaque. Future development of CETP inhibitors may therefore benefit from the use of biomarkers of HDL functionality.

Project description:ObjectivePlasma total HDL (high-density lipoprotein) is a heterogeneous mix of many protein-based subspecies whose functions and associations with coronary heart disease vary. We hypothesize that increasing HDL by CETP (cholesteryl ester transfer protein) inhibition failed to reduce cardiovascular disease risk, in part, because it increased dysfunctional subspecies associated with higher risk such as HDL that contains apoC3. Approach and Results: We studied participants in 2 randomized, double-blind, placebo-controlled trials of a CETP inhibitor on a background of atorvastatin treatment: ACCENTUATE (The Addition of Evacetrapib to Atorvastatin Compared to Placebo, High Intensity Atorvastatin, and Atorvastatin With Ezetimibe to Evaluate LDL-C Lowering in Patients With Primary Hyperlipidemia; 130 mg evacetrapib; n=126) and ILLUMINATE (Phase 3 Multi Center, Double Blind, Randomized, Parallel Group Evaluation of the Fixed Combination Torcetrapib/Atorvastatin, Administered Orally, Once Daily [Qd], Compared With Atorvastatin Alone, on the Occurrence of Major Cardiovascular Events in Subjects With Coronary Heart Disease or Risk Equivalents; 60 mg torcetrapib; n=80). We measured the concentration of apoA1 in total plasma and 17 protein-based HDL subspecies at baseline and 3 months. Both CETP inhibitors increased apoA1 in HDL that contains apoC3 the most of all HDL subspecies (median placebo-adjusted percent increase: evacetrapib 99% and torcetrapib 50%). They also increased apoA1 in other HDL subspecies associated with higher coronary heart disease risk such as those involved in inflammation (α-2-macroglobulin and complement C3) or hemostasis (plasminogen), and in HDL that contains both apoE and apoC3, a complex subspecies associated with higher coronary heart disease risk. ApoA1 in HDL that contains apoC1, associated with lower risk, increased 71% and 40%, respectively. Only HDL that contains apoL1 showed no response to either drug.ConclusionsCETP inhibitors evacetrapib and torcetrapib increase apoA1 in HDL subspecies that contain apoC3 and other HDL subspecies associated with higher risk of coronary heart disease. Subspecies-specific effects shift HDL subspecies concentrations toward a profile associated with higher risk, which may contribute to lack of clinical benefit from raising HDL by pharmaceutical CETP inhibition.

Project description:Although Cholesteryl Ester Transfer Protein (CETP) mediates the transfer of cholesteryl esters and triglycerides between lipoprotein particles and thus plays a crucial role in reverse cholesterol transport, the association of variations in the CETP gene with acute myocardial infarction (MI) remains unclear. In this study we examined whether common genetic variation in the CETP gene is related to early-onset non-fatal MI risk in a population-based case-control study from western Washington State. Genotyping for the CETP -2708 G/A, -971 A/G, -629 A/C, Intron-I TaqI G/A and exon-14 A/G (I405V) SNPs was performed in 578 cases with first acute non-fatal MI and in 666 demographically similar controls, free of clinical cardiovascular disease, identified randomly from the community. In-person interviews and non-fasting blood specimens provided data on coronary heart disease risk factors. In men, there was little evidence for an association between single SNPs and MI risk, but in women the age- and race-adjusted OR was found to be significant in 4 out of the 5 CETP single variants. Haplotype analysis revealed two haplotypes associated with MI risk among men. As compared to men homozygous for the most common haplotype D (-2708 G, -971 G, -629 C, TaqI G and exon-14 A), the fully-adjusted multiplicative model identified haplotype G (-2708 G, -971 A, -629 A, TaqI G and exon-14 G) was associated with a 4.0-6.0-fold increased risk of MI for each additional copy; [95%CI 2.4-14.8] and haplotype B (-2708 G, -971 G, -629 A, TaqI A and exon-14 A) showed a significant decreased risk for early onset MI [OR = 0.18; 95%CI 0.04 - 0.75]. An evolutionary-based haplotype analysis indicated that the two haplotypes associated with the MI risk are most evolutionarily divergent from the other haplotypes. Variation at the CETP gene locus is associated with the risk of early-onset non-fatal MI. This association was found to be independent of HDL-C levels. These data and the sex-specific findings require confirmation in other populations.

Project description:BACKGROUND:Cholesteryl ester transfer protein (CETP) inhibitors raise high-density lipoprotein (HDL) cholesterol, but torcetrapib, the first-in-class inhibitor tested in a large outcome trial, caused an unexpected blood pressure elevation and increased cardiovascular events. Whether the hypertensive effect resulted from CETP inhibition or an off-target action of torcetrapib has been debated. We hypothesized that common single-nucleotide polymorphisms in the CETP gene could help distinguish mechanism-based from off-target actions of CETP inhibitors to inform on the validity of CETP as a therapeutic target. METHODS AND RESULTS:We compared the effect of CETP single-nucleotide polymorphisms and torcetrapib treatment on lipid fractions, blood pressure, and electrolytes in up to 67 687 individuals from genetic studies and 17 911 from randomized trials. CETP single-nucleotide polymorphisms and torcetrapib treatment reduced CETP activity and had a directionally concordant effect on 8 lipid and lipoprotein traits (total, low-density lipoprotein, and HDL cholesterol; HDL2; HDL3; apolipoproteins A-I and B; and triglycerides), with the genetic effect on HDL cholesterol (0.13 mmol/L, 95% confidence interval [CI] 0.11 to 0.14 mmol/L) being consistent with that expected of a 10-mg dose of torcetrapib (0.13 mmol/L, 95% CI 0.10 to 0.15). In trials, 60 mg of torcetrapib elevated systolic and diastolic blood pressure by 4.47 mm Hg (95% CI 4.10 to 4.84 mm Hg) and 2.08 mm Hg (95% CI 1.84 to 2.31 mm Hg), respectively. However, the effect of CETP single-nucleotide polymorphisms on systolic blood pressure (0.16 mm Hg, 95% CI -0.28 to 0.60 mm Hg) and diastolic blood pressure (-0.04 mm Hg, 95% CI -0.36 to 0.28 mm Hg) was null and significantly different from that expected of 10 mg of torcetrapib. CONCLUSIONS:Discordance in the effects of CETP single-nucleotide polymorphisms and torcetrapib treatment on blood pressure despite the concordant effects on lipids indicates the hypertensive action of torcetrapib is unlikely to be due to CETP inhibition or shared by chemically dissimilar CETP inhibitors. Genetic studies could find a place in drug-development programs as a new source of randomized evidence for drug-target validation in humans.

Dataset Information

Cholesteryl Ester Transfer Protein (CETP) polymorphisms affect mRNA splicing, HDL levels, and sex-dependent cardiovascular risk.

Publications

Cholesteryl Ester Transfer Protein (CETP) polymorphisms affect mRNA splicing, HDL levels, and sex-dependent cardiovascular risk.

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