Phase 3, Open-Label, Multi-Center, Double-Blind, Randomized, Parallel Group Study Efficacy and Safety of Fixed Combination Torcetrapib/Atorvastatin, Administered Once Daily (QD) Compared to Fixed Combination Ezetimibe/Simvastatin for 6 Weeks in Subjects With Dyslipidemia.

The Torcetrapib project was terminated on December 2, 2006 due to safety findings.
Cholesterol levels will be measured over six weeks in subjects being treated with two different kinds of combination cholesterol medications to see how the different treatments compare to one another.

Start Date01 Jan 2006

Sponsor / Collaborator

Pfizer Inc.

NCT00267280 / TerminatedPhase 3

A Phase 3, Open-Label, Multisite, Randomized, Parallel Group Study of the Efficacy and Safety of Fixed Combination Torcetrapib/Atorvastatin Administered Once Daily (QD) Compared to Simvastatin for 6 Weeks in Subjects With Hypercholesterolemia (A5091031)

The Torcetrapib project was terminated on December 2, 2006 due to safety findings.
Cholesterol levels will be measured over six weeks in subjects being treated with two different kinds of cholesterol medications to see how the different treatments compare to one another.

Start Date01 Jan 2006

Sponsor / Collaborator

Pfizer Inc.

100 Clinical Results associated with HDL-cholesterol x HMG-CoA reductase x CETP

100 Translational Medicine associated with HDL-cholesterol x HMG-CoA reductase x CETP

0 Patents (Medical) associated with HDL-cholesterol x HMG-CoA reductase x CETP

Literatures (Medical) associated with HDL-cholesterol x HMG-CoA reductase x CETP

01 Nov 2009·The American Journal of Human GeneticsQ1 · BIOLOGY

Gene-centric Association Signals for Lipids and Apolipoproteins Identified via the HumanCVD BeadChip

Q1 · BIOLOGY

Article

Author: Alice Stanton ; Stephen J. Newhouse ; Michael G. Marmot ; Peter Sever ; Mark Caulfield ; Philippa J. Talmud ; Toby Johnson ; Aroon D. Hingorani ; Steve E. Humphries ; Olle Melander ; Debbie A. Lawlor ; Claire Hastie ; George Davey Smith ; Juan Pablo Casas ; Christian Delles ; Ian N. Day ; Mika Kivimaki ; Shah Ebrahim ; Sonia Shah ; Fotios Drenos ; Patricia B. Munroe ; Claudio Verzilli ; Tom R. Gaunt ; Reecha Sofat ; Jacky Pallas ; Anna Dominiczak ; Nilesh J. Samani ; Kawah Li ; Sandosh Padmanabhan ; Ruth Lovering ; Tina Shah ; Denis C. Shields ; John Whittaker ; Jutta Palmen ; Santiago Rodriguez ; Meena Kumari

Blood lipids are important cardiovascular disease (CVD) risk factors with both genetic and environmental determinants. The Whitehall II study (n=5592) was genotyped with the gene-centric HumanCVD BeadChip (Illumina). We identified 195 SNPs in 16 genes/regions associated with 3 major lipid fractions and 2 apolipoprotein components at p<10(-5), with the associations being broadly concordant with prior genome-wide analysis. SNPs associated with LDL cholesterol and apolipoprotein B were located in LDLR, PCSK9, APOB, CELSR2, HMGCR, CETP, the TOMM40-APOE-C1-C2-C4 cluster, and the APOA5-A4-C3-A1 cluster; SNPs associated with HDL cholesterol and apolipoprotein AI were in CETP, LPL, LIPC, APOA5-A4-C3-A1, and ABCA1; and SNPs associated with triglycerides in GCKR, BAZ1B, MLXIPL, LPL, and APOA5-A4-C3-A1. For 48 SNPs in previously unreported loci that were significant at p<10(-4) in Whitehall II, in silico analysis including the British Women's Heart and Health Study, BRIGHT, ASCOT, and NORDIL studies (total n>12,500) revealed previously unreported associations of SH2B3 (p<2.2x10(-6)), BMPR2 (p<2.3x10(-7)), BCL3/PVRL2 (flanking APOE; p<4.4x10(-8)), and SMARCA4 (flanking LDLR; p<2.5x10(-7)) with LDL cholesterol. Common alleles in these genes explained 6.1%-14.7% of the variance in the five lipid-related traits, and individuals at opposite tails of the additive allele score exhibited substantial differences in trait levels (e.g., >1 mmol/L in LDL cholesterol [approximately 1 SD of the trait distribution]). These data suggest that multiple common alleles of small effect can make important contributions to individual differences in blood lipids potentially relevant to the assessment of CVD risk. These genes provide further insights into lipid metabolism and the likely effects of modifying the encoded targets therapeutically.

01 Dec 2008·Pharmacogenetics and GenomicsQ4 · MEDICINE

Pharmacological effects of lipid-lowering drugs recapitulate with a larger amplitude the phenotypic effects of common variants within their target genes

Q4 · MEDICINE

Article

Author: Walker, Max C. ; Matthews, Paul M. ; Vollenweider, Peter ; Townsend, Ray ; Waterworth, Dawn M. ; Knouff, Christopher W. ; Song, Kijoung ; Yuan, Xin ; Waeber, Gerard ; Mooser, Vincent ; Lim, Noha

BACKGROUNDA major expectation underlying the search for novel susceptibility genes for common diseases using genome-wide association studies (GWAS) is that these discoveries will lead to new drug targets. This claim has not been verified yet. Here, we tested the hypothesis that common single nucleotide polymorphisms (SNPs) within drug target genes are associated with the corresponding phenotypes, using a population-based GWAS dataset and lipid-lowering drugs as a test case.METHODSWe examined the association between 36 genotyped and 193 imputed SNPs within four lipid-lowering drug target genes (HMGCR, PPARA, HM74A/GPR109A and CETP) and four non-lipid drug target genes (ACE, AGTR1, P2RY12, and ATP4B) and lipid phenotypes, blood pressure, and coronary artery disease in 5635 adult participants of the Lausanne, Switzerland, CoLaus study, genotyped using the Affymetrix 500K SNP chip technology.RESULTSThe phenotypes associated with SNPs within drug target genes recapitulated to a certain extent the pharmacological effects of the drug. The amplitude of the SNP effect was about 10 times smaller than the pharmacological effect of the corresponding drug. In particular, several CETP SNPs were associated with an elevation in HDL-cholesterol levels, yet a lower diastolic blood pressure, providing evidence that the blood pressure elevation induced by the CETP inhibitor torcetrapib is more likely compound specific than class specific.CONCLUSIONPharmacological modulation of lipid-lowering drug targets recapitulates, and markedly amplifies, the phenotypic effects of common SNPs within these target genes. This data provides indirect evidence that, with certain limitations, large-scale GWAS represent a new tool for the discovery and the development of innovative drugs.

16 Jun 2004·JAMAQ1 · MEDICINE

Pharmacogenetic Study of Statin Therapy and Cholesterol Reduction

Q1 · MEDICINE

Article

Author: Cook, Nancy R. ; Subrahmanyan, Lakshman ; Chasman, Daniel I. ; Posada, David ; Ridker, Paul M. ; Stanton, Vincent P. Jr.

CONTEXTPolymorphisms in genes involved in cholesterol synthesis, absorption, and transport may affect statin efficacy.OBJECTIVETo evaluate systematically whether genetic variation influences response to pravastatin therapy.DESIGN, SETTING, AND POPULATIONThe DNA of 1536 individuals treated with pravastatin, 40 mg/d, was analyzed for 148 single-nucleotide polymorphisms (SNPs) within 10 candidate genes related to lipid metabolism. Variation within these genes was then examined for associations with changes in lipid levels observed with pravastatin therapy during a 24-week period.MAIN OUTCOME MEASUREChanges in lipid levels in response to pravastatin therapy.RESULTSTwo common and tightly linked SNPs (linkage disequilibrium r2 = 0.90; heterozygote prevalence = 6.7% for both) were significantly associated with reduced efficacy of pravastatin therapy. Both of these SNPs were in the gene coding for 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, the target enzyme that is inhibited by pravastatin. For example, compared with individuals homozygous for the major allele of one of the SNPs, individuals with a single copy of the minor allele had a 22% smaller reduction in total cholesterol (-32.8 vs -42.0 mg/dL [-0.85 vs -1.09 mmol/L]; P =.001; absolute difference, 9.2 mg/dL [95% confidence interval [CI], 3.8-14.6 mg/dL]) and a 19% smaller reduction in low-density lipoprotein (LDL) cholesterol (-27.7 vs -34.1 mg/dL [-0.72 vs -0.88 mmol/L]; P =.005; absolute difference, 6.4 mg/dL [95% CI, 2.2-10.6 mg/dL]). The association for total cholesterol reduction persisted even after adjusting for multiple tests on all 33 SNPs evaluated in the HMG-CoA reductase gene as well as for all 148 SNPs evaluated was similar in magnitude and direction among men and women and was present in the ethnically diverse total cohort as well as in the majority subgroup of white participants. No association for either SNP was observed for the change in high-density lipoprotein (HDL) cholesterol (P>.80) and neither was associated with baseline lipid levels among those actively treated or among those who did not receive the drug. Among the remaining genes, less robust associations were found for squalene synthase and change in total cholesterol, apolipoprotein E and change in LDL cholesterol, and cholesteryl ester transfer protein and change in HDL cholesterol, although none of these met our conservative criteria for purely pharmacogenetic effects.CONCLUSIONIndividuals heterozygous for a genetic variant in the HMG-CoA reductase gene may experience significantly smaller reductions in cholesterol when treated with pravastatin.

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