Related Experiment Videos

CETP genotype predicts increased mortality in statin-treated men with proven cardiovascular disease: an adverse

Jakub J Regieli1, J Wouter Jukema, Diederick E Grobbee

  • 1Juliuscenter for Health Sciences and Primary Care, University Medical Center Utrecht (UMCU), Utrecht, The Netherlands.

European Heart Journal
|October 30, 2008
PubMed

Insights

Genetic variations linked to lower cholesteryl ester transfer protein (CETP) levels in patients with coronary artery disease (CAD) are associated with increased long-term mortality despite statin therapy. This highlights the importance of CETP genotype in cardiovascular risk management.

Area of Science:

  • Pharmacogenetics
  • Cardiovascular Medicine
  • Lipid Metabolism

Background:

  • Inhibition of cholesteryl ester transfer protein (CETP) raises HDL-cholesterol but may increase mortality when combined with statins.
  • Previous research suggests patients with intrinsically low CETP levels (TaqIB-B2 allele carriers) may experience reduced statin benefits.

Purpose of the Study:

  • To test the pharmacogenetic hypothesis that CETP genotype influences long-term outcomes in statin-treated coronary artery disease (CAD) patients.
  • To investigate the association between CETP genetic variation and mortality risk over a 10-year period.

Main Methods:

  • A 10-year follow-up analysis of 812 CAD patients from the REGRESS cohort, treated with statins.
  • Analysis of TaqIB-B2 allele carriers for CETP levels, HDL-cholesterol, and mortality endpoints (atherosclerotic disease death, ischemic heart disease death, all-cause mortality).
  • Haplotype-effects analysis to identify genetic risk factors.

Main Results:

  • Carriers of the TaqIB-B2 allele had significantly lower CETP levels and higher HDL-cholesterol.
  • Each copy of the B2 allele was associated with increased hazard ratios for atherosclerotic disease death (1.59), ischemic heart disease death (1.53), and all-cause mortality (1.30).
  • A specific risk-haplotype was identified with strong association to these adverse outcomes.

Conclusions:

  • In male CAD patients treated with statins, genetic variations associated with low CETP levels correlate with increased 10-year mortality.
  • Statin efficacy in reducing cardiovascular risk appears dependent on CETP genotype and plasma levels.
  • These findings warrant consideration for CETP genotype when administering CETP inhibition therapies to CAD patients.
Abstract

Related Concept Videos

Pharmacogenetic Phenotypes: Alterations in Pharmacokinetics, Drug Targets and Biologic Milieu01:29

Pharmacogenetic Phenotypes: Alterations in Pharmacokinetics, Drug Targets and Biologic Milieu

Genetic variations significantly influence drug response through pharmacokinetics, receptor interactions, and biologic milieu modifications. Pharmacokinetic alterations impact drug metabolism and clearance, affecting efficacy and toxicity. Variants in drug-metabolizing enzymes, such as CYP2C9 and CYP2C19, alter drug activation and elimination. For example, CYP2C9 loss-of-function variants require lower warfarin doses to prevent excessive bleeding, while CYP2C19 variants reduce clopidogrel...
Pharmacogenetics of Phase I Enzymes: Cytochrome P450 Isozymes01:28

Pharmacogenetics of Phase I Enzymes: Cytochrome P450 Isozymes

Cytochrome P450 (CYP450) enzymes are a superfamily of heme-containing monooxygenases that play a pivotal role in Phase I drug metabolism by catalyzing oxidation and reduction reactions.These enzymes transform lipophilic xenobiotics into more hydrophilic metabolites, facilitating subsequent Phase II conjugation and eventual excretion. The CYP450 family is classified into families (e.g., CYP1–CYP3) and subfamilies (e.g., CYP2A, CYP2C), based on amino acid sequence homology.CYP450 isoenzymes,...
Pharmacogenetics of Drug Metabolism: Overview01:27

Pharmacogenetics of Drug Metabolism: Overview

Genetic polymorphism in drug metabolism is crucial to the inter-individual variability observed in drug responses. Drug metabolism primarily involves the chemical modification of drugs and other xenobiotics to enhance their elimination by increasing their polarity. Two main classes of enzymes mediate this biotransformation process: Phase I enzymes, primarily cytochrome P450s, catalyze oxidation and reduction reactions, while other enzymes, such as esterases, mediate hydrolysis, and Phase II...
Pharmacogenomics: Identification of New Drug Targets01:29

Pharmacogenomics: Identification of New Drug Targets

Advances in genomics have profoundly influenced drug discovery by increasing both the speed and accuracy of pharmaceutical development. Pharmacogenomics, which examines how genetic variation influences drug response, facilitates the identification of novel therapeutic targets and enables patient stratification for personalized treatment. These strategies contribute to improved drug efficacy, minimized adverse effects, and more efficient clinical trial design.Mapping genetic differences...
Pharmacogenetics of Drug Targets: β₂-Adrenergic Receptors, Apo E, Thymidylate Synthase01:11

Pharmacogenetics of Drug Targets: β₂-Adrenergic Receptors, Apo E, Thymidylate Synthase

Genetic polymorphisms in drug targets have emerged as critical determinants of interindividual variability in drug response and toxicity. Pharmacogenomic investigations increasingly focus on identifying these variations to personalize and optimize therapeutic interventions. A drug target may be a receptor, enzyme, or signaling protein involved in pharmacologic responses or disease-related pathways. While early pharmacogenetic studies focused primarily on drug metabolism, current research...
Pharmacogenetics of Drug Transporters: P-Glycoprotein and Solute Carrier Transporters01:16

Pharmacogenetics of Drug Transporters: P-Glycoprotein and Solute Carrier Transporters

The pharmacogenetics of drug transporters is increasingly recognized as a critical factor influencing interindividual variability in drug absorption, distribution, and elimination. These membrane-bound proteins regulate drugs' movement across cellular barriers by actively pumping them out (efflux) or facilitating their uptake (influx). Among the major transporter families, ATP-binding cassette (ABC) and solute carrier (SLC) transporters play particularly prominent roles. Genetic polymorphisms...