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Related Experiment Videos

Novel variants in human and monkey CETP.

David B Lloyd1, Jennifer M Reynolds, Melissa T Cronan

  • 1Department of Pharmacogenomics, Pfizer Global Research and Development, Eastern Point Road, MS8118D-3069, Groton, CT 06340, USA.

Biochimica Et Biophysica Acta
|October 18, 2005
PubMed
Summary

Cholesteryl ester transfer protein (CETP) variations impact HDL-C levels and heart disease risk. Novel variants were identified, with some affecting protein function and secretion, influencing drug efficacy.

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Area of Science:

  • Genetics
  • Cardiovascular Disease Research
  • Biochemistry

Background:

  • Cholesteryl ester transfer protein (CETP) genetic variations are linked to high-density lipoprotein cholesterol (HDL-C) levels and cardiovascular disease (CVD) risk.
  • Understanding CETP variation is crucial for developing effective CVD treatments.

Purpose of the Study:

  • To characterize novel genetic variations in CETP.
  • To investigate the functional impact of identified CETP variants on protein activity and secretion.
  • To assess CETP variation across species and its association with HDL-C levels.

Main Methods:

  • Resequencing of CETP promoter and exonic DNA in 189 individuals with extreme HDL-C or age.
  • Expression and functional analysis of novel CETP variants (V-12D, Y361C, R137W).

Related Experiment Videos

  • In vitro assessment of Torcetrapib inhibition on wild-type and variant CETP.
  • Resequencing and genotyping of CETP in cynomolgus monkeys.

    • Main Results:

    • Two novel human amino acid variants (V-12D, Y361C) and one previously unstudied variant (R137W) were identified.
    • V-12D showed no secretion or activity; C361 and W137 had reduced secretion but retained cholesteryl ester transfer activity.
    • Torcetrapib uniformly inhibited wild-type, W137, and C361 CETP.
    • Monkey CETP analysis revealed intronic and silent SNPs, plus two variable amino acids; no significant association with HDL-C was found.

    Conclusions:

    • Novel CETP variants exhibit altered functional properties, impacting HDL-C metabolism.
    • The identified variants do not uniformly affect Torcetrapib's inhibitory action.
    • Cross-species CETP variation analysis provides insights into evolutionary conservation and functional constraints.