Skip to main content
Article thumbnail
Location of Repository

Cholesteryl Ester Transfer Protein (CETP) Polymorphisms Affect mRNA Splicing, HDL Levels, and Sex-Dependent Cardiovascular Risk

By Audrey C. Papp, Julia K. Pinsonneault, Danxin Wang, Leslie C. Newman, Yan Gong, Julie A. Johnson, Carl J. Pepine, Meena Kumari, Aroon D. Hingorani, Philippa J. Talmud, Sonia Shah, Steve E. Humphries and Wolfgang Sadee


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 (Δ9), has been shown to prevent CETP secretion in a dominant-negative manner. The Δ 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

Topics: Research Article
Publisher: Public Library of Science
OAI identifier:
Provided by: PubMed Central
Download PDF:
Sorry, we are unable to provide the full text but you may find it at the following location(s):
  • http://www.pubmedcentral.nih.g... (external link)
  • Suggested articles


    1. (1996). A
    2. (2003). A calcium antagonist vs a non-calcium antagonist hypertension treatment strategy for patients with coronary artery disease. The International VerapamilTrandolapril Study (INVEST): a randomized controlled trial.
    3. (1998). A point mutation in an intronic branch site results in aberrant splicing of COL5A1 and in Ehlers-Danlos syndrome type II in two British families.
    4. (1988). A simple salting out procedure for extracting DNA from human nucleated cells.
    5. (2003). A systematic review of association studies investigating genes coding for serotonin receptors and the serotonin transporter: I. Affective disorders.
    6. (1997). Alternative splicing of human plasma cholesteryl ester transfer protein mRNA in Caco-2 cells and its modulation by oleic acid.
    7. (1992). Alternative splicing of the mRNA encoding the human cholesteryl ester transfer protein.
    8. (2000). Association of cholesteryl ester transfer protein-TaqIB polymorphism with variations in lipoprotein subclasses and coronary heart disease risk.
    9. (2009). Association of circulating cholesteryl ester transfer protein activity with incidence of cardiovascular disease in the community.
    10. (2000). Association of TaqIB polymorphism in the cholesteryl ester transfer protein gene with plasma lipid levels in a healthy Spanish population.
    11. (2008). CETP genotype predicts increased mortality in statin-treated men with proven cardiovascular disease: an adverse pharmacogenetic interaction.
    12. (2007). CETP genotypes and HDL-cholesterol phenotypes in the HERITAGE Family Study.
    13. (2004). Cholesteryl ester transfer protein concentration is associated with progression of atherosclerosis and response to pravastatin in men with coronary artery disease (REGRESS).
    14. (2007). Cholesteryl ester transfer protein gene haplotypes, plasma high-density lipoprotein levels and the risk of coronary heart disease.
    15. (2005). Cholesteryl ester transfer protein TaqIB variant, high-density lipoprotein cholesterol levels, cardiovascular risk, and efficacy of pravastatin treatment: individual patient meta-analysis of 13,677 subjects.
    16. (2009). Common variants at 30 loci contribute to polygenic dyslipidemia.
    17. (2004). Effects of an inhibitor of cholesteryl ester transfer protein on HDL cholesterol.
    18. (2007). Effects of torcetrapib in patients at high risk for coronary events.
    19. (2008). Expression of CETP and of splice variants induces the same level of ER stress despite secretion efficiency differences.
    20. (2000). Extensive association analysis between the CETP gene and coronary heart disease phenotypes reveals several putative functional polymorphisms and geneenvironment interaction.
    21. (2009). Forty-three loci associated with plasma lipoprotein size, concentration, and cholesterol content in genome-wide analysis.
    22. (2005). Functional interaction between -629C/A, -971G/A and -1337C/T polymorphisms in the CETP gene is a major determinant of promoter activity and plasma CETP concentration in the REGRESS Study.
    23. (2009). Gene-centric association signals for lipids and apolipoproteins identified via the HumanCVD BeadChip.
    24. (2003). Haplotype analyses of cholesteryl ester transfer protein gene promoter: a clue to an unsolved mystery of TaqIB polymorphism.
    25. (2008). HDL-cholesterol levels and cardiovascular risk: acCETPing the context.
    26. (1991). Health inequalities among British civil servants: the Whitehall II study.
    27. (2004). HelixTreeH Genetics Analysis Software.
    28. (2007). ILLUMINATE Investigators. Effects of torcetrapib in patients at high risk for coronary events.
    29. (1996). Increased coronary heart disease in Japanese-American men with mutation in the cholesteryl ester transfer protein gene despite increased HDL levels.
    30. (2007). KCNMB1 genotype influences response to verapamil SR and adverse outcomes in the INternational VErapamil SR/Trandolapril STudy (INVEST).
    31. (2007). PLINK: a tool set for whole-genome association and population-based linkage analyses.
    32. (2007). Polymorphisms in human dopamine D2 receptor gene affect gene expression, splicing,andneuronalactivityduring working memory.ProcNatl
    33. (2003). Single nucleotide polymorphism genotyping using allele-specific PCR and fluorescence melting curves.
    34. (2002). Single nucleotide polymorphism haplotypes in the cholesteryl-ester transfer protein (CETP) gene and lipid phenotypes.
    35. (2003). The cholesteryl ester transfer protein Taq1B gene polymorphism predicts clinical benefit of statin therapy in patients with significant coronary artery disease.
    36. (1998). The role of a common variant of the cholesteryl ester transfer protein gene in the progression of coronary atherosclerosis.

    To submit an update or takedown request for this paper, please submit an Update/Correction/Removal Request.