Cholesteryl ester transfer protein (CETP) polymorphisms affect mRNA splicing, HDL levels, and sex-dependent cardiovascular risk

Papp, Audrey C., Pinsonneault, Julia K., Wang, Danxin, Newman, Leslie C., Gong, Yan, Johnson, Julie A., Pepine, Carl J., Kumari, Meena, Hingorani, Aroon D., Talmud, Philippa J., Shah, Sonia, Humphries, Steve E. and Sadee, Wolfgang (2012) Cholesteryl ester transfer protein (CETP) polymorphisms affect mRNA splicing, HDL levels, and sex-dependent cardiovascular risk. PLoS ONE, 7 3: e31930.1-e31930.9. doi:10.1371/journal.pone.0031930

Author Papp, Audrey C.
Pinsonneault, Julia K.
Wang, Danxin
Newman, Leslie C.
Gong, Yan
Johnson, Julie A.
Pepine, Carl J.
Kumari, Meena
Hingorani, Aroon D.
Talmud, Philippa J.
Shah, Sonia
Humphries, Steve E.
Sadee, Wolfgang
Title Cholesteryl ester transfer protein (CETP) polymorphisms affect mRNA splicing, HDL levels, and sex-dependent cardiovascular risk
Journal name PLoS ONE   Check publisher's open access policy
ISSN 1932-6203
Publication date 2012-03-05
Year available 2012
Sub-type Article (original research)
DOI 10.1371/journal.pone.0031930
Open Access Status DOI
Volume 7
Issue 3
Start page e31930.1
End page e31930.9
Total pages 9
Place of publication San Francisco United States
Publisher Public Library of Science (PLoS)
Language eng
Formatted 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 (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.

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.
Keyword Multidisciplinary Sciences
Science & Technology - Other Topics
Q-Index Code C1
Q-Index Status Provisional Code
Grant ID GM61390
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: Queensland Brain Institute Publications
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Citation counts: TR Web of Science Citation Count  Cited 31 times in Thomson Reuters Web of Science Article | Citations
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