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

Papp, AC; Pinsonneault, JK; Wang, D; Newman, LC; Gong, Y; Johnson, JA; Pepine, CJ; ... Sadee, W; + view all (2012) Cholesteryl ester transfer protein (CETP) polymorphisms affect mRNA splicing, HDL levels, and sex-dependent cardiovascular risk. PLoS ONE , 7 (3) , Article e31930. 10.1371/journal.pone.0031930. Green open access

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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.

Type: Article
Title: Cholesteryl ester transfer protein (CETP) polymorphisms affect mRNA splicing, HDL levels, and sex-dependent cardiovascular risk
Open access status: An open access version is available from UCL Discovery
DOI: 10.1371/journal.pone.0031930
Publisher version: http://dx.doi.org/10.1371/journal.pone.0031930
Language: English
Additional information: © 2012 Papp et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. This study was in part supported by National Institutes of Health (NIH) grants from the General Medical Sciences GM61390, U01 GM092655 to WS. The work on Whitehall II was supported by the British Heart Foundation (BHF) PG/07/133/24260, RG/08/008, SP/07/007/23671 and a Senior Fellowship to ADH (FS/2005/125). SEH is a BHF Chairholder. The WH-II study has been supported by grants from the Medical Research Council; British Heart Foundation; Health and Safety Executive; Department of Health; National Institute on Aging (AG13196), US, NIH; Agency for Health Care Policy Research (HS06516); and the John D. and Catherine T. MacArthur Foundation Research Networks on Successful Midlife Development and Socio-economic Status and Health). PJT and SEH are funded by the British Heart Foundation (RG008/08). ADH is a British Heart Foundation Senior Fellow (FS/2005/125). INVEST-GENES was funded by NIH grants HL074730, HL69758, HL077113, GM074492 and RR017568. CP and JAJ recieved a grant from Abbott Pharmaceuticals and the Florida Opportunity Fund. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The authors have read the journal's policy and have the following conflicts: CP and JAJ have received funding from Abbott Pharmaceuticals. This does not alter the authors' adherence to all PLoS ONE policies on sharing data and materials.
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Cardiovascular Science
URI: https://discovery.ucl.ac.uk/id/eprint/1377012
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