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Published on: September 30, 2025
Cholesteryl Ester Transfer Protein (CETP) polymorphisms affect mRNA splicing, HDL levels, and sex-dependent
Audrey C Papp1, Julia K Pinsonneault, Danxin Wang
1Program in Pharmacogenomics, Department of Pharmacology, College of Medicine, The Ohio State University, Columbus, Ohio, United States of America.
Insights
Genetic variants near the Cholesteryl Ester Transfer Protein (CETP) gene influence its splicing and impact cardiovascular disease risk in males. These CETP gene polymorphisms affect HDL-C levels and mortality, independent of HDL-C levels.
Area of Science:
- Genetics and Molecular Biology
- Cardiovascular Disease Research
- Pharmacogenomics
Background:
- Polymorphisms in the Cholesteryl Ester Transfer Protein (CETP) gene are linked to HDL levels, coronary artery disease (CAD) risk, and treatment response.
- The precise mechanisms by which these genetic variations influence CETP function and clinical outcomes remain largely undefined.
Purpose of the Study:
- To identify genetic variants that affect CETP levels and function using mRNA allelic expression and splice isoform measurements.
- To investigate the impact of identified CETP polymorphisms on cardiovascular risk factors and clinical outcomes in human populations.
Main Methods:
- Analyzed mRNA allelic expression and splice isoform levels in human liver tissues.
- Associated genetic variants (e.g., rs247616, rs5883, rs9930761) with CETP expression and splicing.
- Evaluated the clinical effects of key polymorphisms in two large cohorts (Whitehall II and INVEST-GENE).
Main Results:
- Variants upstream of the CETP gene (e.g., rs247616) were associated with allelic mRNA expression.
- A common alternatively spliced CETP isoform (Δ9) was exclusively linked to specific exon 9 (rs5883) and intron 8 (rs9930761) polymorphisms.
- These polymorphisms (rs247616, rs5883T/rs9930761C) were independently associated with increased HDL-C in males and, in one cohort, with increased incidence of MI, stroke, and mortality, with no significant effect in females.
Conclusions:
- Genetic variations in and around the CETP gene, particularly those affecting splicing, play a significant sex-dependent role in cardiovascular risk.
- The observed effects on cardiovascular outcomes appear to be mediated through mechanisms independent of circulating HDL-C levels.
- These findings elucidate a novel genetic pathway influencing cardiovascular risk through sex-specific CETP splicing.
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.
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