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Cholesteryl ester transfer protein polymorphism (TaqIB) associates with risk in postinfarction patients with high C-reactive protein and high-density lipoprotein cholesterol levels.

ABSTRACT: To investigate the roles of inflammation and a cholesteryl ester transfer protein (CETP) polymorphism potentially related to recent findings demonstrating coronary risk with increasing high-density lipoprotein cholesterol (HDL-C) level.A novel graphical exploratory data analysis tool allowed the examination of coronary risk in postinfarction patients relating to HDL-C and C-reactive protein levels. Results demonstrated a high-risk subgroup, defined by high HDL-C and C-reactive protein levels, exhibiting larger HDL particles and lower lipoprotein-associated phospholipaseA(2) levels than lower-risk patients. Subgroup CETP-associated risk was probed using a functional CETP polymorphism (TaqIB, rs708272). In the high-risk subgroup, multivariable modeling revealed greater risk for B2 allele carriers (less CETP activity) versus B1 homozygotes (hazard ratio, 2.41; 95% CI, 1.04 to 5.60; P=0.04). Within the high-risk subgroup, B2 allele carriers had higher serum amyloid A levels than B1 homozygotes. Evidence also demonstrates that CETP genotypic differences in HDL subfraction distributions regarding non-HDL-C and lipoprotein-associated phospholipaseA(2) may potentially relate to impaired HDL remodeling.Postinfarction patients with high HDL-C and C-reactive protein levels demonstrate increased risk for recurrent events. Future studies should aim at characterizing altered HDL particles from such patients and at elucidating the mechanistic details related to inflammation and HDL particle remodeling. Such patients should be considered in drug trials involving an increase in HDL-C level.

SUBMITTER: Corsetti JP

PROVIDER: S-EPMC3051187 | biostudies-literature | 2010 Aug

REPOSITORIES: biostudies-literature

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Cholesteryl ester transfer protein polymorphism (TaqIB) associates with risk in postinfarction patients with high C-reactive protein and high-density lipoprotein cholesterol levels.

Corsetti James P JP Ryan Dan D Rainwater David L DL Moss Arthur J AJ Zareba Wojciech W Sparks Charles E CE

Arteriosclerosis, thrombosis, and vascular biology 20100520 8

<h4>Objective</h4>To investigate the roles of inflammation and a cholesteryl ester transfer protein (CETP) polymorphism potentially related to recent findings demonstrating coronary risk with increasing high-density lipoprotein cholesterol (HDL-C) level.<h4>Methods and results</h4>A novel graphical exploratory data analysis tool allowed the examination of coronary risk in postinfarction patients relating to HDL-C and C-reactive protein levels. Results demonstrated a high-risk subgroup, defined b ...[more]

PMID: 20489166

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Project description:Cholesteryl ester transfer protein (CETP) inhibition reduces vascular event risk, but confusion surrounds its effects on low-density lipoprotein (LDL) cholesterol. Here, we clarify associations of genetic inhibition of CETP on detailed lipoprotein measures and compare those to genetic inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR). We used an allele associated with lower CETP expression (rs247617) to mimic CETP inhibition and an allele associated with lower HMGCR expression (rs12916) to mimic the well-known effects of statins for comparison. The study consists of 65,427 participants of European ancestries with detailed lipoprotein subclass profiling from nuclear magnetic resonance spectroscopy. Genetic associations were scaled to 10% reduction in relative risk of coronary heart disease (CHD). We also examined observational associations of the lipoprotein subclass measures with risk of incident CHD in 3 population-based cohorts totalling 616 incident cases and 13,564 controls during 8-year follow-up. Genetic inhibition of CETP and HMGCR resulted in near-identical associations with LDL cholesterol concentration estimated by the Friedewald equation. Inhibition of HMGCR had relatively consistent associations on lower cholesterol concentrations across all apolipoprotein B-containing lipoproteins. In contrast, the associations of the inhibition of CETP were stronger on lower remnant and very-low-density lipoprotein (VLDL) cholesterol, but there were no associations on cholesterol concentrations in LDL defined by particle size (diameter 18-26 nm) (-0.02 SD LDL defined by particle size; 95% CI: -0.10 to 0.05 for CETP versus -0.24 SD, 95% CI -0.30 to -0.18 for HMGCR). Inhibition of CETP was strongly associated with lower proportion of triglycerides in all high-density lipoprotein (HDL) particles. In observational analyses, a higher triglyceride composition within HDL subclasses was associated with higher risk of CHD, independently of total cholesterol and triglycerides (strongest hazard ratio per 1 SD higher triglyceride composition in very large HDL 1.35; 95% CI: 1.18-1.54). In conclusion, CETP inhibition does not appear to affect size-specific LDL cholesterol but is likely to lower CHD risk by lowering concentrations of other atherogenic, apolipoprotein B-containing lipoproteins (such as remnant and VLDLs). Inhibition of CETP also lowers triglyceride composition in HDL particles, a phenomenon reflecting combined effects of circulating HDL, triglycerides, and apolipoprotein B-containing particles and is associated with a lower CHD risk in observational analyses. Our results reveal that conventional composite lipid assays may mask heterogeneous effects of emerging lipid-altering therapies.

Dataset Information

Cholesteryl ester transfer protein polymorphism (TaqIB) associates with risk in postinfarction patients with high C-reactive protein and high-density lipoprotein cholesterol levels.

Publications

Cholesteryl ester transfer protein polymorphism (TaqIB) associates with risk in postinfarction patients with high C-reactive protein and high-density lipoprotein cholesterol levels.

Similar Datasets

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