Common cholesteryl ester transfer protein gene variation related to high-density lipoprotein cholesterol is not associated with decreased coronary heart disease risk after a 10-year follow-up in a Mediterranean cohort: Modulation by alcohol consumption

Objective: Plasma total HDL (high-density lipoprotein) is a heterogeneous mix of many protein-based subspecies whose functions and associations with coronary heart disease vary. We hypothesize that increasing HDL by CETP (cholesteryl ester transfer protein) inhibition failed to reduce cardiovascular disease risk, in part, because it increased dysfunctional subspecies associated with higher risk such as HDL that contains apoC3. Approach and Results: We studied participants in 2 randomized, double-blind, placebo-controlled trials of a CETP inhibitor on a background of atorvastatin treatment: ACCENTUATE (130 mg evacetrapib; n=126) and ILLUMINATE (60 mg torcetrapib; n=80). We measured the concentration of apoA1 in total plasma and 17 protein-based HDL subspecies at baseline and 3 months. Both CETP inhibitors increased apoA1 in HDL that contains apoC3 the most of all HDL subspecies (median placebo-adjusted percent increase: evacetrapib 99% and torcetrapib 50%). They also increased apoA1 in other HDL subspecies associated with higher coronary heart disease risk such as those involved in inflammation (α-2-macroglobulin and complement C3) or hemostasis (plasminogen), and in HDL that contains both apoE and apoC3, a complex subspecies associated with higher coronary heart disease risk. ApoA1 in HDL that contains apoC1, associated with lower risk, increased 71% and 40%, respectively. Only HDL that contains apoL1 showed no response to either drug. Conclusions: CETP inhibitors evacetrapib and torcetrapib increase apoA1 in HDL subspecies that contain apoC3 and other HDL subspecies associated with higher risk of coronary heart disease. Subspecies-specific effects shift HDL subspecies concentrations toward a profile associated with higher risk, which may contribute to lack of clinical benefit from raising HDL by pharmaceutical CETP inhibition.

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Interaction Effects of High-Density Lipoprotein Metabolism Gene Variation and Alcohol Consumption on Coronary Heart Disease Risk: The Atherosclerosis Risk in Communities Study

Journal of Studies on Alcohol and Drugs ◽

10.15288/jsad.2007.68.485 ◽

2007 ◽

Vol 68 (4) ◽

pp. 485-492 ◽

Cited By ~ 10

Author(s):

Kelly Volcik ◽

Christie M. Ballantyne ◽

Henry J. Pownall ◽

A. Richey Sharrett ◽

Eric Boerwinkle

Keyword(s):

Coronary Heart Disease ◽

Heart Disease ◽

Disease Risk ◽

Lipoprotein Metabolism ◽

Density Lipoprotein ◽

Atherosclerosis Risk In Communities ◽

Gene Variation ◽

Atherosclerosis Risk ◽

Heart Disease Risk ◽

Metabolism Gene

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Isolation of plasma small-dense low-density lipoprotein using a simple air-driven ultracentrifuge and quantification using immunassay of apolipoprotein B

Clinical Chemistry and Laboratory Medicine (CCLM) ◽

10.1515/cclm.2004.007 ◽

2004 ◽

Vol 42 (1) ◽

Cited By ~ 2

Author(s):

Valentine C. Menys ◽

Yifen Liu ◽

Michael I. Mackness ◽

See Kwok ◽

Muriel J. Caslake ◽

...

Keyword(s):

Coronary Heart Disease ◽

Heart Disease ◽

Coronary Heart Disease Risk ◽

Apolipoprotein B ◽

Disease Risk ◽

Low Density Lipoprotein ◽

Density Lipoprotein ◽

Low Density ◽

Heart Disease Risk

AbstractSmall-dense low-density lipoprotein (SD-LDL) is associated with coronary heart disease risk. Current methods for its quantification are expensive, complex and time-consuming. Plasma was adjusted to a density (D) of 1.044 g/ml in a volume of 0.18 ml and centrifuged in a Beckman Airfuge at 160 000×

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