Dataset Information

Genetic and observational evidence: No independent role for cholesterol efflux over static high-density lipoprotein concentration measures in coronary heart disease risk assessment.

ABSTRACT:

Background

Observational findings for high-density lipoprotein (HDL)-mediated cholesterol efflux capacity (HDL-CEC) and coronary heart disease (CHD) appear inconsistent, and knowledge of the genetic architecture of HDL-CEC is limited.

Objectives

A large-scale observational study on the associations of HDL-CEC and other HDL-related measures with CHD and the largest genome-wide association study (GWAS) of HDL-CEC.

Participants/methods

Six independent cohorts were included with follow-up data for 14,438 participants to investigate the associations of HDL-related measures with incident CHD (1,570 events). The GWAS of HDL-CEC was carried out in 20,372 participants.

Results

HDL-CEC did not associate with CHD when adjusted for traditional risk factors and HDL cholesterol (HDL-C). In contradiction, almost all HDL-related concentration measures associated consistently with CHD after corresponding adjustments. There were no genetic loci associated with HDL-CEC independent of HDL-C and triglycerides.

Conclusion

HDL-CEC is not unequivocally associated with CHD in contrast to HDL-C, apolipoprotein A-I, and most of the HDL subclass particle concentrations.

SUBMITTER: Kuusisto S

PROVIDER: S-EPMC9311699 | biostudies-literature | 2022 Jul

REPOSITORIES: biostudies-literature

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Publications

Genetic and observational evidence: No independent role for cholesterol efflux over static high-density lipoprotein concentration measures in coronary heart disease risk assessment.

Kuusisto Sanna S Karjalainen Minna K MK Tillin Therese T Kangas Antti J AJ Holmes Michael V MV Kähönen Mika M Lehtimäki Terho T Viikari Jorma J Perola Markus M Chaturvedi Nishi N Salomaa Veikko V Raitakari Olli T OT Järvelin Marjo-Riitta MR Kettunen Johannes J Ala-Korpela Mika M

Journal of internal medicine 20220322 1

<h4>Background</h4>Observational findings for high-density lipoprotein (HDL)-mediated cholesterol efflux capacity (HDL-CEC) and coronary heart disease (CHD) appear inconsistent, and knowledge of the genetic architecture of HDL-CEC is limited.<h4>Objectives</h4>A large-scale observational study on the associations of HDL-CEC and other HDL-related measures with CHD and the largest genome-wide association study (GWAS) of HDL-CEC.<h4>Participants/methods</h4>Six independent cohorts were included wit ...[more]

PMID: 35289444

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Project description:BackgroundHigh-density lipoprotein (HDL) may provide cardiovascular protection by promoting reverse cholesterol transport from macrophages. We hypothesized that the capacity of HDL to accept cholesterol from macrophages would serve as a predictor of atherosclerotic burden.MethodsWe measured cholesterol efflux capacity in 203 healthy volunteers who underwent assessment of carotid artery intima-media thickness, 442 patients with angiographically confirmed coronary artery disease, and 351 patients without such angiographically confirmed disease. We quantified efflux capacity by using a validated ex vivo system that involved incubation of macrophages with apolipoprotein B-depleted serum from the study participants.ResultsThe levels of HDL cholesterol and apolipoprotein A-I were significant determinants of cholesterol efflux capacity but accounted for less than 40% of the observed variation. An inverse relationship was noted between efflux capacity and carotid intima-media thickness both before and after adjustment for the HDL cholesterol level. Furthermore, efflux capacity was a strong inverse predictor of coronary disease status (adjusted odds ratio for coronary disease per 1-SD increase in efflux capacity, 0.70; 95% confidence interval [CI], 0.59 to 0.83; P<0.001). This relationship was attenuated, but remained significant, after additional adjustment for the HDL cholesterol level (odds ratio per 1-SD increase, 0.75; 95% CI, 0.63 to 0.90; P=0.002) or apolipoprotein A-I level (odds ratio per 1-SD increase, 0.74; 95% CI, 0.61 to 0.89; P=0.002). Additional studies showed enhanced efflux capacity in patients with the metabolic syndrome and low HDL cholesterol levels who were treated with pioglitazone, but not in patients with hypercholesterolemia who were treated with statins.ConclusionsCholesterol efflux capacity from macrophages, a metric of HDL function, has a strong inverse association with both carotid intima-media thickness and the likelihood of angiographic coronary artery disease, independently of the HDL cholesterol level. (Funded by the National Heart, Lung, and Blood Institute and others.).

Project description:Objective- The cell-cholesterol efflux capacity of HDL (high-density lipoprotein) is inversely associated with coronary heart disease risk. ABCA1 (ATP-binding cassette transporter A1) plays a crucial role in cholesterol efflux from macrophages to preβ-1-HDL. We tested the hypothesis that coronary heart disease patients have functionally abnormal preβ-1-HDL. Approach and Results- HDL cell-cholesterol efflux capacity via the ABCA1 and the SR-BI (scavenger receptor class B type I) pathways, HDL antioxidative capacity, apo (apolipoprotein) A-I-containing HDL particles, and inflammatory- and oxidative-stress markers were measured in a case-control study of 100 coronary heart disease cases and 100 sex-matched controls. There were significant positive correlations between ABCA1-dependent cholesterol efflux and the levels of small lipid-poor preβ-1 particles ( R2=0.535) and between SR-BI-dependent cholesterol efflux and the levels of large lipid-rich (α-1+α-2) HDL particles ( R2=0.712). Cases had significantly higher (87%) preβ-1 concentrations than controls, but the functionality of their preβ-1 particles (preβ-1 concentration normalized ABCA1-dependent efflux capacity) was significantly lower (-31%). Cases had significantly lower (-12%) mean concentration of large HDL particles, but the functionality of their particles (α-1+α-2 concentration normalized SR-BI-dependent efflux capacity) was significantly higher (22%) compared with that of controls. HDL antioxidative capacity was significantly lower (-16%) in cases than in controls. There were no significant correlations between either preβ-1 functionality or large HDL particle functionality with HDL antioxidative capacity or the concentrations of inflammatory- and oxidative-stress markers. Conclusions- HDL cell-cholesterol efflux capacity is significantly influenced by both the concentration and the functionality of specific HDL particles participating in cell-cholesterol efflux. Coronary heart disease patients have higher than normal preβ-1 concentrations with decreased functionality and lower than normal large HDL particle concentrations with enhanced functionality.

Dataset Information

Genetic and observational evidence: No independent role for cholesterol efflux over static high-density lipoprotein concentration measures in coronary heart disease risk assessment.

Background

Objectives

Participants/methods

Results

Conclusion

Publications

Genetic and observational evidence: No independent role for cholesterol efflux over static high-density lipoprotein concentration measures in coronary heart disease risk assessment.

Similar Datasets

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