Dataset Information

Relationship of lipoprotein-associated apolipoprotein C-III with lipid variables and coronary artery disease risk: The EPIC-Norfolk prospective population study.

ABSTRACT: BACKGROUND:Plasma apolipoprotein C-III (apoC-III) levels are associated with coronary artery disease (CAD) risk. OBJECTIVE:To assess whether lipoprotein-associated apoC-III levels predict risk of CAD events. METHODS:apoC-III associated with apoB, apoAI, and Lp(a) (apoCIII-apoB, apoCIII-apoAI, and apoCIII-Lp(a), respectively) were measured using high-throughput chemiluminescent enzyme-linked immunoassays in 2711 subjects (1879 controls and 832 cases with CAD) in the European Prospective Investigation into Cancer and Nutrition-Norfolk prospective population study with 7.4 years of follow-up. These measures were correlated with a variety of lipid measurements and the presence of CAD. The indices of "total apoCIII-apoB" and "total apoCIII-apoAI" were derived by multiplying plasma apoB and apoAI, respectively. RESULTS:apoCIII-apoB (P = .001), apoCIII-Lp(a) (P < .001), apoCIII-apoAI (P = .005) were higher in cases vs controls; tended to correlate positively with body mass index, hsCRP, apoC-III, low-density lipoprotein (LDL) cholesterol, triglycerides, remnant cholesterol, very low density lipoprotein, LDL and high-density lipoprotein particle number and very low density lipoprotein size; but negatively with LDL and high-density lipoprotein particle size (P < .001 for all). apoCIII-apoB, apoCIII-apoAI, apoCIII-Lp(a), total apoCIII-Lp(a), and total apoCIII-apoB were predictors of CAD after adjustment of age, sex, body mass index, smoking, diabetes, hypertensive and lipid-lowering drug use, but they lost their significance after further adjustment of lipid and lipoprotein variables. CONCLUSIONS:This study suggests that enzyme-linked immunoassay-measured lipoprotein-associated apoC-III markers reflect atherogenic lipid particles but do not independently predict risk of CAD events.

SUBMITTER: van Capelleveen JC

PROVIDER: S-EPMC6970616 | biostudies-literature | 2018 Nov - Dec

REPOSITORIES: biostudies-literature

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Relationship of lipoprotein-associated apolipoprotein C-III with lipid variables and coronary artery disease risk: The EPIC-Norfolk prospective population study.

van Capelleveen Julian C JC Lee Sang-Rok SR Verbeek Rutger R Kastelein John J P JJP Wareham Nicholas J NJ Stroes Erik S G ESG Hovingh G Kees GK Khaw Kay-Tee KT Boekholdt S Matthijs SM Witztum Joseph L JL Tsimikas Sotirios S

Journal of clinical lipidology 20180829 6

<h4>Background</h4>Plasma apolipoprotein C-III (apoC-III) levels are associated with coronary artery disease (CAD) risk.<h4>Objective</h4>To assess whether lipoprotein-associated apoC-III levels predict risk of CAD events.<h4>Methods</h4>apoC-III associated with apoB, apoAI, and Lp(a) (apoCIII-apoB, apoCIII-apoAI, and apoCIII-Lp(a), respectively) were measured using high-throughput chemiluminescent enzyme-linked immunoassays in 2711 subjects (1879 controls and 832 cases with CAD) in the European ...[more]

PMID: 30249512

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Project description:OBJECTIVE:Apolipoprotein C-III (apoC-III) is a key regulator of triglyceride metabolism. Elevated triglyceride-rich lipoproteins and apoC-III levels are causally linked to coronary artery disease (CAD) risk. The mechanism(s) through which apoC-III increases CAD risk remains largely unknown. The aim was to confirm the association between apoC-III plasma levels and CAD risk and to explore which lipoprotein subfractions contribute to this relationship between apoC-III and CAD risk. APPROACH AND RESULTS:Plasma apoC-III levels were measured in baseline samples from a nested case-control study in the European Prospective Investigation of Cancer (EPIC)-Norfolk study. The study comprised 2711 apparently healthy study participants, of whom 832 subsequently developed CAD. We studied the association of baseline apoC-III levels with incident CAD risk, lipoprotein subfractions measured by nuclear magnetic resonance spectroscopy and inflammatory biomarkers. ApoC-III levels were significantly associated with CAD risk (odds ratio, 1.91; 95% confidence interval, 1.48-2.48 for highest compared with lowest quintile), retaining significance after adjustment for traditional CAD risk factors (odds ratio, 1.47; 95% confidence interval, 1.11-1.94). ApoC-III levels were positively correlated with triglyceride levels, (r=0.39), particle numbers of very-low-density lipoprotein (r=0.25), intermediate-density lipoprotein (r=0.23), small dense low-density lipoprotein (r=0.26), and high-sensitivity C-reactive protein (r=0.15), whereas an inverse correlation was observed with large low-density lipoprotein particle number (r=-0.11), P<0.001 for each. Mediation analysis indicated that the association between apoC-III and CAD risk could be explained by triglyceride elevation (triglyceride, very-low-density lipoprotein, and intermediate-density lipoprotein particles), small low-density lipoprotein particle size, and high-sensitivity C-reactive protein. CONCLUSIONS:ApoC-III levels are significantly associated with incident CAD risk. Elevated levels of remnant lipoproteins, small dense low-density lipoprotein, and low-grade inflammation may explain this association.

Project description:(1) Background: Apolipoprotein E(ApoE) plays a critical role in lipid transport. The specific allele of APOE being expressed is associated with the development of coronary heart disease (CHD), however the specific mechanisms by which ApoE drives disease are unclear. In this study, we investigated the relationship between APOE allele, lipoprotein metabolome, and CHD severity to provide evidence for the efficacy of clinical cholesterol-lowering therapy; (2) Methods: Blood samples were collected from 360 patients with CHD that were actively being treated with statins. The lipoprotein profile, including particle numbers, particle size, and lipoprotein composition concentrates, was measured by nuclear magnetic resonance (NMR) spectroscopy. The severity of CHD was determined by quantifying coronary angiography results using the Gensini scoring system; (3) Results: We found there was no significant difference in low-density lipoprotein cholesterol (LDL-C) levels among ε2+ (ε2 allele carriers, consisting of ε2/ε2 and ε2/ε3 genotypes), ε3 (consisting of ε3/ε3 and ε2/ε4 genotypes), and ε4+ (ε4 allele carriers, consisting of ε3/ε4 and ε4/ε4 genotypes) participants receiving statin treatment. Compared with the ε3 group, patients with the ε2+ genotype showed lower concentrations of total low-density lipoprotein (LDL), small-LDL, and middle-LDL particles, as well as a larger LDL size, higher very low-density lipoprotein (VLDL) composition concentrates, and higher intermediate density lipoprotein (IDL) composition concentrates. The ε4+ group showed higher concentrations of total LDL, small LDL particles, and LDL compositions with smaller LDL size. The higher level of small LDL concentration was associated with a high Gensini score (B = 0.058, p = 0.024). Compared with the ε3 group, the risk of increased branch lesions in the ε2+ group was lower (OR = 0.416, p = 0.027); (4) Conclusions: The specific allele of APOE being expressed can affect the severity of CHD by altering components of the lipoprotein profile, such as the concentration of small LDL and LDL size.

Project description:BackgroundThe lipoprotein(a) pathway is a causal factor in coronary heart disease. We used a genetic approach to distinguish the relevance of two distinct components of this pathway, apolipoprotein(a) isoform size and circulating lipoprotein(a) concentration, to coronary heart disease.MethodsIn this mendelian randomisation study, we measured lipoprotein(a) concentration and determined apolipoprotein(a) isoform size with a genetic method (kringle IV type 2 [KIV2] repeats in the LPA gene) and a serum-based electrophoretic assay in patients and controls (frequency matched for age and sex) from the Pakistan Risk of Myocardial Infarction Study (PROMIS). We calculated odds ratios (ORs) for myocardial infarction per 1-SD difference in either LPA KIV2 repeats or lipoprotein(a) concentration. In a genome-wide analysis of up to 17 503 participants in PROMIS, we identified genetic variants associated with either apolipoprotein(a) isoform size or lipoprotein(a) concentration. Using a mendelian randomisation study design and genetic data on 60 801 patients with coronary heart disease and 123 504 controls from the CARDIoGRAMplusC4D consortium, we calculated ORs for myocardial infarction with variants that produced similar differences in either apolipoprotein(a) isoform size in serum or lipoprotein(a) concentration. Finally, we compared phenotypic versus genotypic ORs to estimate whether apolipoprotein(a) isoform size, lipoprotein(a) concentration, or both were causally associated with coronary heart disease.FindingsThe PROMIS cohort included 9015 patients with acute myocardial infarction and 8629 matched controls. In participants for whom KIV2 repeat and lipoprotein(a) data were available, the OR for myocardial infarction was 0·93 (95% CI 0·90-0·97; p<0·0001) per 1-SD increment in LPA KIV2 repeats after adjustment for lipoprotein(a) concentration and conventional lipid concentrations. The OR for myocardial infarction was 1·10 (1·05-1·14; p<0·0001) per 1-SD increment in lipoprotein(a) concentration, after adjustment for LPA KIV2 repeats and conventional lipids. Genome-wide analysis identified rs2457564 as a variant associated with smaller apolipoprotein(a) isoform size, but not lipoprotein(a) concentration, and rs3777392 as a variant associated with lipoprotein(a) concentration, but not apolipoprotein(a) isoform size. In 60 801 patients with coronary heart disease and 123 504 controls, OR for myocardial infarction was 0·96 (0·94-0·98; p<0·0001) per 1-SD increment in apolipoprotein(a) protein isoform size in serum due to rs2457564, which was directionally concordant with the OR observed in PROMIS for a similar change. The OR for myocardial infarction was 1·27 (1·07-1·50; p=0·007) per 1-SD increment in lipoprotein(a) concentration due to rs3777392, which was directionally concordant with the OR observed for a similar change in PROMIS.InterpretationHuman genetic data suggest that both smaller apolipoprotein(a) isoform size and increased lipoprotein(a) concentration are independent and causal risk factors for coronary heart disease. Lipoprotein(a)-lowering interventions could be preferentially effective in reducing the risk of coronary heart disease in individuals with smaller apolipoprotein(a) isoforms.FundingBritish Heart Foundation, US National Institutes of Health, Fogarty International Center, Wellcome Trust, UK Medical Research Council, UK National Institute for Health Research, and Pfizer.

Project description:ObjectiveTriglyceride-rich lipoproteins have emerged as causal risk factors for developing coronary heart disease independent of low-density lipoprotein cholesterol levels. Apolipoprotein C-III (ApoC-III) modulates triglyceride-rich lipoprotein metabolism through inhibition of lipoprotein lipase and hepatic uptake of triglyceride-rich lipoproteins. Mutations causing loss-of-function of ApoC-III lower triglycerides and reduce coronary heart disease risk, suggestive of a causal role for ApoC-III. Little data exist about the relationship of ApoC-III, triglycerides, and atherosclerosis in patients with type 2 diabetes mellitus (T2DM). Here, we examined the relationships between plasma ApoC-III, triglycerides, and coronary artery calcification in patients with T2DM.Approach and resultsPlasma ApoC-III levels were measured in a cross-sectional study of 1422 subjects with T2DM but without clinically manifest coronary heart disease. ApoC-III levels were positively associated with total cholesterol (Spearman r=0.36), triglycerides (r=0.59), low-density lipoprotein cholesterol (r=0.16), fasting glucose (r=0.16), and glycosylated hemoglobin (r=0.12; P<0.0001 for all). In age, sex, and race-adjusted analysis, ApoC-III levels were positively associated with coronary artery calcification (Tobit regression ratio, 1.78; 95% confidence interval, 1.27-2.50 per SD increase in ApoC-III; P<0.001). As expected for an intermediate mediator, these findings were attenuated when adjusted for both triglycerides (Tobit regression ratio, 1.43; 95% confidence interval, 0.94-2.18; P=0.086) and separately for very low-density lipoprotein cholesterol (Tobit regression ratio, 1.14; 95% confidence interval, 0.75-1.71; P=0.53).ConclusionsIn persons with T2DM, increased plasma ApoC-III is associated with higher triglycerides, less favorable cardiometabolic phenotypes, and higher coronary artery calcification, a measure of subclinical atherosclerosis. Therapeutic inhibition of ApoC-III may thus be a novel strategy for reducing plasma triglyceride-rich lipoproteins and cardiovascular risk in T2DM.

Dataset Information

Relationship of lipoprotein-associated apolipoprotein C-III with lipid variables and coronary artery disease risk: The EPIC-Norfolk prospective population study.

Publications

Relationship of lipoprotein-associated apolipoprotein C-III with lipid variables and coronary artery disease risk: The EPIC-Norfolk prospective population study.

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