Effects of exercise training on ANGPTL3/8 and ANGPTL4/8 and their associations with cardiometabolic traits.

Angiopoietin-like protein (ANGPTL) complexes 3/8 and 4/8 are established inhibitors of LPL and novel therapeutic targets for dyslipidemia. However, the effects of regular exercise on ANGPTL3/8 and ANGPTL4/8 are unknown. We characterized ANGPTL3/8 and ANGPTL4/8 and their relationship with in vivo measurements of lipase activities and cardiometabolic traits before and after a 5-month endurance exercise training intervention in 642 adults from the HERITAGE (HEalth, RIsk factors, exercise Training And GEnetics) Family Study. At baseline, higher levels of both ANGPTL3/8 and ANGPTL4/8 were associated with a worse lipid, lipoprotein, and cardiometabolic profile, with only ANGPTL3/8 associated with postheparin LPL and HL activities. ANGPTL3/8 significantly decreased with exercise training, which corresponded with increases in LPL activity and decreases in HL activity, plasma triglycerides, apoB, visceral fat, and fasting insulin (all P < 5.1 × 10-4). Exercise-induced changes in ANGPTL4/8 were directly correlated to concomitant changes in total cholesterol, LDL-C, apoB, and HDL-triglycerides and inversely related to change in insulin sensitivity index (all P < 7.0 × 10-4). In conclusion, exercise-induced decreases in ANGPTL3/8 and ANGPTL4/8 were related to concomitant improvements in lipase activity, lipid profile, and cardiometabolic risk factors. These findings reveal the ANGPTL3-4-8 model as a potential molecular mechanism contributing to adaptations in lipid metabolism in response to exercise training.

[Laboratory diagnostics of lipid metabolism disorders]. / Labordiagnostik von Fettstoffwechselstörungen.

Clinically, disorders of lipid metabolism often remain without symptoms. Typical skin lesions, however, can be indicative. Secondary hyperlipoproteinemias (HLP) are more common than primary hyperlipoproteinemias; they can (partially) be improved by treating the underlying disease. Basic diagnostics consist of the determination of cholesterol, triglycerides, LDL cholesterol and HDL cholesterol. To exclude secondary HLP, glucose, HbA1C, TSH, transaminases, creatinine, urea, protein and protein in the urine are useful. Since virtually all routine methods for LDL-C are biased by high triglycerides, lipoprotein electrophoresis is indicated for triglycerides above 400 mg/dl (4.7 mmol/l). Primary HLPs have known or yet unknown genetic causes. Primary hyperlipidemias should be taken into consideration especially in young patients with an LDL cholesterol concentration are above 190 mg/dl (4.9 mmol/l) and/or triglycerides above 400 mg/dl (10 mmol/l) and secondary HLP (obesity, alcohol, diabetes mellitus, kidney disease) is excluded. The basic diagnostics is meaningfully extended by the measurement of lipoprotein (a) (Lp(a)). It is indicated in moderate and high risk of vascular disease, progression of atherosclerosis in "well-controlled" LDL cholesterol, familial clustering of atherosclerosis or high Lp(a), evidence for elevated Lp(a) coming from lipoprotein electrophoresis, aortic stenosis and in patients in whom statins have a poor effect. Genetic diagnostics needs to be considered if primary HLP is suspected. It is most frequently conducted for suspected familial hypercholesterolemia and has already been recommended in guidelines.

Prevention of cardiovascular disease in young adults: Focus on gender differences. A collaborative review from the EAS Young Fellows.

A steady rise in cardiovascular morbidity and mortality has been observed in young adults within the last decades. This trend corresponds to an increasing prevalence of traditional cardiovascular risk factors such as obesity and diabetes mellitus type 2 among young adults living in developed countries. Moreover, age-specific risk factors, such as substance abuse, contraceptive medication, and pregnancy-related diseases also correlate with an increased incidence of cardiovascular diseases. In this review, we discuss the available data for young adults on the epidemiology and the rationale for the causality of traditional and newly emerging risk factors of atherosclerotic cardiovascular diseases. We focus on gender-related differences in the exposure to these risk factors, investigate the recent data regarding screening and risk stratification in the young adult population, and describe the current state of the art on lifestyle and therapeutic intervention strategies in the primary prevention setting.

Cardiovascular diseases and their associations with lipid parameters and endothelial dysfunction in giant cell arteritis.

OBJECTIVES: Evaluation of endothelial dysfunction, lipid metabolism, prevalence and development of cardiovascular diseases in patients with giant cell arteritis (GCA). METHODS: 138 GCA patients and 100 controls were evaluated for prevalent cardiovascular diseases in 2012. Cholesterol, lipoproteins and triglycerides, intima-media thickness, arterial stiffness, asymmetric and symmetric dimethylarginine were also measured in 2012. Cardiovascular events, mortality and relapse were retrieved by chart review in 2020. RESULTS: Prevalent carotid and vertebral artery disease was higher in GCA patients than in controls (p<0.001). GCA patients had higher levels of total cholesterol, low-density lipoprotein (LDL), intermediate-density lipoprotein, high-density lipoprotein, apolipoprotein A1 and B, and augmentation index (all with p<0.05). Target LDL levels were less frequently achieved at study inclusion by GCA patients (p=0.001), who developed more frequently new cardiovascular events, also with a higher amount, during follow-up (all with p<0.001). Statin treatment in GCA patients was associated with lower levels of asymmetric dimethylarginine, monocytes and C reactive protein (all with p<0.05). Relapse was independently associated with higher risk of future cardiovascular events (OR 5.01 (95% CI 1.55 to 16.22), p=0.007). CONCLUSIONS: GCA patients are at a high risk of developing cardiovascular diseases. Of relevance, there was underuse of statins and a large proportion of these patients showed LDL cholesterol concentrations above the treatment targets for high-risk patients. These data underscore the need for improvement of preventive strategies to reduce cardiovascular risk in GCA patients.

Inverse association between apolipoprotein C-II and cardiovascular mortality: role of lipoprotein lipase activity modulation.

AIMS: Apolipoprotein C-II (ApoC-II) is thought to activate lipoprotein lipase (LPL) and is therefore a possible target for treating hypertriglyceridemia. Its relationship with cardiovascular risk has not been investigated in large-scale epidemiologic studies, particularly allowing for apolipoprotein C-III (ApoC-III), an LPL antagonist. Furthermore, the exact mechanism of ApoC-II-mediated LPL activation is unclear. METHODS AND RESULTS: ApoC-II was measured in 3141 LURIC participants of which 590 died from cardiovascular diseases during a median (inter-quartile range) follow-up of 9.9 (8.7-10.7) years. Apolipoprotein C-II-mediated activation of the glycosylphosphatidylinositol high-density lipoprotein binding protein 1 (GPIHBP1)-LPL complex was studied using enzymatic activity assays with fluorometric lipase and very low-density lipoprotein (VLDL) substrates. The mean ApoC-II concentration was 4.5 (2.4) mg/dL. The relationship of ApoC-II quintiles with cardiovascular mortality exhibited a trend toward an inverse J-shape, with the highest risk in the first (lowest) quintile and lowest risk in the middle quintile. Compared with the first quintile, all other quintiles were associated with decreased cardiovascular mortality after multivariate adjustments including ApoC-III as a covariate (all P < 0.05). In experiments using fluorometric substrate-based lipase assays, there was a bell-shaped relationship for the effect of ApoC-II on GPIHBP1-LPL activity when exogenous ApoC-II was added. In ApoC-II-containing VLDL substrate-based lipase assays, GPIHBP1-LPL enzymatic activity was almost completely blocked by a neutralizing anti-ApoC-II antibody. CONCLUSION: The present epidemiologic data suggest that increasing low circulating ApoC-II levels may reduce cardiovascular risk. This conclusion is supported by the observation that optimal ApoC-II concentrations are required for maximal GPIHBP1-LPL enzymatic activity.

Independent Effects of Kidney Function and Cholesterol Efflux on Cardiovascular Mortality.

BACKGROUND: Impaired renal function is associated with cardiovascular and all-cause mortality. In the general population, HDL-cholesterol is associated with cardiovascular events, which is not true in patients with chronic kidney disease (CKD). This has been attributed to abnormal HDL function in CKD. METHODS: In this study, we analyzed the association of genetic markers for kidney function with cholesterol efflux capacity as one of the major HDL functions, as well as with cardiovascular mortality, in 2469 patients of the Ludwigshafen Risk and Cardiovascular Health Study who all underwent coronary angiography. RESULTS: A genetic score of 53 SNPs associated with GRF and the uromodulin SNP rs12917707 were inversely correlated with cholesterol efflux capacity. This was in line with the observed association between cholesterol efflux capacity and kidney function in these patients. Adjustment for eGFR and uromodulin as markers of kidney function did not affect the relationship between cholesterol efflux and cardiovascular mortality. CONCLUSIONS: Our data propose the view that cholesterol efflux and kidney function are exerting their effects on cardiovascular mortality via different and independent pathways. Decreased cholesterol efflux may therefore not mediate the effects of impaired kidney function on cardiovascular mortality.

Comparison of Two Nuclear Magnetic Resonance Spectroscopy Methods for the Measurement of Lipoprotein Particle Concentrations.

Background: Measuring lipoprotein particle concentrations may help to improve cardiovascular risk stratification. Both the lipofit (Numares) and lipoprofile (LabCorp) NMR methods are widely used for the quantification of lipoprotein particle concentrations. Objective: The aim of the present work was to perform a method comparison between the lipofit and lipoprofile NMR methods. In addition, there was the objective to compare lipofit and lipoprofile measurements of standard lipids with clinical chemistry-based results. Methods: Total, LDL, and HDL cholesterol and triglycerides were measured with ß-quantification in serum samples from 150 individuals. NMR measurements of standard lipids and lipoprotein particle concentrations were performed by Numares and LabCorp. Results: For both NMR methods, differences of mean concentrations compared to ß-quantification-derived measurements were ≤5.5% for all standard lipids. There was a strong correlation between ß-quantification- and NMR-derived measurements of total and LDL cholesterol and triglycerides (all r > 0.93). For both, the lipofit (r = 0.81) and lipoprofile (r = 0.84) methods, correlation coefficients were lower for HDL cholesterol. There was a reasonable correlation between LDL and HDL lipoprotein particle concentrations measured with both NMR methods (both r > 0.9). However, mean concentrations of major and subclass lipoprotein particle concentrations were not as strong. Conclusions: The present analysis suggests that reliable measurement of standard lipids is possible with these two NMR methods. Harmonization efforts would be needed for better comparability of particle concentration data.

The LDL Apolipoprotein B-to-LDL Cholesterol Ratio: Association with Cardiovascular Mortality and a Biomarker of Small, Dense LDLs.

Background and Objective: Small, dense low-density lipoproteins (LDLs) are considered more atherogenic than normal size LDLs. However, the measurement of small, dense LDLs requires sophisticated laboratory methods, such as ultracentrifugation, gradient gel electrophoresis, or nuclear magnetic resonance. We aimed to analyze whether the LDL apolipoprotein B (LDLapoB)-to-LDL cholesterol (LDLC) ratio is associated with cardiovascular mortality and whether this ratio represents a biomarker for small, dense LDLs. Methods: LDLC and LDLapoB were measured (beta-quantification) and calculated (according to Friedewald and Baca, respectively) for 3291 participants of the LURIC Study, with a median (inter-quartile range) follow-up for cardiovascular mortality of 9.9 (8.7−10.7) years. An independent replication cohort included 1660 participants. Associations of the LDLapoB/LDLC ratio with LDL subclass particle concentrations (ultracentrifugation) were tested for 282 participants. Results: In the LURIC Study, the mean (standard deviation) LDLC and LDLapoB concentrations were 117 (34) and 85 (22) mg/dL, respectively; 621 cardiovascular deaths occurred. Elevated LDLapoB/LDLC (calculated and measured) ratios were significantly and independently associated with increased cardiovascular mortality in the entire cohort (fourth vs. first quartile: hazard ratio (95% confidence interval) = 2.07 (1.53−2.79)) and in statin-naïve patients. The association between calculated LDLapoB/LDLC ratio and cardiovascular mortality was replicated in an independent cohort. High LDLapoB/LDLC ratios were associated with higher LDL5 and LDL6 concentrations (both p < 0.001), but not with concentrations of larger LDLs. Conclusions: Elevated measured and calculated LDLapoB/LDLC ratios are associated with increased cardiovascular mortality. Use of LDLapoB/LDLC ratios allows estimation of the atherogenic risk conferred by small, dense LDLs.

High cholesterol absorption is associated with increased cardiovascular risk in haemodialysis patients: insights from the AURORA study.

AIMS: Statin treatment did not reduce the risk of cardiovascular events in haemodialysis patients in the 4D and AURORA trials. Post hoc analyses in the 4D study suggested that high cholesterol absorption was associated with increased cardiovascular risk and that atorvastatin would reduce cardiovascular risk in haemodialysis patients with low cholesterol absorption but not in those with high cholesterol absorption. METHODS AND RESULTS: AURORA is a randomized, double-blind, placebo-controlled, multi-centre trial in haemodialysis patients. The participants were randomly assigned to receive either rosuvastatin, 10 mg daily, or a matching placebo. There was a follow-up for cardiovascular death with a median duration of 3.9 years. The cholestanol and lathosterol to cholesterol ratios were used to estimate cholesterol absorption and synthesis, respectively. Measurement of non-cholesterol sterols was available in 2332 participants of the 2733 patients included in the primary analysis of the AURORA study. A total of 598 participants died from cardiovascular diseases. The 3rd vs. the 1st tertile of the cholestanol-to-cholesterol ratio was significantly associated with increased risk of cardiovascular death [hazard ratio, HR (95% confidence interval, CI) = 1.36 (1.11-1.65)] in univariate (P = 0.002) and multivariate models (P = 0.034). In contrast, the 3rd vs. the 1st tertile of the lathosterol-to-cholesterol ratio was significantly associated with decreased risk of cardiovascular death [HR (95% CI) = 0.81 (0.67-0.99)] in univariate (P = 0.041) and multivariate (P = 0.019) models. There was no significant interaction between the cholestanol and lathosterol to cholesterol tertiles and treatment group in predicting cardiovascular death. CONCLUSION: The present data from the AURORA study confirm that high cholesterol absorption is associated with increased cardiovascular risk in haemodialysis patients. Assessment of the individual cholesterol absorption rate to guide initiation of statin treatment is not supported by the findings in the AURORA study.

Lipoprotein(a) and Pulmonary Embolism Severity-A Retrospective Data Analysis.

AIM: We aimed to investigate a correlation between PE severity and Lp(a) levels. METHODS: We performed a retrospective data analysis from our medical records of PE patients admitted to the University Hospital Graz, Austria. Patients with an Lp(a) reading within a 1-year interval before and after PE diagnosis were included. In accordance with the 2019 ESC guidelines for the diagnosis and management of acute PE, severity assessment was carried out classifying patients into four groups: low risk (LR), intermediate low risk (IML), intermediate high risk (IMH) and high risk (HR). The study period of interest was between January 1, 2002 and August 1, 2020. RESULTS: We analyzed 811 patients with PE, of whom 323 (40%) had low-risk PE, 343 (42%) had intermediate-low-risk PE, 64 (8%) had intermediate-high-risk PE, and 81 (10%) had high-risk PE, respectively. We did not observe an association between PE severity and Lp(a) concentrations. In detail, median Lp(a) concentrations were 17 mg/dL [25-75th percentile: 10-37] in low-risk PE patients, 16 mg/dL [10-37] in intermediate-low-risk PE patients, 15mg/dL [10-48] in intermediate-high-risk PE patients, and 13mg/dL [10-27] in high-risk PE patients, respectively (Kruskal-Wallis p = 0.658, p for linear trend = 0.358). CONCLUSION: The current findings suggest no correlation between PE severity and Lp(a) levels.

Short-Term Treatment with Alirocumab, Flow-Dependent Dilatation of the Brachial Artery and Use of Magnetic Resonance Diffusion Tensor Imaging to Evaluate Vascular Structure: An Exploratory Pilot Study.

BACKGROUND: Short-term effects of alirocumab on vascular function have hardly been investigated. Moreover, there is a scarce of reliable non-invasive methods to evaluate atherosclerotic changes of the vasculature. The ALIROCKS trial was performed to address these issues using standard ultrasound-based procedures and a completely novel magnetic resonance-based imaging technique. METHODS: A total of 24 patients with an indication for treatment with PCSK9 antibodies were recruited. There were 2 visits to the study site, the first before initiation of treatment with alirocumab and the second after 10 weeks of treatment. The key outcome measures included the change of carotid vessel wall fractional anisotropy, a novel magnetic resonance-based measure of vascular integrity, and the changes of carotid intima-media thickness and flow-dependent dilatation of the brachial artery measured with ultrasound. RESULTS: A total of 19 patients completed the trial, 2 patients stopped treatment, 3 patients did not undergo the second visit due to the COVID pandemic. All of them had atherosclerotic vascular disease. Their mean (standard deviation) LDL-cholesterol concentration was 154 (85) mg/dL at baseline and was reduced by 76 (44) mg/dL in response to alirocumab treatment (p < 0.001, n = 19). P-selectin and vascular endothelial growth factors remained unchanged. Flow-dependent dilatation of the brachial artery (+41%, p = 0.241, n = 18), carotid intima-media thickness (p = 0.914, n = 18), and fractional anisotropy of the carotid artery (p = 0.358, n = 13) also did not significantly change. CONCLUSION: Despite a nominal amelioration for flow-dependent dilatation, significant effects of short-term treatment with alirocumab on vascular function were not detectable. More work would be needed to evaluate, whether fractional anisotropy may be useful in clinical atherosclerosis research.

Effects of Alirocumab on Triglyceride Metabolism: A Fat-Tolerance Test and Nuclear Magnetic Resonance Spectroscopy Study.

BACKGROUND: PCSK9 antibodies strongly reduce LDL cholesterol. The effects of PCSK9 antibodies on triglyceride metabolism are less pronounced. The present study aimed to investigate in detail the effects of alirocumab on triglycerides, triglyceride-rich lipoproteins, and lipase regulators. METHODS: A total of 24 patients with an indication for treatment with PCSK9 antibodies were recruited. There were two visits at the study site: the first before initiation of treatment with alirocumab and the second after 10 weeks of treatment. Fat-tolerance tests, nuclear magnetic resonance spectroscopy, and enzyme-linked immunosorbent assays were performed to analyze lipid metabolism. RESULTS: A total of 21 participants underwent the first and second investigation. Among these, two participants only received alirocumab twice and 19 patients completed the trial per protocol. All of them had atherosclerotic vascular disease. There was no significant effect of alirocumab treatment on fasting triglycerides, post-prandial triglycerides, or lipoprotein-lipase regulating proteins. Total, large, and small LDL particle concentrations decreased, while the HDL particle concentration increased (all p < 0.001). Mean total circulating PCSK9 markedly increased in response to alirocumab treatment (p < 0.001). Whereas PCSK9 increased more than three-fold in all 19 compliant patients, it remained unchanged in those two patients with two injections only. CONCLUSION: Significant effects of alirocumab on triglyceride metabolism were not detectable in the ALIROCKS trial. The total circulating PCSK9 concentration might be a useful biomarker to differentiate non-adherence from non-response to PCSK9 antibodies.

Cholesterol and glaucoma: a systematic review and meta-analysis.

PURPOSE: Intraocular pressure is the main risk factor for glaucoma; however, additional risk factors may also matter. This systematic review and meta-analysis were conducted to summarize the evidence regarding the association of cholesterol parameters (total cholesterol, low-density lipoprotein (LDL) and high-density lipoprotein (HDL) levels) and glaucoma. METHODS: Four electronic databases were searched for all publications containing 'glaucoma' and one of various forms of 'cholesterol' or 'lipoprotein'. Two independent reviewers screened abstracts and potentially full texts of identified articles for eligibility. Risk of bias was assessed with the Newcastle-Ottawa Scale. A random-effects meta-analysis was used to investigate the differences in total cholesterol, LDL and HDL levels between patients with and without glaucoma. RESULTS: Overall, 29 observational studies were included in the systematic review and 26 reported quantitative information to investigate differences in cholesterol parameters between patients with glaucoma (N = 7196) and patients without glaucoma (N = 350 441). Patients with glaucoma had significantly higher total cholesterol levels than patients without glaucoma (Mean Difference (MD) 7.9 mg/dl, 95% CI 3.3 to 12.5, p = 0.001) and lower mean HDL levels (MD -2.0 mg/dl, 95% CI: -3.1 to -0.9, p = 0.001). Patients with glaucoma had higher mean LDL levels than patients without glaucoma, albeit not statistically significant (MD 6.1 mg/dl, 95% CI: -4.3 to 16.4, p = 0.251). CONCLUSION: This systematic review and meta-analysis of observational studies found an association of glaucoma and high total cholesterol and low HDL levels, respectively. Although this supports the hypothesis that lipid levels pose an additional risk for glaucoma development, heterogeneity was substantial and causality cannot be presumed from identified observational studies.

Triglyceride-Rich Lipoproteins, Apolipoproteins, and Atherosclerotic Cardiovascular Events Among Patients with Diabetes Mellitus and End-Stage Renal Disease on Hemodialysis.

Hypertriglyceridemia may be implicated in the high atherosclerotic cardiovascular disease (ASCVD) risk experienced by patients with end-stage renal disease (ESRD). In this post-hoc analysis of the "Die Deutsche Diabetes Dialyse Studie (4D)" clinical trial, we examined incident ASCVD events, defined as myocardial infarction, ischemic stroke, or a coronary revascularization procedure, among 1255 participants with type 2 diabetes and ESRD treated with hemodialysis. Cox-regression methods were used to evaluate the association of triglycerides, very-low density lipoprotein cholesterol (VLDL-C), and apolipoproteins B (Apo B) and C-III (Apo C-III) with ASCVD. During a median follow-up time of 2.3 years, 340 (27%) participants experienced an ASCVD event. Higher concentrations of triglycerides were not associated with ASCVD risk: Hazard ratio (HR) 0.95; 95% CI (0.83, 1.10) per doubling concentration. Similarly, VLDL-C HR 1.01; 95% CI (0.90, 1.13); Apo B HR 1.04; 95% CI (0.93, 1.16); and Apo C-III HR 0.97; 95% CI (0.86, 1.09) (per one standard deviation higher concentrations), were not associated with ASCVD events. These associations did not differ by allocation to treatment to atorvastatin or by concentrations of markers of inflammation or malnutrition. In conclusion, we found no evidence that triglycerides, triglyceride-rich lipoproteins, or apolipoproteins B or C-III were associated with risk of ASCVD events among patients with type 2 diabetes and ESRD on hemodialysis. These results suggest that lowering triglycerides may not decrease atherosclerotic cardiovascular risk in this population.

Improved Lipid Target Level Attainment in Patients with Peripheral Artery Disease.

BACKGROUND: Patients with peripheral artery disease (PAD) fall under the category of a very high cardiovascular risk. Although consequent lipid-lowering therapy (LLT) is advised, only sparse data on attained target level in PAD exists. OBJECTIVES: We aimed to analyse contemporary guideline recommendations for LLT in symptomatic PAD patients. METHODS: A monocentric, prospective, observational study involving 200 symptomatic PAD patients was conducted. Guideline target level attainment and LLT were analysed between 2017 and 2019. RESULTS: Overall, 78.5% of the patients were on statin therapy, mainly of high intensity, with atorvastatin in 50% and rosuvastatin in 33% of the cases. The average statin dosage adjusted for simvastatin was 55 mg/d. Low density lipoprotein-cholesterol (LDL-C) was <1.8 mmol/L in 53% and <1.4 mmol/L in 34% of the cases. Mean LDL-C levels were at 1.85 ± 0.88 mmol/L. We observed no difference in the treatment and the target level attainment of patients with a stable PAD (intermittent claudication) or chronic critical PAD. However, patients with ≥ 1 vascular region affected (i.e., coronary and/or cerebrovascular) were treated more intensively and had lower LDL-C levels than patients with PAD alone. CONCLUSION: It appears that there are more awareness and improvement of previously documented undertreatment of LDL-C levels in symptomatic PAD patients. Although statin treatment is initiated in the majority of patients, our findings call for a continuously intensified LLT in symptomatic PAD patients.

Common APOC3 variants are associated with circulating ApoC-III and VLDL cholesterol but not with total apolipoprotein B and coronary artery disease.

BACKGROUND AND AIMS: Very rare loss-of-function mutations in the apolipoprotein C3 (APOC3) gene have been associated with low circulating apoC-III, low triglycerides, and reduced cardiovascular risk. We aimed to analyze the impact of common APOC3 variants on key parameters of lipid metabolism and coronary artery disease in the largest sample so far. METHODS: Common variants in APOC3 were tested for associations with circulating apoC-III, lipids, and apolipoprotein B (apoB) in 3041 participants of the LUdwigshafen RIsk and Cardiovascular health study (LURIC). These variants were then tested for associations with coronary artery disease in a meta-analysis comprising up to 332,389 participants of the CARDIOGRAMplusC4D consortium and the UK Biobank. RESULTS: The mean (standard deviation) apoC-III concentration was 14.6 (5.1) mg/dl. Seven common variants in APOC3 (rs734104, rs4520, rs5142, rs5141, rs5130, rs5128, and rs4225) were associated with circulating apoC-III (all p < 0.05). The alleles that modestly raised apoC-III were also associated with markedly higher total triglycerides and very low density lipoprotein (VLDL) triglycerides and cholesterol (all p < 0.05), but not with low density lipoprotein (LDL) cholesterol and total apoB (all p > 0.05). These variants were not associated with coronary artery disease in the CARDIOGRAMplusC4D consortium and the UK Biobank (all p > 0.1). CONCLUSIONS: Modest, genetically caused elevations of apoC-III are associated with a marked increase of triglyceride-rich lipoproteins but not with an increase of LDL cholesterol, total apoB, and coronary artery disease. Whether effective inhibition of apoC-III production with antisense oligomers will be instrumental to reduce cardiovascular risk remains to be demonstrated.