Evaluating the relationship between circulating lipoprotein lipids and apolipoproteins with risk of coronary heart disease: A multivariable Mendelian randomisation analysis

Richardson, Tom G; Sanderson, Eleanor; Palmer, Tom; Ala‐Korpela, Mika; Ference, Brian А.; Smith, George Davey; Holmes, Michael V

doi:10.1371/journal.pmed.1003062

Cited by 609 publications

(544 citation statements)

References 72 publications

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“…25 The MR-Egger regression approach can detect and correct for directional pleiotropy albeit with compromised power. 25 Given genetic and phenotypic correlations across lipid-related traits (Pearson's R ranging from −0.49 to 0.96; Supplementary Table S3), 9 we further used multivariable inverse-variance weighted method to disentangle and compare the effects of correlated lipidtraits on ischemic stroke and subtypes. Odd ratios (ORs) and corresponding 95% confidence intervals (CIs) for outcomes were scaled to one-SD increase in levels of lipid-related traits.…”

Section: Resultsmentioning

confidence: 99%

“…Genetic instruments for LDL and HDL cholesterol, triglycerides, and apoA-I and apoB were selected based on the UK Biobank study. 9 Data for the associations of the lipid-related traits associated singlenucleotide polymorphisms (SNPs) with ischemic stroke and subtypes were available from the MEGASTROKE consortium. 20 The univariable MR analysis aimed to investigate the association of individual lipid-related traits with ischemic stroke and the multivariable MR analysis aimed to compare the independent effects of correlated lipid-related traits on ischemic stroke.…”

Section: Methodsmentioning

confidence: 99%

“…Genetic variants, in this case SNPs, associated with LDL and HDL cholesterol, triglycerides, and apoA-I and apoB levels were extracted as instrumental variables for corresponding lipid-related traits at the genomewide significance level (p < 5 × 10 −8 ) from the UK Biobank study including up to 343,992 individuals of European ancestry. 9 The mean age of included participants was 56.9 years old and approximately 54% were women. The mean (standard deviation [SD]) levels were 3.57 (0.87) mmol/L for LDL cholesterol and 1.45 (0.38) mmol/L for HDL cholesterol.…”

Section: Genetic Instrument Selectionmentioning

confidence: 99%

“…hemorrhagic stroke. 8 However, given high phenotypic and genetic correlation across different lipids and apolipoproteins, 9 it remains unclear whether one or more lipid-related entities account for the observed associations between lipids and stroke. Disentangling the associations of atherogenic lipoprotein lipids and risk of stroke is of great public health and clinical importance.…”

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confidence: 99%

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Circulating Lipoprotein Lipids, Apolipoproteins and Ischemic Stroke

Yuan

Tang

Zheng

et al. 2020

Annals of Neurology

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Objective: We conducted a Mendelian randomization (MR) study to disentangle the comparative effects of lipids and apolipoproteins on ischemic stroke. Methods: Single-nucleotide polymorphisms associated with low-and high-density lipoprotein (LDL and HDL) cholesterol, triglycerides, and apolipoprotein A-I and B (apoA-I and apoB) at the level of genomewide significance (p < 5 × 10 −8) in the UK Biobank were used as instrumental variables. Summary-level data for ischemic stroke and its subtypes were obtained from the MEGASTROKE consortium with 514,791 individuals (60,341 ischemic stroke cases, and 454,450 non-cases). Results: Increased levels of apoB, LDL cholesterol, and triglycerides were associated with higher risk of any ischemic stroke, large artery stroke, and small vessel stroke in the main and sensitivity univariable MR analyses. In multivariable MR analysis including apoB, LDL cholesterol, and triglycerides in the same model, apoB retained a robust effect (p < 0.05), whereas the estimate for LDL cholesterol was reversed, and that for triglycerides largely attenuated. Decreased levels of apoA-I and HDL cholesterol were robustly associated with increased risk of any ischemic stroke, large artery stroke, and small vessel stroke in all univariable MR analyses, but the association for apoA-I was attenuated to the null after mutual adjustment. Interpretation: The present MR study reveals that apoB is the predominant trait that accounts for the etiological basis of apoB, LDL cholesterol, and triglycerides in relation to ischemic stroke, in particular large artery and small vessel stroke. Whether HDL cholesterol exerts a protective effect on ischemic stroke independent of apoA-I needs further investigation.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Genetic Instrument Selectionmentioning

confidence: 99%

mentioning

confidence: 99%

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Circulating Lipoprotein Lipids, Apolipoproteins and Ischemic Stroke

Yuan

Tang

Zheng

et al. 2020

Annals of Neurology

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“…Importantly, the molar ratio of VLDL-TG (particle TG content) to VLDL-ApoB100 (the number of particles) is elevated in non-diabetic obese individuals with high intrahepatic TG (measured by MRS), suggesting that the secreted VLDL particles are larger and resemble the pro-atherogenic VLDL 1 [ 65 ]. Since other studies indicated that plasma ApoB concentration is a stronger predictor of CVD risk than LDL-C or plasma TG concentrations [ 67 ], further investigation is required to dissect the contribution of ApoB particle concentration vs particle content (TG or cholesterol) in determining CVD risk. It is important to bear in mind that the majority of the aforementioned studies focused on differences in intrahepatic TG and not necessarily NASH per se.…”

Section: Dyslipidemia: Linking Hepatic Lipid Metabolism and The Heartmentioning

confidence: 99%

Dysregulated lipid metabolism links NAFLD to cardiovascular disease

Deprince

Haas

Staels

2020

Molecular Metabolism

314

161

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Background Non-alcoholic fatty liver disease (NAFLD) is rapidly becoming a global health problem. Cardiovascular diseases (CVD) are the most common cause of mortality in NAFLD patients. NAFLD and CVD share several common risk factors including obesity, insulin resistance, and type 2 diabetes (T2D). Atherogenic dyslipidemia, characterized by plasma hypertriglyceridemia, increased small dense low-density lipoprotein (LDL) particles, and decreased high-density lipoprotein cholesterol (HDL-C) levels, is often observed in NAFLD patients. Scope of review In this review, we highlight recent epidemiological studies evaluating the link between NAFLD and CVD risk. We further focus on recent mechanistic insights into the links between NAFLD and altered lipoprotein metabolism. We also discuss current therapeutic strategies for NAFLD and their potential impact on NAFLD-associated CVD risk. Major conclusions Alterations in hepatic lipid and lipoprotein metabolism are major contributing factors to the increased CVD risk in NAFLD patients, and many promising NASH therapies in development also improve dyslipidemia in clinical trials.

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Association of Apolipoprotein B–Containing Lipoproteins and Risk of Myocardial Infarction in Individuals With and Without Atherosclerosis

et al. 2022

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IMPORTANCE Lipid management typically focuses on levels of low-density lipoprotein cholesterol (LDL-C) and, to a lesser extent, triglycerides (TG). However, animal models and genetic studies suggest that the atherogenic particle subpopulations (LDL and very-low-density lipoprotein [VLDL]) are both important and that the number of particles is more predictive of cardiac events than their lipid content. OBJECTIVE To determine whether common measures of cholesterol concentration, TG concentration, or their ratio are associated with cardiovascular risk beyond the number of apolipoprotein B (apoB)-containing lipoproteins. DESIGN, SETTING, AND PARTICIPANTSThis prospective cohort analysis included individuals from the population-based UK Biobank and from 2 large international clinical trials, FOURIER and IMPROVE-IT. The median (IQR) follow-up was 11.1 (10.4-11.8) years in UK Biobank and 2.5 (2.0-4.7) years in the clinical trials. Two populations were studied in this analysis: 389 529 individuals in the primary prevention group who were not taking lipid-lowering therapy and 40 430 patients with established atherosclerosis who were receiving statin treatment.EXPOSURES ApoB, non-high-density lipoprotein cholesterol (HDL-C), LDL-C, and TG. MAIN OUTCOME AND MEASURES The primary study outcome was incident myocardial infarction (MI).RESULTS Of the 389 529 individuals in the primary prevention group, 224 097 (58%) were female, and the median (IQR) age was 56.0 (49.5-62.5) years. Of the 40 430 patients with established atherosclerosis, 9647 (24%) were female, and the median (IQR) age was 63 (56.2-69.0) years. In the primary prevention cohort, apoB, non-HDL-C, and TG each individually were associated with incident MI. However, when assessed together, only apoB was associated (adjusted hazard ratio [aHR] per 1 SD, 1.27; 95% CI, 1.15-1.40; P < .001). Similarly, only apoB was associated with MI in the secondary prevention cohort. Adjusting for apoB, there was no association between the ratio of TG to LDL-C (a surrogate for the ratio of TG-rich lipoproteins to LDL) and risk of MI, implying that for a given concentration of apoB-containing lipoproteins, the relative proportions of particle subpopulations may no longer be a predictor of risk. CONCLUSIONS AND RELEVANCEIn this cohort study, risk of MI was best captured by the number of apoB-containing lipoproteins, independent from lipid content (cholesterol or TG) or type of lipoprotein (LDL or TG-rich). This suggests that apoB may be the primary driver of atherosclerosis and that lowering the concentration of all apoB-containing lipoproteins should be the focus of therapeutic strategies.

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Evaluating the relationship between circulating lipoprotein lipids and apolipoproteins with risk of coronary heart disease: A multivariable Mendelian randomisation analysis

Cited by 609 publications

References 72 publications

Circulating Lipoprotein Lipids, Apolipoproteins and Ischemic Stroke

Circulating Lipoprotein Lipids, Apolipoproteins and Ischemic Stroke

Dysregulated lipid metabolism links NAFLD to cardiovascular disease

Association of Apolipoprotein B–Containing Lipoproteins and Risk of Myocardial Infarction in Individuals With and Without Atherosclerosis

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