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Association of Triglyceride-Lowering LPL Variants and LDL-C–Lowering LDLR Variants With Risk of Coronary Heart Disease

Educational Objective
To understand that the clinical benefits of lowering triglyceride and low-density lipoprotein cholesterol (LDL-C) levels may be related to the absolute reduction in apolipoprotein B (ApoB)–containing lipoprotein particles.
1 Credit CME
Key Points

Question  What is the clinical benefit of lowering plasma triglyceride levels compared with lowering low-density lipoprotein cholesterol levels?

Findings  In mendelian randomization analyses involving 654 783 participants, triglyceride-lowering variants in the lipoprotein lipase gene and low-density lipoprotein cholesterol (LDL-C)–lowering variants in the LDL receptor gene were associated with similar lower risk of coronary heart disease per 10-mg/dL lower level of apolipoprotein B (ApoB)–containing lipoproteins (odds ratios of 0.771 and 0.773, respectively).

Meaning  The clinical benefit of lower triglyceride levels was similar to the clinical benefit of lower LDL-C levels per unit difference in ApoB and may be related to the absolute reduction in ApoB-containing lipoprotein particles.

Abstract

Importance  Triglycerides and cholesterol are both carried in plasma by apolipoprotein B (ApoB)–containing lipoprotein particles. It is unknown whether lowering plasma triglyceride levels reduces the risk of cardiovascular events to the same extent as lowering low-density lipoprotein cholesterol (LDL-C) levels.

Objective  To compare the association of triglyceride-lowering variants in the lipoprotein lipase (LPL) gene and LDL-C–lowering variants in the LDL receptor gene (LDLR) with the risk of cardiovascular disease per unit change in ApoB.

Design, Setting, and Participants  Mendelian randomization analyses evaluating the associations of genetic scores composed of triglyceride-lowering variants in the LPL gene and LDL-C–lowering variants in the LDLR gene, respectively, with the risk of cardiovascular events among participants enrolled in 63 cohort or case-control studies conducted in North America or Europe between 1948 and 2017.

Exposures  Differences in plasma triglyceride, LDL-C, and ApoB levels associated with the LPL and LDLR genetic scores.

Main Outcomes and Measures  Odds ratio (OR) for coronary heart disease (CHD)—defined as coronary death, myocardial infarction, or coronary revascularization—per 10-mg/dL lower concentration of ApoB-containing lipoproteins.

Results  A total of 654 783 participants, including 91 129 cases of CHD, were included (mean age, 62.7 years; 51.4% women). For each 10-mg/dL lower level of ApoB-containing lipoproteins, the LPL score was associated with 69.9-mg/dL (95% CI, 68.1-71.6; P = 7.1 × 10−1363) lower triglyceride levels and 0.7-mg/dL (95% CI, 0.03-1.4; P = .04) higher LDL-C levels; while the LDLR score was associated with 14.2-mg/dL (95% CI, 13.6-14.8; P = 1.4 × 10−465) lower LDL-C and 1.9-mg/dL (95% CI, 0.1-3.9; P = .04) lower triglyceride levels. Despite these differences in associated lipid levels, the LPL and LDLR scores were associated with similar lower risk of CHD per 10-mg/dL lower level of ApoB-containing lipoproteins (OR, 0.771 [95% CI, 0.741-0.802], P = 3.9 × 10−38 and OR, 0.773 [95% CI, 0.747-0.801], P = 1.1 × 10−46, respectively). In multivariable mendelian randomization analyses, the associations between triglyceride and LDL-C levels with the risk of CHD became null after adjusting for differences in ApoB (triglycerides: OR, 1.014 [95% CI, 0.965-1.065], P = .19; LDL-C: OR, 1.010 [95% CI, 0.967-1.055], P = .19; ApoB: OR, 0.761 [95% CI, 0.723-0.798], P = 7.51 × 10−20).

Conclusions and Relevance  Triglyceride-lowering LPL variants and LDL-C–lowering LDLR variants were associated with similar lower risk of CHD per unit difference in ApoB. Therefore, the clinical benefit of lowering triglyceride and LDL-C levels may be proportional to the absolute change in ApoB.

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Article Information

Corresponding Author: Brian A. Ference, MD, MPhil, MSc, Centre for Naturally Randomized Trials, University of Cambridge, 2 Worts’ Causeway, Cambridge CB1 8RN, UK (baf29@medschl.cam.ac.uk).

Accepted for Publication: December 17, 2018.

Author Contributions: Dr Ference had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Ference, Laufs, Catapano.

Acquisition, analysis, or interpretation of data: Ference, Kastelein, Ray, Ginsberg, Packard, Chapman, Oliver-Williams, Wood, Butterworth, Di Angelantonio, Danesh, Nicholls, Bhatt, Sabatine.

Drafting of the manuscript: Ference, Packard, Laufs.

Critical revision of the manuscript for important intellectual content: Ference, Kastelein, Ray, Ginsberg, Chapman, Laufs, Oliver-Williams, Wood, Butterworth, Di Angelantonio, Danesh, Nicholls, Bhatt, Sabatine, Catapano.

Statistical analysis: Ference, Packard, Oliver-Williams, Wood.

Obtained funding: Ference, Butterworth, Di Angelantonio.

Administrative, technical, or material support: Danesh, Nicholls.

Supervision: Ference, Kastelein, Ray, Butterworth, Catapano.

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Ference reported receiving personal fees from Merck & Co, Amgen, Esperion Therapeutics, Regeneron, Sanofi, Pfizer, dalCOR, The Medicines Company, CiVi BioPharma, KrKA Pharmaceuticals, American College of Cardiology, European Society of Cardiology, and the European Atherosclerosis Society and grants from Merck & Co, Amgen, Novartis, and Esperion Therapeutics. Dr Kastelein reported receiving personal fees from Affiris, Amgen, Corvidia, CSL Behring, CiVi Biopharma, Esperion, Gemphire, Madrigal, The Medicines Company, North Sea Therapeutics, Novartis, Regeneron, Staten Biotech, Merck & Co, Eli Lilly, Roche, Pfizer, and Dezima. Dr Ray reported receiving personal fees from Sanofi, Amgen, Regeneron, Merck Sharp & Dohme, Cipla, Cerenis, Akcea, Eli Lilly, The Medicines Company, AstraZeneca, Pfizer, Kowa, Algorithm, IONIS, Esperion, Novo Nordisk, Takeda, Boehringer Ingelheim, Resverlogix, and Abbvie and grants from Merck & Co, Merck Sharp & Dohme, Sanofi, Regeneron, Pfizer, and Amgen. Dr Ginsberg reported receiving personal fees and grants from Merck & Co, Kowa, Sanofi, Regeneron, Esperion, Akcea, and Amgen. Dr Chapman reported receiving personal fees from Akcea, Alexion, Amarin, Amgen, Daiichi-Sankyo, Kowa, Merck & Co, Pfizer, Sanofi, Regeneron, and Unilever and grants from Amgen, CSL, Kowa, Merck & Co, and Pfizer. Dr Packard reported receiving personal fees from Merck Sharp & Dohme, Merck & Co, Amgen, Pfizer, Sanofi, Regeneron, and Daiichi-Sankyo. Dr Laufs reported receiving personal fees from Merck & Co, Amgen, Pfizer, Esperion, and Sanofi. Dr Oliver-Williams reported receiving prize money from Novartis. Dr Butterworth reported receiving grants from the UK Medical Research Council, British Heart Foundation, European Union Framework Programme 7, and the National Institute for Health during the conduct of the study and grants from Pfizer, AstraZeneca, Merck & Co, Novartis, Biogen, and the European Research Council. Dr Di Angelantonio reported receiving grants from the National Institute for Health Research, Medical Research Council, British Heart Foundation, and NHS Blood and Transplant. Dr Danesh reported receiving personal fees from Merck Sharp & Dohme, Merck & Co, Novartis, Pfizer, and Sanofi; nonfinancial support from diaDexus; and grants from the British Heart Foundation, Bupa Foundation, diaDexus, European Research Council, European Union, Evelyn Trust, Fogarty International Center, GlaxoSmithKline, Merck & Co, National Heart, Lung, and Blood Institute, National Institute for Health Research, National Institute of Neurological Disorders and Stroke, NHS Blood and Transplant, Novartis, Pfizer, AstraZeneca, UK Medical Research Council, Wellcome Trust, and the UK Biobank. Dr Nicholls reported receiving personal fees from Eli Lilly, AstraZeneca, Amgen, Anthera, Omthera, Takeda, Novartis, Resverlogix, Sanofi, Regeneron, Esperion, Merck, Boehringer Ingelheim, CSL Behring, and Roche and grants from Eli Lilly, AstraZeneca, Amgen, Anthera, InfraReDx, LipoScience, Novartis, Resverlogix, Sanofi, Regeneron, Cerenis, Esperion, Merck & Co, and The Medicines Company. Dr Bhatt reported receiving grants from Amarin during the conduct of the study; grants from Amarin, AstraZeneca, Bristol-Myers Squibb, Eisai, Ethicon, Medtronic, Sanofi Aventis, Roche, Pfizer, Forest Laboratories/AstraZeneca, Ischemix, Amgen, Eli Lilly, Chiesi, Ironwood, Abbott, Regeneron, PhaseBio, Idorsia, Synaptic, and The Medicines Company; personal fees or nonfinancial support, including travel and lodging, from FlowCo, PLx Pharma, Takeda, Medscape Cardiology, Regado Biosciences, Boston VA Research Institute, Clinical Cardiology, VA, St Jude Medical (now Abbott), Biotronik, Cardax, the American College of Cardiology, Boston Scientific, Merck, Svelte, and Novo Nordisk; personal fees from Duke Clinical Research Institute, Mayo Clinic, Population Health Research Institute, American College of Cardiology, Belvoir Publications, Slack Publications, WebMD, Elsevier, the Society of Cardiovascular Patient Care, , HMP Global, Harvard Clinical Research Institute (now Baim Institute for Clinical Research), Journal of the American College of Cardiology, Cleveland Clinic, Mount Sinai School of Medicine, TobeSoft, Boehringer Ingelheim, and Bayer; and nonfinancial support from the American Heart Association outside the submitted work. Dr Sabatine reported receiving personal fees from Amgen, AstraZeneca, Bristol-Myers Squibb, Dyrnamix, Intarcia, Merck & Co, Janssen Research Development, MedImmune, Alnylam, CVS Caremark, Ionis, Cubist, Esperion, The Medicines Company, MyoKardia, and Zeus Scientific and grants from Abbott Laboratories, Amgen, AstraZeneca, Critical Diagnostics, Daiichi-Sankyo, Gilead, GlaxoSmithKline, Intarcia, Merck & Co, Roche Diagnostics, Takeda, Novartis, Poxel, Janssen Research and Development, MedImmune, Eisai, Genzyme, and Pfizer. Dr Catapano reported receiving personal fees from AstraZeneca, Amgen, Aegerion, Genzyme, Sanofi, Merck & Co, Menarini, Kowa, and Pfizer and grants from Amgen, Eli Lilly, Genzyme, Mediolanum, Sanofi, Merck & Co, Pfizer, Regeneron, Rottapharm, Recordati, and Sigma tau. No other disclosures were reported.

Funding/Support: Dr Ference is supported by the National Institute for Health Research Cambridge Biomedical Research Centre at the Cambridge University Hospitals NHS Foundation Trust. Dr Oliver-Williams is supported by Homerton College, University of Cambridge. Dr Butterworth is supported by the European Research Council. Dr Danesh is supported by the Medical Research Council, British Heart Foundation, and the National Institute for Health Research.

Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

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