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Original Investigation
January 29, 2019

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

Author Affiliations
  • 1Centre for Naturally Randomized Trials, University of Cambridge, Cambridge, United Kingdom
  • 2Institute for Advanced Studies, University of Bristol, Bristol, United Kingdom
  • 3MRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom
  • 4Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands
  • 5Imperial Centre for Cardiovascular Disease Prevention, Department of Primary Care and Public Health, School of Public Health, Imperial College London, London, United Kingdom
  • 6Irving Institute for Clinical and Translational Research, Columbia University Vagelos College of Physicians and Surgeons, New York, New York
  • 7National Institute for Health and Medical Research (INSERM), Pitie-Salpetriere University Hospital, Paris, France
  • 8Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom
  • 9Department of Cardiology, University of Leipzig, Leipzig, Germany
  • 10Monash Cardiovascular Research Centre, University, Melbourne, Australia
  • 11Thrombolysis in Myocardial Infarction Study Group, Division of Cardiovascular Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts
  • 12Department of Pharmacological and Biomolecular Sciences, University of Milan, Multimedica IRCCS, Milano, Italy
JAMA. 2019;321(4):364-373. doi:10.1001/jama.2018.20045
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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