Brian A Ference1,2,3, John J P Kastelein4, Kausik K Ray5, Henry N Ginsberg6, M John Chapman7, Chris J Packard8, Ulrich Laufs9, Clare Oliver-Williams3, Angela M Wood3, Adam S Butterworth3, Emanuele Di Angelantonio3, John Danesh3, Stephen J Nicholls10, Deepak L Bhatt11, Marc S Sabatine11, Alberico L Catapano12. 1. Centre for Naturally Randomized Trials, University of Cambridge, Cambridge, United Kingdom. 2. Institute for Advanced Studies, University of Bristol, Bristol, United Kingdom. 3. MRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom. 4. Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands. 5. Imperial Centre for Cardiovascular Disease Prevention, Department of Primary Care and Public Health, School of Public Health, Imperial College London, London, United Kingdom. 6. Irving Institute for Clinical and Translational Research, Columbia University Vagelos College of Physicians and Surgeons, New York, New York. 7. National Institute for Health and Medical Research (INSERM), Pitie-Salpetriere University Hospital, Paris, France. 8. Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom. 9. Department of Cardiology, University of Leipzig, Leipzig, Germany. 10. Monash Cardiovascular Research Centre, University, Melbourne, Australia. 11. Thrombolysis in Myocardial Infarction Study Group, Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts. 12. Department of Pharmacological and Biomolecular Sciences, University of Milan, Multimedica IRCCS, Milano, Italy.
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.
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.
Authors: Anette Varbo; Marianne Benn; Anne Tybjærg-Hansen; Anders B Jørgensen; Ruth Frikke-Schmidt; Børge G Nordestgaard Journal: J Am Coll Cardiol Date: 2012-12-19 Impact factor: 24.094
Authors: Brian A Ference; Wonsuk Yoo; Issa Alesh; Nitin Mahajan; Karolina K Mirowska; Abhishek Mewada; Joel Kahn; Luis Afonso; Kim Allan Williams; John M Flack Journal: J Am Coll Cardiol Date: 2012-10-17 Impact factor: 24.094
Authors: H B Rubins; S J Robins; D Collins; C L Fye; J W Anderson; M B Elam; F H Faas; E Linares; E J Schaefer; G Schectman; T J Wilt; J Wittes Journal: N Engl J Med Date: 1999-08-05 Impact factor: 91.245
Authors: Henry N Ginsberg; Marshall B Elam; Laura C Lovato; John R Crouse; Lawrence A Leiter; Peter Linz; William T Friedewald; John B Buse; Hertzel C Gerstein; Jeffrey Probstfield; Richard H Grimm; Faramarz Ismail-Beigi; J Thomas Bigger; David C Goff; William C Cushman; Denise G Simons-Morton; Robert P Byington Journal: N Engl J Med Date: 2010-03-14 Impact factor: 91.245
Authors: A Keech; R J Simes; P Barter; J Best; R Scott; M R Taskinen; P Forder; A Pillai; T Davis; P Glasziou; P Drury; Y A Kesäniemi; D Sullivan; D Hunt; P Colman; M d'Emden; M Whiting; C Ehnholm; M Laakso Journal: Lancet Date: 2005-11-26 Impact factor: 79.321
Authors: Nadeem Sarwar; Manjinder S Sandhu; Sally L Ricketts; Adam S Butterworth; Emanuele Di Angelantonio; S Matthijs Boekholdt; Willem Ouwehand; Hugh Watkins; Nilesh J Samani; Danish Saleheen; Debbie Lawlor; Muredach P Reilly; Aroon D Hingorani; Philippa J Talmud; John Danesh Journal: Lancet Date: 2010-05-08 Impact factor: 79.321
Authors: C Baigent; L Blackwell; J Emberson; L E Holland; C Reith; N Bhala; R Peto; E H Barnes; A Keech; J Simes; R Collins Journal: Lancet Date: 2010-11-08 Impact factor: 79.321
Authors: Edward K Duran; Aaron W Aday; Nancy R Cook; Julie E Buring; Paul M Ridker; Aruna D Pradhan Journal: J Am Coll Cardiol Date: 2020-05-05 Impact factor: 24.094
Authors: Nicholas A Marston; Robert P Giugliano; KyungAh Im; Michael G Silverman; Michelle L O'Donoghue; Stephen D Wiviott; Brian A Ference; Marc S Sabatine Journal: Circulation Date: 2019-09-18 Impact factor: 29.690
Authors: Tsion Aberra; Eric D Peterson; Neha J Pagidipati; Hillary Mulder; Daniel M Wojdyla; Sephy Philip; Craig Granowitz; Ann Marie Navar Journal: J Clin Lipidol Date: 2020-05-06 Impact factor: 4.766
Authors: Najmeh Ahangari; Mohammad Doosti; Majid Ghayour Mobarhan; Amirhossein Sahebkar; Gordon A Ferns; Alireza Pasdar Journal: Ann Med Date: 2020-08-24 Impact factor: 4.709
Authors: Marios K Georgakis; Rainer Malik; Christopher D Anderson; Klaus G Parhofer; Jemma C Hopewell; Martin Dichgans Journal: Brain Date: 2020-02-01 Impact factor: 13.501
Authors: Julio Alejandro Lamprea-Montealegre; Natalie Staplin; William G Herrington; Richard Haynes; Jonathan Emberson; Colin Baigent; Ian H de Boer Journal: Clin J Am Soc Nephrol Date: 2019-12-12 Impact factor: 8.237