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Association of Triglyceride-Lowering LPL Variants and LDL-C-Lowering LDLR Variants With Risk of Coronary Heart Disease.
JAMA. 2019 01 29; 321(4):364-373.JAMA

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.

Authors+Show Affiliations

Centre for Naturally Randomized Trials, University of Cambridge, Cambridge, United Kingdom. Institute for Advanced Studies, University of Bristol, Bristol, United Kingdom. MRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom.Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.Imperial Centre for Cardiovascular Disease Prevention, Department of Primary Care and Public Health, School of Public Health, Imperial College London, London, United Kingdom.Irving Institute for Clinical and Translational Research, Columbia University Vagelos College of Physicians and Surgeons, New York, New York.National Institute for Health and Medical Research (INSERM), Pitie-Salpetriere University Hospital, Paris, France.Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom.Department of Cardiology, University of Leipzig, Leipzig, Germany.MRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom.MRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom.MRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom.MRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom.MRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom.Monash Cardiovascular Research Centre, University, Melbourne, Australia.Thrombolysis in Myocardial Infarction Study Group, Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.Thrombolysis in Myocardial Infarction Study Group, Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.Department of Pharmacological and Biomolecular Sciences, University of Milan, Multimedica IRCCS, Milano, Italy.

Pub Type(s)

Comparative Study
Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

30694319

Citation

Ference, Brian A., et al. "Association of Triglyceride-Lowering LPL Variants and LDL-C-Lowering LDLR Variants With Risk of Coronary Heart Disease." JAMA, vol. 321, no. 4, 2019, pp. 364-373.
Ference BA, Kastelein JJP, Ray KK, et al. Association of Triglyceride-Lowering LPL Variants and LDL-C-Lowering LDLR Variants With Risk of Coronary Heart Disease. JAMA. 2019;321(4):364-373.
Ference, B. A., Kastelein, J. J. P., Ray, K. K., Ginsberg, H. N., Chapman, M. J., Packard, C. J., Laufs, U., Oliver-Williams, C., Wood, A. M., Butterworth, A. S., Di Angelantonio, E., Danesh, J., Nicholls, S. J., Bhatt, D. L., Sabatine, M. S., & Catapano, A. L. (2019). Association of Triglyceride-Lowering LPL Variants and LDL-C-Lowering LDLR Variants With Risk of Coronary Heart Disease. JAMA, 321(4), 364-373. https://doi.org/10.1001/jama.2018.20045
Ference BA, et al. Association of Triglyceride-Lowering LPL Variants and LDL-C-Lowering LDLR Variants With Risk of Coronary Heart Disease. JAMA. 2019 01 29;321(4):364-373. PubMed PMID: 30694319.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Association of Triglyceride-Lowering LPL Variants and LDL-C-Lowering LDLR Variants With Risk of Coronary Heart Disease. AU - Ference,Brian A, AU - Kastelein,John J P, AU - Ray,Kausik K, AU - Ginsberg,Henry N, AU - Chapman,M John, AU - Packard,Chris J, AU - Laufs,Ulrich, AU - Oliver-Williams,Clare, AU - Wood,Angela M, AU - Butterworth,Adam S, AU - Di Angelantonio,Emanuele, AU - Danesh,John, AU - Nicholls,Stephen J, AU - Bhatt,Deepak L, AU - Sabatine,Marc S, AU - Catapano,Alberico L, PY - 2019/1/30/entrez PY - 2019/1/30/pubmed PY - 2019/3/21/medline SP - 364 EP - 373 JF - JAMA JO - JAMA VL - 321 IS - 4 N2 - 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. SN - 1538-3598 UR - https://www.unboundmedicine.com/medline/citation/30694319/Association_of_Triglyceride_Lowering_LPL_Variants_and_LDL_C_Lowering_LDLR_Variants_With_Risk_of_Coronary_Heart_Disease_ L2 - https://jamanetwork.com/journals/jama/fullarticle/10.1001/jama.2018.20045 DB - PRIME DP - Unbound Medicine ER -