Association of Triglyceride-Lowering LPL Variants and LDL-C-Lowering LDLR Variants With Risk of Coronary Heart Disease.
Kastelein, John JP
Ray, Kausik K
Ginsberg, Henry N
Chapman, M John
Packard, Chris J
Bhatt, Deepak L
Sabatine, Marc S
American Medical Association (AMA)
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Ference, B., Kastelein, J. J., Ray, K. K., Ginsberg, H. N., Chapman, M. J., Packard, C. J., Laufs, U., et al. (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
IMPORTANCE: Triglycerides and cholesterol are both carried in plasma by apolipoprotein B (apoB)-containing lipoprotein particles. Whether lowering plasma triglycerides reduces the risk of cardiovascular events to the same extent as lowering low-density lipoprotein cholesterol (LDL-C) is unknown. 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 triglycerides, 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 decrease in 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 decrease in apoB-containing lipoproteins, the LPL score was associated with 69.9 (95%CI:68.1-71.6;p=7.1x10-1363) mg/dl lower triglycerides and 0.7 (95%CI:0.03-1.4;p=0.039) mg/dl higher LDL-C; while the LDLR score was associated with 14.2 (95%CI:13.6-14.8;p=1.4x10-465) mg/dl lower LDL-C and 1.9 (95%CI:0.1-3.9;p=0.036) mg/dl lower triglycerides. Despite these differences in associated lipid changes, the LPL and LDLR scores were associated with very similar reductions in the risk of CHD per 10 mg/dl decrease in apoB-containing lipoproteins (OR: 0.771, 4 95%CI:0.741-0.802,p=3.9x10-38; OR: 0.773, 95%CI:0.747-0.801,p=1.1x10-46, respectively). In multivariable Mendelian randomization analyses, the associations between triglycerides and LDL-C with the risk of CHD became null after adjusting for changes in apoB (triglycerides OR:1.014, 95%:0.965-1.065,p=0.189; LDL-C OR:1.010, 95%:0.967-1.055,p=0.186; apoB OR:0.761, 95%CI:0.723-0.798,p=7.51x10-20). CONCLUSIONS AND RELEVANCE: Triglyceride-lowering LPL variants and LDL-C lowering LDLR variants were associated with similar reductions in the risk of CHD per unit change in apoB. Therefore, the clinical benefit of lowering triglycerides and LDL-C may be proportional to the absolute change in apoB.
Humans, Coronary Disease, Genetic Predisposition to Disease, Lipoprotein Lipase, Triglycerides, Apolipoproteins B, Receptors, LDL, Risk Factors, Case-Control Studies, Prospective Studies, Middle Aged, Female, Male, Cholesterol, LDL, Metabolic Networks and Pathways, Genetic Variation, Mendelian Randomization Analysis, Loss of Function Mutation
Dr. Ference is supported by the National Institute for Health Research Cambridge Biomedical Research Centre at the Cambridge University Hospitals NHS Foundation Trust. Dr. Clare 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.
British Heart Foundation (RG/13/13/30194)
British Heart Foundation (RG/18/13/33946)
External DOI: https://doi.org/10.1001/jama.2018.20045
This record's URL: https://www.repository.cam.ac.uk/handle/1810/289244