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Association of Genetically Enhanced Lipoprotein Lipase-Mediated Lipolysis and Low-Density Lipoprotein Cholesterol-Lowering Alleles With Risk of Coronary Disease and Type 2 Diabetes.

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Lotta, Luca A 
Stewart, Isobel D 
Sharp, Stephen J 
Day, Felix R 


IMPORTANCE: Pharmacological enhancers of lipoprotein lipase (LPL) are in preclinical or early clinical development for cardiovascular prevention. Studying whether these agents will reduce cardiovascular events or diabetes risk when added to existing lipid-lowering drugs would require large outcome trials. Human genetics studies can help prioritize or deprioritize these resource-demanding endeavors. OBJECTIVE: To investigate the independent and combined associations of genetically determined differences in LPL-mediated lipolysis and low-density lipoprotein cholesterol (LDL-C) metabolism with risk of coronary disease and diabetes. DESIGN, SETTING, AND PARTICIPANTS: In this genetic association study, individual-level genetic data from 392 220 participants from 2 population-based cohort studies and 1 case-cohort study conducted in Europe were included. Data were collected from January 1991 to July 2018, and data were analyzed from July 2014 to July 2018. EXPOSURES: Six conditionally independent triglyceride-lowering alleles in LPL, the p.Glu40Lys variant in ANGPTL4, rare loss-of-function variants in ANGPTL3, and LDL-C-lowering polymorphisms at 58 independent genomic regions, including HMGCR, NPC1L1, and PCSK9. MAIN OUTCOMES AND MEASURES: Odds ratio for coronary artery disease and type 2 diabetes. RESULTS: Of the 392 220 participants included, 211 915 (54.0%) were female, and the mean (SD) age was 57 (8) years. Triglyceride-lowering alleles in LPL were associated with protection from coronary disease (approximately 40% lower odds per SD of genetically lower triglycerides) and type 2 diabetes (approximately 30% lower odds) in people above or below the median of the population distribution of LDL-C-lowering alleles at 58 independent genomic regions, HMGCR, NPC1L1, or PCSK9. Associations with lower risk were consistent in quintiles of the distribution of LDL-C-lowering alleles and 2 × 2 factorial genetic analyses. The 40Lys variant in ANGPTL4 was associated with protection from coronary disease and type 2 diabetes in groups with genetically higher or lower LDL-C. For a genetic difference of 0.23 SDs in LDL-C, ANGPTL3 loss-of-function variants, which also have beneficial associations with LPL lipolysis, were associated with greater protection against coronary disease than other LDL-C-lowering genetic mechanisms (ANGPTL3 loss-of-function variants: odds ratio, 0.66; 95% CI, 0.52-0.83; 58 LDL-C-lowering variants: odds ratio, 0.90; 95% CI, 0.89-0.91; P for heterogeneity = .009). CONCLUSIONS AND RELEVANCE: Triglyceride-lowering alleles in the LPL pathway are associated with lower risk of coronary disease and type 2 diabetes independently of LDL-C-lowering genetic mechanisms. These findings provide human genetics evidence to support the development of agents that enhance LPL-mediated lipolysis for further clinical benefit in addition to LDL-C-lowering therapy.



Aged, Angiopoietin-Like Protein 4, Cholesterol, LDL, Coronary Artery Disease, Diabetes Mellitus, Type 2, Female, Genetic Association Studies, Genetic Predisposition to Disease, Humans, Hydroxymethylglutaryl CoA Reductases, Lipolysis, Lipoprotein Lipase, Male, Membrane Proteins, Membrane Transport Proteins, Middle Aged, Odds Ratio, Proprotein Convertase 9

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JAMA Cardiol

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American Medical Association (AMA)
Medical Research Council (MC_UU_12015/1)
MRC (MC_PC_13048)
Wellcome Trust (204623/Z/16/Z)
Wellcome Trust (107064/Z/15/Z)
Medical Research Council (MC_UU_12015/2)
Department of Health (via National Institute for Health Research (NIHR)) (NF-SI-0617-10149)
Department of Health (via National Institute for Health Research (NIHR)) (NF-SI-0512-10135)
MRC (MC_PC_13046)
European Commission (602068)
Medical Research Council (G0401527)
Medical Research Council (G1000143)
Medical Research Council (MR/L003120/1)
Medical Research Council (MC_UU_12012/5)
Medical Research Council (MR/N003284/1)
Wellcome Trust (100574/Z/12/Z)
Wellcome Trust (095515/Z/11/Z)
British Heart Foundation (None)
Medical Research Council (MC_UU_00002/7)
MRC (1950385)
Medical Research Council (MC_PC_12012)
Medical Research Council (G0401527/1)
This study was funded by the United Kingdom’s Medical Research Council through grants MC_UU_12015/1, MC_PC_13046, MC_PC_13048 and MR/L00002/1. This work was supported by the MRC Metabolic Diseases Unit (MC_UU_12012/5) and the Cambridge NIHR Biomedical Research Centre and EU/EFPIA Innovative Medicines Initiative Joint Undertaking (EMIF grant: 115372). EPIC-InterAct Study funding: funding for the InterAct project was provided by the EU FP6 programme (grant number LSHM_CT_2006_037197). S. B. is supported by a Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (Grant Number 204623/Z/16/Z). D. B. S. is supported by the Wellcome Trust grant n. 107064. M. McC. is a Wellcome Trust Senior Investigator and is supported by the following grants from the Wellcome Trust: 090532 and 098381. M. McC. was supported by the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre (BRC) and the views expressed are those of the Author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. S. O. R. acknowleges funding from the Wellcome Trust (Wellcome Trust Senior Investigator Award: 095515/Z/11/Z and Wellcome Trust Strategic Award: 100574/Z/12/Z).