Apolipoprotein A-V is a potential target for treating coronary artery disease: evidence from genetic and metabolomic analyses.

Dorina Ibi, Dorina Ibi, Manon Boot, Manon Boot, Martijn E T Dollé, Martijn E T Dollé, J Wouter Jukema, J Wouter Jukema, Frits R Rosendaal, Frits R Rosendaal, Constantinos Christodoulides, Constantinos Christodoulides, Matt J Neville, Matt J Neville, Robert Koivula, Robert Koivula, Patrick C N Rensen, Patrick C N Rensen, Fredrik Karpe, Fredrik Karpe, Raymond Noordam, Raymond Noordam, Ko Willems van Dijk, Ko Willems van Dijk

Journal: Journal of lipid research 2022;63(5):100193

PMID: 35278410

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Abstract

Triglyceride (TG)-lowering LPL variants in combination with genetic LDL-C-lowering variants are associated with reduced risk of coronary artery disease (CAD). Genetic variation in the APOA5 gene encoding apolipoprotein A-V also strongly affects TG levels, but the potential clinical impact and underlying mechanisms are yet to be resolved. Here, we aimed to study the effects of APOA5 genetic variation on CAD risk and plasma lipoproteins through factorial genetic association analyses. Using data from 309,780 European-ancestry participants from the UK Biobank, we evaluated the effects of lower TG levels as a result of genetic variation in APOA5 and/or LPL on CAD risk with or without a background of reduced LDL-C. Next, we compared lower TG levels via APOA5 and LPL variation with over 100 lipoprotein measurements in a combined sample from the Netherlands Epidemiology of Obesity study (N = 4,838) and the Oxford Biobank (N = 6,999). We found that lower TG levels due to combined APOA5 and LPL variation and genetically-influenced lower LDL-C levels afforded the largest reduction in CAD risk (odds ratio: 0.78 (0.73-0.82)). Compared to patients with genetically-influenced lower TG via LPL, genetically-influenced lower TG via APOA5 had similar and independent, but notably larger, effects on the lipoprotein profile. Our results suggest that lower TG levels as a result of APOA5 variation have strong beneficial effects on CAD risk and the lipoprotein profile, which suggest apo A-V may be a potential novel therapeutic target for CAD prevention.

Address: Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands; Department of Public Health and Primary Care, National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands. Electronic address: [email protected].; Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.; Department of Public Health and Primary Care, National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands.; Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands; Netherlands Heart Institute, Utrecht, The Netherlands.; Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands.; Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom.; Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom; NIHR Oxford Biomedical Research Centre, Oxford University Hospitals Foundation Trust, Oxford, United Kingdom.; Division of Endocrinology, Department of Internal Medicine, Leiden University Medical Center, Leiden, The Netherlands; Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands.; Division of Gerontology and Geriatrics, Department of Internal Medicine, Leiden University Medical Center, Leiden, The Netherlands.; Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands; Division of Endocrinology, Department of Internal Medicine, Leiden University Medical Center, Leiden, The Netherlands; Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands.

DOI: 10.1016/j.jlr.2022.100193

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MeSH Terms: Apolipoprotein A-V, Apolipoproteins A, Cholesterol, LDL, Coronary Artery Disease, Humans, Lipoproteins, Triglycerides