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Cited by 9Lipid metabolism and disordersLipoproteins and Cardiovascular HealthGenetic Associations and Epidemiology

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

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Ibi, Dorina, Boot, Manon, Dollé, Martijn E.T., Jukema, J. Wouter, Rosendaal, Frits R., Christodoulides, Constantinos, Neville, Matt J., Koivula, Robert +4 more·2022·Journal of Lipid Research
DOI 10.1016/j.jlr.2022.100193PMC PMC9062431
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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.

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  • Mendelian randomization analyses confirm a causal relationship between lifelong TRL elevation and ASCVD.

    “Observational cohorts demonstrate that higher TG and remnant cholesterol predict cardiovascular events independently of LDL-C, while Mendelian randomization analyses confirm a causal relationship between lifelong TRL elevation and ASCVD.”

    From Targeting triglycerides for cardiovascular risk reduction (2026) · cites this paper as [63]

    The Introduction (page unavailable) reports prior Mendelian randomization analyses linking genetically lower triglycerides via LPL to reduced coronary artery disease risk, and the Results find a similar genetic association. But the Discussion explicitly says this study is not a proper Mendelian randomization test of whether triglycerides cause coronary artery disease. It does not confirm a causal effect of lifelong TRL elevation on ASCVD. (LLM, conf=0.86)

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Authors
Ibi, D., Boot, M., Dollé, M. E. T., Jukema, J. W., Rosendaal, F. R., Christodoulides, C., Neville, M. J., Koivula, R., Rensen, P. C. N., Karpe, F., Noordam, R., & Willems van Dijk, K.
Affiliations
  • Leiden University Medical Center (NL)
  • National Institute for Public Health and the Environment (NL)
  • University of Oxford (GB)
Corresponding author
Ibi, Dorina
ORCID
Venue
Journal of Lipid Research
Publisher
Elsevier BV
Published
2022-05
Volume
63
Issue
5
Pages
100193
ISSN
0022-2275 (ISSN-L)
DOI
10.1016/j.jlr.2022.100193
PMC
PMC9062431
OpenAlex
W4220837451
Cited by
9
References
8
Citations by year
2026: 3 · 2025: 2 · 2023: 2 · 2022: 2
FWCI
1.04
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Lipid Research (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Leiden Repository (Leiden University) (submittedVersion, cc-by)
  • Data Archiving and Networked Services (DANS) (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
  • Rivm Repository (Netherlands National Institute for Public Health and the Environment) (submittedVersion)
  • Rivm (National Institute for Public Health and the Environment) (submittedVersion)
Funders
  • National Institute for Health and Care Research
  • British Heart Foundation (FS/16/45/32359)
  • Universiteit Leiden
  • Leids Universitair Medisch Centrum
  • Medical Research Council (MC_PC_17228)
Topics
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
  • Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
Keywords
apolipoprotein A-V, APOA5, lipoprotein lipase, triglyceride lowering, LDL cholesterol lowering, coronary artery disease risk, serum lipoproteins, genetic association, metabolomics, therapeutic target
MeSH terms
Apolipoprotein A-V, Apolipoproteins A, Coronary Artery Disease, Humans, Lipoproteins, Cholesterol, LDL, Triglycerides

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