Circulating apolipoprotein E concentration and cardiovascular disease risk: meta-analysis of results from three studies
Open accessAbstract
BACKGROUND: The association of APOE genotype with circulating apolipoprotein E (ApoE) concentration and cardiovascular disease (CVD) risk is well established. However, the relationship of circulating ApoE concentration and CVD has received little attention. METHODS AND FINDINGS: To address this, we measured circulating ApoE concentration in 9,587 individuals (with 1,413 CVD events) from three studies with incident CVD events: two population-based studies, the English Longitudinal Study of Ageing (ELSA) and the men-only Northwick Park Heart Study II (NPHSII), and a nested sub-study of the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT). We examined the association of circulating ApoE with cardiovascular risk factors in the two population-based studies (ELSA and NPHSII) and the relationship between ApoE concentration and coronary heart disease and stroke in all three studies. Analyses were carried out within study, and, where appropriate, pooled effect estimates were derived using meta-analysis. In the population-based samples, circulating ApoE was associated with systolic blood pressure (correlation coefficient 0.08, p < 0.001, in both ELSA and NPHSII), total cholesterol (correlation coefficient 0.46 and 0.34 in ELSA and NPHSII, respectively; both p < 0.001), low-density lipoprotein cholesterol (correlation coefficient 0.30 and 0.14, respectively; both p < 0.001), high-density lipoprotein (correlation coefficient 0.16 and -0.14, respectively; both p < 0.001), and triglycerides (correlation coefficient 0.43 and 0.46, respectivly; both p < 0.001). In NPHSII, ApoE concentration was additionally associated with apolipoprotein B (correlation coefficient 0.13, p = 0.001) and lipoprotein(a) (correlation coefficient -0.11, p < 0.001). In the pooled analysis of ASCOT, ELSA, and NPHSII, there was no association of ApoE with CVD events; the odds ratio (OR) for CVD events per 1-standard-deviation higher ApoE concentration was 1.02 (95% CI 0.96, 1.09). After adjustment for cardiovascular risk factors, the OR for CVD per 1-standard-deviation higher ApoE concentration was 0.97 (95% CI 0.82, 1.15). Limitations of these analyses include a polyclonal method of ApoE measurement, rather than isoform-specific measurement, a moderate sample size (although larger than any other study to our knowledge and with a long lag between ApoE measures), and CVD events that may attenuate an effect. CONCLUSIONS: In the largest study to date on this question, we found no evidence of an association of circulating ApoE concentration with CVD events. The established association of APOE genotype with CVD events may be explained by isoform-specific functions as well as other mechanisms, rather than circulating concentrations of ApoE.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
A few studies have addressed the association between plasma apoE and cardiovascular mortality.
“A few studies have addressed the association between plasma apoE and cardiovascular mortality.26,27”
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Human apolipoprotein E. The complete amino acid sequence
Rall, S. C., Weisgraber, K. H., & Mahley, R. W. (1982) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)34702-1 · Cited by 741 · see citing works
Familial apolipoprotein E deficiency.
Schaefer, E. J., Gregg, R. E., Ghiselli, G., Forte, T. M., Ordovas, J. M., Zech, L. A., & Brewer, H. B. (1986) · Journal of Clinical Investigation · doi:10.1172/jci112704 · Cited by 313 · see citing works
ApoE Plasma Levels and Risk of Cardiovascular Mortality in Old Age
Mooijaart, S. P., Berbée, J. F. P., van Heemst, D., Havekes, L. M., de Craen, A. J. M., Slagboom, P. E., Rensen, P. C. N., & Westendorp, R. G. J. (2006) · PLoS Medicine · doi:10.1371/journal.pmed.0030176 · Cited by 129 · see citing works
McKay, G. J., Silvestri, G., Chakravarthy, U., Dasari, S., Fritsche, L. G., Weber, B. H., Keilhauer, C. N., Klein, M. L., Francis, P. J., Klaver, C. C., et al. (2011) · American Journal of Epidemiology · doi:10.1093/aje/kwr015 · Cited by 105 · see citing works
Self-citationPlasma levels of apolipoprotein E and risk of ischemic heart disease in the general population
Rasmussen, K. L., Tybjærg-Hansen, A., Nordestgaard, B. G., & Frikke-Schmidt, R. (2016) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2015.12.038 · Cited by 47 · see citing works
Flagged first, then by citations
Research works printed but not linked: 21
- [1]Blum CB (1982) Dynamics of apolipoprotein E metabolism in humans. J Lipid Res 23: 1308– 1316. 7161560
- [2]Mahley RW (1988) Apolipoprotein E: cholesterol transport protein with expanding role in cell biology. Science 240: 622– 630. 10.1126/science.3283935 3283935 · DOI · Paper page
- [3]Utermann G (1975) Isolation and partial characterization of an arginine-rich apolipoprotein from human plasma very-low-density lipoproteins: apolipoprotein E. Hoppe Seylers Z Physiol Chem 356: 1113– 1121. 10.1515/bchm2.1975.356.2.1113 172422 · DOI
- [6]Hofker MH, van Vlijmen BJ, Havekes LM (1998) Transgenic mouse models to study the role of APOE in hyperlipidemia and atherosclerosis. Atherosclerosis 137: 1– 11. 10.1016/S0021-9150(97)00266-9 9568731 · DOI
- [7]Vincent-Viry M, Schiele F, Gueguen R, Bohnet K, Visvikis S, Siest G (1998) Biological variations and genetic reference values for apolipoprotein E serum concentrations: results from the STANISLAS cohort study. Clin Chem 44: 957– 965. 9590368
- [8]Bennet AM, Di Angelantonio E, Ye Z, Wensley F, Dahlin A, Ahlbom A, et al (2007) Association of apolipoprotein E genotypes with lipid levels and coronary risk. JAMA 298: 1300– 1311. 10.1001/jama.298.11.1300 17878422 · DOI · Paper page
- [10]van Vliet P, Mooijaart SP, de Craen AJ, Rensen PC, van Heemst D, Westendorp RG (2007) Plasma levels of apolipoprotein E and risk of stroke in old age. Ann N Y Acad Sci 1100: 140– 147. 10.1196/annals.1395.012 17460172 · DOI
- [11]Corsetti JP, Gansevoort RT, Bakker SJ, Navis G, Sparks CE, Dullaart RP (2012) Apolipoprotein E predicts incident cardiovascular disease risk in women but not in men with concurrently high levels of high-density lipoprotein cholesterol and C-reactive protein. Metabolism 61: 996– 1002. 10.1016/j.metabol.2011.11.010 22225956 · DOI · Paper page
- [13]Ioannidis JP, Trikalinos TA (2005) Early extreme contradictory estimates may appear in published research: the Proteus phenomenon in molecular genetics research and randomized trials. J Clin Epidemiol 58: 543– 549. 10.1016/j.jclinepi.2004.10.019 15878467 · DOI
- [14]Miller GJ, Bauer KA, Barzegar S, Cooper JA, Rosenberg RD (1996) Increased activation of the haemostatic system in men at high risk of fatal coronary heart disease. Thromb Haemost 75: 767– 771. 8725721
- [16]Dahlof B, Sever PS, Poulter NR, Wedel H, Beevers DG, Caulfield M, et al (2005) Prevention of cardiovascular events with an antihypertensive regimen of amlodipine adding perindopril as required versus atenolol adding bendroflumethiazide as required, in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA): a multicentre randomised controlled trial. Lancet 366: 895– 906. 10.1016/S0140-6736(05)67185-1 16154016 · DOI · Paper page
- [17]Rasmussen KL, Tybjaerg-Hansen A, Nordestgaard BG, Frikke-Schmidt R (2015) Plasma levels of apolipoprotein E and risk of dementia in the general population. Ann Neurol 77: 301– 311. 10.1002/ana.24326 25469919 · DOI · Paper page
- [19]Lambert JC, Ibrahim-Verbaas CA, Harold D, Naj AC, Sims R, Bellenguez C, et al (2013) Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer’s disease. Nat Genet 45: 1452– 1458. 10.1038/ng.2802 24162737 PMC3896259 · DOI · Paper page
- [20]Fritsche LG, Chen W, Schu M, Yaspan BL, Yu Y, Thorleifsson G, et al (2013) Seven new loci associated with age-related macular degeneration. Nat Genet 45: 433– 439. 10.1038/ng.2578 23455636 PMC3739472 · DOI · Paper page
- [21]Schneider WJ, Kovanen PT, Brown MS, Goldstein JL, Utermann G, Weber W, et al (1981) Familial dysbetalipoproteinemia. Abnormal binding of mutant apoprotein E to low density lipoprotein receptors of human fibroblasts and membranes from liver and adrenal of rats, rabbits, and cows. J Clin Invest 68: 1075– 1085. 10.1172/JCI110330 6270194 PMC370895 · DOI · Paper page
- [22]Weisgraber KH, Innerarity TL, Mahley RW (1982) Abnormal lipoprotein receptor-binding activity of the human E apoprotein due to cysteine-arginine interchange at a single site. J Biol Chem 257: 2518– 2521. 6277903
- [23]Dong LM, Wilson C, Wardell MR, Simmons T, Mahley RW, Weisgraber KH, et al (1994) Human apolipoprotein E. Role of arginine 61 in mediating the lipoprotein preferences of the E3 and E4 isoforms. J Biol Chem 269: 22358– 22365. 8071364
- [24]Sing CF, Davignon J (1985) Role of the apolipoprotein E polymorphism in determining normal plasma lipid and lipoprotein variation. Am J Hum Genet 37: 268– 285. 3985008 PMC1684560
- [25]Teslovich TM, Musunuru K, Smith AV, Edmondson AC, Stylianou IM, Koseki M, et al (2010) Biological, clinical and population relevance of 95 loci for blood lipids. Nature 466: 707– 713. 10.1038/nature09270 20686565 PMC3039276 · DOI · Paper page
- [26]Talmud PJ, Drenos F, Shah S, Shah T, Palmen J, Verzilli C, et al (2009) Gene-centric association signals for lipids and apolipoproteins identified via the HumanCVD BeadChip. Am J Hum Genet 85: 628– 642. 10.1016/j.ajhg.2009.10.014 19913121 PMC2775832 · DOI
- [27]Wensley F, Gao P, Burgess S, Kaptoge S, Di Angelantonio E, Shah T, et al (2011) Association between C reactive protein and coronary heart disease: Mendelian randomisation analysis based on individual participant data. BMJ 342: d548 10.1136/bmj.d548 21325005 PMC3039696 · DOI · Paper page
Cited by
Sorted by citations
Program, T. M. V., Evangelou, E., Warren, H. R., Mosen-Ansorena, D., Mifsud, B., Pazoki, R., Gao, H., Ntritsos, G., Dimou, N., Cabrera, C. P., et al. (2018) · Nature Genetics · doi:10.1038/s41588-018-0205-x · Cited by 1,381 · see citing works
Self-citationApolipoprotein E in lipoprotein metabolism, health and cardiovascular disease
Marais, A. D. (2019) · Pathology · doi:10.1016/j.pathol.2018.11.002 · Cited by 382 · see citing works
Rasmussen, K. L., Tybjærg-Hansen, A., Nordestgaard, B. G., & Frikke-Schmidt, R. (2019) · European Heart Journal · doi:10.1093/eurheartj/ehz402 · Cited by 86 · see citing works
Update on the laboratory investigation of dyslipidemias
Ramasamy, I. (2018) · Clinica Chimica Acta · doi:10.1016/j.cca.2018.01.015 · Cited by 50 · see citing works
- Authors
- Sofat, R., Cooper, J. A., Kumari, M., Casas, J. P., Mitchell, J. P., Acharya, J., Thom, S., Hughes, A. D., Humphries, S. E., & Hingorani, A. D.
- Affiliations
- University College London (GB)
- Farr Institute (GB)
- Hammersmith Hospital (GB)
- Corresponding author
- Sofat, Reecha
- ORCID
- Venue
- PLOS Medicine
- Publisher
- Public Library of Science (PLoS)
- Published
- 2016-10-18
- Volume
- 13
- Issue
- 10
- Pages
- e1002146
- ISSN
- 1549-1277 (ISSN-L)
- 1549-1676
- PMC
- PMC5068709
- OpenAlex
- W2537275996
- Cited by
- 42
- References
- 5
- Citations by year
- 2026: 4 · 2025: 2 · 2024: 3 · 2023: 4 · 2022: 2 · 2021: 6 · 2020: 6 · 2019: 6 · 2018: 5 · 2017: 4
- FWCI
- 0.99
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- PLoS Medicine (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Open Access at Essex (University of Essex) (acceptedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- UCL Discovery (University College London) (submittedVersion)
- Figshare (submittedVersion, cc-by)
- Spiral (Imperial College London) (submittedVersion, other-oa)
- Funders
- British Heart Foundation (FS/07/011, PG08/008)
- National Institute on Aging (R01AG1764406S1)
- Topics
- Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Health and Risk Factors
- Keywords
- apolipoprotein E, cardiovascular risk, coronary artery disease, stroke, APOE genotype, serum lipids, systolic blood pressure, triglycerides, apolipoprotein B, lipoprotein(a), cardiovascular risk factors, incident cardiovascular events, English Longitudinal Study of Ageing
- MeSH terms
- Apolipoproteins E, Cardiovascular Diseases, Female, Genotype, Humans, Male, Middle Aged, Myocardial Infarction, Risk Factors, Stroke
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
