CoChat
Sign Up
Cited by 55Lipoproteins and Cardiovascular HealthMetabolomics and Mass Spectrometry StudiesDiabetes, Cardiovascular Risks, and Lipoproteins

The effect of apolipoprotein E polymorphism on serum metabolome – a population-based 10-year follow-up study

Open access
Karjalainen, Juho-Pekka, Mononen, Nina, Hutri-Kähönen, Nina, Lehtimäki, Miikael, Juonala, Markus, Ala-Korpela, Mika, Kähönen, Mika, Raitakari, Olli +1 more·2019·Scientific Reports
DOI 10.1038/s41598-018-36450-9PMC PMC6346097
Open this paper in CoChat — free accountOpen PDF

Abstract

Apolipoprotein E (apoE) is the key regulator of plasma lipids, mediating altered functionalities in lipoprotein metabolism – affecting the risk of coronary artery (CAD) and Alzheimer’s diseases, as well as longevity. Searching pathways influenced by apoE prior to adverse manifestations, we utilized a metabolome dataset of 228 nuclear-magnetic-resonance-measured serum parameters with a 10-year follow-up from the population-based Young Finns Study cohort of 2,234 apoE-genotyped (rs7412, rs429358) adults, aged 24–39 at baseline. At the end of our follow-up, by limiting FDR-corrected p < 0.05, regression analyses revealed 180/228 apoE-polymorphism-related associations with the studied metabolites, in all subjects – without indications of apoE x sex interactions. Across all measured apoE- and apoB-containing lipoproteins, ε4 allele had consistently atherogenic and ε2 protective effect on particle concentrations of free/esterified cholesterol, triglycerides, phospholipids and total lipids. As novel findings, ε4 associated with glycoprotein acetyls, LDL-diameter and isoleucine – all reported biomarkers of CAD-risk, inflammation, diabetes and total mortality. ApoE-subgroup differences persisted through our 10-year follow-up, although some variation of individual metabolite levels was noticed. In conclusion, apoE polymorphism associate with a complex metabolic change, including aberrations in multiple novel biomarkers related to elevated cardiometabolic and all-cause mortality risk, extending our understanding about the role of apoE in health and disease.

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.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1038/s41598-018-36450-9

Cites

4 of 4 references verified0 citation errors · 0 not checkable

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.

A few free checks a day · papers already verified open instantly · results are public

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?

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

Flagged first, then by citations

Research works printed but not linked: 50

  1. [4]Nelson CP Association analyses based on false discovery rate implicate new loci for coronary artery disease Nat. Genet. 2017 49 1385 1391 10.1038/ng.3913 28714975 · DOI
  2. [7]Lehtimaki T Apolipoprotein E phenotypes in Finnish youths: a cross-sectional and 6- year follow-up study Journal of Lipid Research 1990 31 487 2341810
  3. [8]Ilveskoski E Age-dependent association of apolipoprotein E genotype with coronary and aortic atherosclerosis in middle-aged men: an autopsy study Circulation 1999 100 608 613 10.1161/01.CIR.100.6.608 10441097 · DOI
  4. [9]Ilveskoski E Apolipoprotein E polymorphism and carotid artery intima-media thickness in a random sample of middle-aged men Atherosclerosis 2000 153 147 153 10.1016/S0021-9150(00)00383-X 11058709 · DOI
  5. [10]Natarajan P Multiethnic Exome-Wide Association Study of Subclinical Atherosclerosis Circ Cardiovasc Genet 2016 9 511 520 10.1161/CIRCGENETICS.116.001572 27872105 PMC5418659 · DOI · Paper page
  6. [11]Villeneuve S Brisson D Marchant NL Gaudet D The potential applications of Apolipoprotein E in personalized medicine Front Aging Neurosci 2014 6 154 10.3389/fnagi.2014.00154 25071563 PMC4085650 · DOI
  7. [12]Seripa D The genetics of the human APOE polymorphism Rejuvenation Res 2011 14 491 500 10.1089/rej.2011.1169 21958003 · DOI
  8. [13]Ehnholm C Lukka M Kuusi T Nikkilä E Utermann G Apolipoprotein E polymorphism in the Finnish population: gene frequencies and relation to lipoprotein concentrations J. Lipid Res. 1986 27 227 235 3734624
  9. [14]Laaksonen R Identifying new Risk Markers and Potential Targets for Coronary Artery Disease: The Value of the Lipidome and Metabolome Cardiovasc Drugs Ther 2016 30 19 32 10.1007/s10557-016-6651-8 26896184 · DOI
  10. [15]März W Low-density lipoprotein triglycerides associated with low-grade systemic inflammation, adhesion molecules, and angiographic coronary artery disease: the Ludwigshafen Risk and Cardiovascular Health study Circulation 2004 110 3068 3074 10.1161/01.CIR.0000146898.06923.80 15505088 · DOI
  11. [16]Zhu H The association of apolipoprotein E (APOE) gene polymorphisms with atherosclerosis susceptibility: a meta-analysis Minerva Cardioangiol 2016 64 47 54 26005211
  12. [17]Zhao QR Lei YY Li J Jiang N Shi JP Association between apolipoprotein E polymorphisms and premature coronary artery disease: a meta-analysis Clin. Chem. Lab. Med. 2017 55 284 298 10.1515/cclm-2016-0145 27394044 · DOI
  13. [18]Xu M Apolipoprotein E Gene Variants and Risk of Coronary Heart Disease: A Meta-Analysis Biomed Res Int 2016 2016 3912175 10.1155/2016/3912175 27868062 PMC5102878 · DOI
  14. [19]Kumar A Association between Apolipoprotein ε4 Gene Polymorphism and Risk of Ischemic Stroke: A Meta-Analysis Ann Neurosci 2016 23 113 121 10.1159/000443568 27647962 PMC5020389 · DOI
  15. [20]Viiri LE Relations of APOE promoter polymorphisms to LDL cholesterol and markers of subclinical atherosclerosis in young adults J. Lipid Res. 2006 47 1298 1306 10.1194/jlr.M600033-JLR200 16528057 · DOI
  16. [21]Grönroos P Relation of apolipoprotein E polymorphism to markers of early atherosclerotic changes in young adults–the Cardiovascular Risk in Young Finns Study Circ. J. 2008 72 29 34 10.1253/circj.72.29 18159095 · DOI
  17. [22]Viiri LE The association of the apolipoprotein E gene promoter polymorphisms and haplotypes with serum lipid and lipoprotein concentrations Atherosclerosis 2005 179 161 167 10.1016/j.atherosclerosis.2004.10.004 15721023 · DOI
  18. [23]Grönroos P Influence of apolipoprotein E polymorphism on serum lipid and lipoprotein changes: a 21-year follow-up study from childhood to adulthood. The Cardiovascular Risk in Young Finns Study Clin. Chem. Lab. Med. 2007 45 592 598 10.1515/CCLM.2007.116 17484618 · DOI
  19. [24]Bennet AM Association of apolipoprotein E genotypes with lipid levels and coronary risk JAMA 2007 298 1300 1311 10.1001/jama.298.11.1300 17878422 · DOI · Paper page
  20. [25]Soininen P Kangas AJ Würtz P Suna T Ala-Korpela M Quantitative serum nuclear magnetic resonance metabolomics in cardiovascular epidemiology and genetics Circ Cardiovasc Genet 2015 8 192 206 10.1161/CIRCGENETICS.114.000216 25691689 · DOI
  21. [26]Raitakari OT Cohort profile: the cardiovascular risk in Young Finns Study Int J Epidemiol 2008 37 1220 1226 10.1093/ije/dym225 18263651 · DOI
  22. [28]Würtz P Quantitative Serum Nuclear Magnetic Resonance Metabolomics in Large-Scale Epidemiology: A Primer on -Omic Technologies Am. J. Epidemiol. 2017 186 1084 1096 10.1093/aje/kwx016 29106475 PMC5860146 · DOI
  23. [29]Soininen P High-throughput serum NMR metabonomics for cost-effective holistic studies on systemic metabolism Analyst 2009 134 1781 1785 10.1039/b910205a 19684899 · DOI
  24. [30]Nuotio, J. et al. Prediction of Adult Dyslipidemia Using Genetic and Childhood Clinical Risk Factors: The Cardiovascular Risk in Young Finns Study. Circ Cardiovasc Genet10, 10.1161/CIRCGENETICS.116.001604 (2017). 28620070 · DOI
  25. [31]Benjamini Y Drai D Elmer G Kafkafi N Golani I Controlling the false discovery rate in behavior genetics research Behav. Brain Res. 2001 125 279 284 10.1016/S0166-4328(01)00297-2 11682119 · DOI · Paper page
  26. [32]Lehtimäki, T. Apolipoprotein E phenotypes in Finnish children and young adults. PhD Thesis, University of Tampere, 94, ISBN: 9789514431319 (1992).
  27. [33]Eichner JE Apolipoprotein E polymorphism and cardiovascular disease: a HuGE review Am. J. Epidemiol. 2002 155 487 495 10.1093/aje/155.6.487 11882522 · DOI · Paper page
  28. [34]Liehn, E. A. et al. Apolipoprotein E in Cardiovascular Diseases: Novel Aspects of an Old-fashioned Enigma. Arch. Med. Res, 10.1016/j.arcmed.2018.08.008 (2018). 30213474 · DOI
  29. [35]Downer B Estus S Katsumata Y Fardo DW Longitudinal trajectories of cholesterol from midlife through late life according to apolipoprotein E allele status International journal of environmental research and public health 2014 11 10663 10693 10.3390/ijerph111010663 25325355 PMC4211000 · DOI
  30. [36]Gueguen R Visvikis S Steinmetz J Siest G Boerwinkle E An analysis of genotype effects and their interactions by using the apolipoprotein E polymorphism and longitudinal data Am. J. Hum. Genet. 1989 45 793 802 2816943 PMC1683423
  31. [37]Nordestgaard BG Triglyceride-Rich Lipoproteins and Atherosclerotic Cardiovascular Disease: New Insights From Epidemiology, Genetics, and Biology Circ. Res. 2016 118 547 563 10.1161/CIRCRESAHA.115.306249 26892957 · DOI · Paper page
  32. [38]Choi HY Hafiane A Schwertani A Genest J High-Density Lipoproteins: Biology, Epidemiology, and Clinical Management Can J Cardiol 2017 33 325 333 10.1016/j.cjca.2016.09.012 28063740 · DOI
  33. [39]Rosenson RS HDL and atherosclerotic cardiovascular disease: genetic insights into complex biology Nat Rev Cardiol 2018 15 9 19 10.1038/nrcardio.2017.115 28795686 · DOI
  34. [40]Vitali C Khetarpal SA Rader DJ HDL Cholesterol Metabolism and the Risk of CHD: New Insights from Human Genetics Curr Cardiol Rep 2017 19 132 10.1007/s11886-017-0940-0 29103089 · DOI
  35. [41]Superko HR High-density lipoprotein subclasses and their relationship to cardiovascular disease J Clin Lipidol 2012 6 496 523 10.1016/j.jacl.2012.03.001 23312047 · DOI
  36. [42]Karathanasis SK Freeman LA Gordon SM Remaley AT The Changing Face of HDL and the Best Way to Measure It Clin. Chem. 2017 63 196 210 10.1373/clinchem.2016.257725 27879324 · DOI
  37. [43]Rosenson RS The High-Density Lipoprotein Puzzle: Why Classic Epidemiology, Genetic Epidemiology, and Clinical Trials Conflict? Arterioscler. Thromb. Vasc. Biol. 2016 36 777 782 10.1161/ATVBAHA.116.307024 26966281 · DOI
  38. [44]Swirski, F. K. Inflammation and CVD in 2017: From clonal haematopoiesis to the CANTOS trial. Nat Rev Cardiol, 10.1038/nrcardio.2017.208 (2017). 29263444 · DOI
  39. [45]Grönroos P Association of high sensitive C-reactive protein with apolipoprotein E polymorphism in children and young adults: the Cardiovascular Risk in Young Finns Study Clin. Chem. Lab. Med. 2008 46 179 186 10.1515/CCLM.2008.033 18324906 · DOI
  40. [46]Lawler PR Circulating N-Linked Glycoprotein Acetyls and Longitudinal Mortality Risk Circ. Res. 2016 118 1106 1115 10.1161/CIRCRESAHA.115.308078 26951635 PMC4836171 · DOI
  41. [47]Connelly MA Otvos JD Shalaurova I Playford MP Mehta NN GlycA, a novel biomarker of systemic inflammation and cardiovascular disease risk J Transl Med 2017 15 219 10.1186/s12967-017-1321-6 29078787 PMC5658936 · DOI
  42. [48]Fischer K Biomarker profiling by nuclear magnetic resonance spectroscopy for the prediction of all-cause mortality: an observational study of 17,345 persons PLoS Med. 2014 11 e1001606 10.1371/journal.pmed.1001606 24586121 PMC3934819 · DOI · Paper page
  43. [49]Grammer TB Low-density lipoprotein particle diameter and mortality: the Ludwigshafen Risk and Cardiovascular Health Study Eur. Heart J. 2015 36 31 38 10.1093/eurheartj/ehu055 24569029 · DOI
  44. [50]Superko HR Gadesam RR Is it LDL particle size or number that correlates with risk for cardiovascular disease? Curr Atheroscler Rep 2008 10 377 385 10.1007/s11883-008-0059-2 18706278 · DOI
  45. [51]Zhang S Zeng X Ren M Mao X Qiao S Novel metabolic and physiological functions of branched chain amino acids: a review J Anim Sci Biotechnol 2017 8 10 10.1186/s40104-016-0139-z 28127425 PMC5260006 · DOI · Paper page
  46. [52]Würtz P Branched-chain and aromatic amino acids are predictors of insulin resistance in young adults Diabetes Care 2013 36 648 655 10.2337/dc12-0895 23129134 PMC3579331 · DOI
  47. [53]Würtz P Metabolite profiling and cardiovascular event risk: a prospective study of 3 population-based cohorts Circulation 2015 131 774 785 10.1161/CIRCULATIONAHA.114.013116 25573147 PMC4351161 · DOI
  48. [54]Lehtimaki T Association between serum lipids and apolipoprotein E phenotype is influenced by diet in a population-based sample of free-living children and young adults: the Cardiovascular Risk in Young Finns Study Journal of Lipid Research 1995 36 653 7616113
  49. [55]Calabuig-Navarro MV A randomized trial and novel SPR technique identifies altered lipoprotein-LDL receptor binding as a mechanism underlying elevated LDL-cholesterol in APOE4s Sci Rep 2017 7 44119 10.1038/srep44119 28276521 PMC5343425 · DOI
  50. [56]Anroedh, S. S. et al. Plasma concentrations of molecular lipid species predict long-term clinical outcome in coronary artery disease patients. J. Lipid Res, 10.1194/jlr.P081281 (2018). PMC6121931 29858423 · DOI

Cited by

Sorted by citations

Authors
Karjalainen, J.-P., Mononen, N., Hutri-Kähönen, N., Lehtimäki, M., Juonala, M., Ala-Korpela, M., Kähönen, M., Raitakari, O., & Lehtimäki, T.
Affiliations
  • Tampere University (FI)
  • Fimlab (Finland) (FI)
  • University of Turku (FI)
  • Tampere University Hospital (FI)
Corresponding author
Karjalainen, Juho-Pekka
ORCID
Venue
Scientific Reports
Publisher
Springer Science and Business Media LLC
Published
2019-01-24
Volume
9
Issue
1
Pages
458-458
ISSN
2045-2322 (ISSN-L)
DOI
10.1038/s41598-018-36450-9
PMC
PMC6346097
OpenAlex
W2912601519
Cited by
55
References
4
Citations by year
2026: 8 · 2025: 5 · 2024: 4 · 2023: 8 · 2022: 12 · 2021: 7 · 2020: 6 · 2019: 5
FWCI
7.17
Type
journal article
Language
en
Open access
Licence
Locations
  • Scientific Reports (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, other-oa)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Explore Bristol Research (publishedVersion, cc-by)
  • Bristol Research (University of Bristol) (publishedVersion, cc-by)
  • UTUPub (University of Turku) (submittedVersion)
  • UTUPub (University of Turku) (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
  • Tampere University Institutional Repository (Tampere University) (submittedVersion, cc-by)
Funders
  • Foundation for Cardiovascular Research
  • Yrjö Jahnssonin Säätiö
  • Wellcome Trust
  • British Heart Foundation
  • European Commission (755320)
  • University of Bristol (MC_UU_12013/1, MC_UU_12013)
  • Kela (X51001)
  • Academy of Finland (X51001, 124,282, 134309, 121584, 286,284, 129378, 126925, 121584, 124282, 129378, 755320, 126,925, 41071, 117787)
  • Fondation pour la Recherche Médicale
  • Suomen Kulttuurirahasto
  • Tekes
  • Juho Vainion Säätiö
  • Novo Nordisk
  • Päivikki ja Sakari Sohlbergin Säätiö
  • Signe ja Ane Gyllenbergin Säätiö
  • Tampereen Yliopisto (X51001)
  • Emil Aaltosen Säätiö (286284, 755320, X51001)
  • Sydäntutkimussäätiö (121584, 286284, 124282, 755320, X51001, 134309, 126925, 129378, 117787, 41071)
  • Oulun Yliopisto
  • Tampereen Tuberkuloosisäätiö (755320, 286284, X51001)
  • Diabetesliitto
  • Paavo Nurmen Säätiö
  • Novo Nordisk Fonden
  • Diabetestutkimussäätiö
  • Medical Research Council (MC_UU_12013, MCUU12013/1, MC_UU_00011/1)
  • Pirkanmaan Rahasto
  • H2020 European Research Council (742927)
Topics
  • Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolomics and Mass Spectrometry Studies
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
Keywords
APOE polymorphism, APOE ε4, serum metabolome, lipoproteins, coronary artery disease risk, glycoprotein acetyls, isoleucine, triglycerides, esterified cholesterol, phospholipids, cardiometabolic biomarkers, all-cause mortality, Young Finns Study
MeSH terms
Adult, Alleles, Apolipoproteins E, Cross-Sectional Studies, Disease Susceptibility, Female, Gene Frequency, Genotype, Humans, Longitudinal Studies, Male, Polymorphism, Genetic, Biomarkers, Metabolomics, Metabolome, Young Adult

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