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Apolipoprotein E (APOE) genotype-associated disease risks: a phenome-wide, registry-based, case-control study utilising the UK Biobank
Open accessAbstract
Background The three main alleles of the APOE gene (ε4, ε3 and ε2) carry differential risks for conditions including Alzheimer's disease (AD) and cardiovascular disease. Due to their clinical significance, we explored disease associations of the APOE genotypes using a hypothesis-free, data-driven, phenome-wide association study (PheWAS) approach. Methods We used data from the UK Biobank to screen for associations between APOE genotypes and over 950 disease outcomes using genotype ε3ε3 as a reference. Data was restricted to 337,484 white British participants (aged 37–73 years). Findings After correction for multiple testing, PheWAS analyses identified associations with 37 outcomes, representing 18 distinct diseases. As expected, ε3ε4 and ε4ε4 genotypes associated with increased odds of AD (p ≤ 7.6 × 10 −46 ), hypercholesterolaemia (p ≤ 7.1 × 10 −17 ) and ischaemic heart disease (p ≤ 2.3 × 10 −4 ), while ε2ε3 provided protection for the latter two conditions (p ≤ 3.7 × 10 −10 ) compared to ε3ε3. In contrast, ε4-associated disease protection was seen against obesity, chronic airway obstruction, type 2 diabetes, gallbladder disease, and liver disease (all p ≤ 5.2 × 10 −4 ) while ε2ε2 homozygosity increased risks of peripheral vascular disease, thromboembolism, arterial aneurysm, peptic ulcer, cervical disorders, and hallux valgus (all p ≤ 6.1 × 10 −4 ). Sensitivity analyses using brain neuroimaging, blood biochemistry, anthropometric, and spirometric biomarkers supported the PheWAS findings on APOE associations with respective disease outcomes. Interpretation PheWAS confirms strong associations between APOE and AD, hypercholesterolaemia, and ischaemic heart disease, and suggests potential ε4-associated disease protection and harmful effects of the ε2ε2 genotype, for several conditions. Funding National Health and Medical Research Council of Australia.
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“By contrast, in the same registries, APOEε2 has been associated with lower LDL cholesterol levels, increased triglyceride levels and increased risk of peripheral vascular disease87,88.”
From Multifaceted roles of APOE in Alzheimer disease (2024) · cites this paper as [88]
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“Besides AD43, APOE has been associated with at least eighteen other diseases, including heart disease and high cholesterol44.”
From Proteogenomic analysis of human cerebrospinal fluid identifies neurologically relevant regulation and implicates causal proteins for Alzheimer’s disease (2024) · cites this paper as [44]
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“APOE genotype was determined using SNP data at rs429358 and rs7412, which define the three major APOE isoforms (ε2, ε3, and ε4) based on established haplotypes. Genotypes were assigned according to allele combinations, consistent with prior UK Biobank studies,79”
From TET2-mutant myeloid cells mitigate Alzheimer’s disease progression via CNS infiltration and enhanced phagocytosis in mice (2025) · cites this paper as [79]
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“a risk increase also recently reported cross-sectionally in the UK Biobank [42]”
From APOE and vascular disease: Sequencing and genotyping in general population cohorts (2023) · cites this paper as [42]
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“In large health registries such as the UK BioBank, the APOEε4 allele has been associated with higher LDL cholesterol and triglycerides levels, lower HDL cholesterol levels and an increased risk of coronary artery disease.”
From Multifaceted roles of APOE in Alzheimer disease (2024) · cites this paper as [88]
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Controlling the False Discovery Rate: A Practical and Powerful Approach to Multiple Testing
Benjamini, Y., & Hochberg, Y. (1995) · Journal of the Royal Statistical Society Series B: Statistical Methodology · doi:10.1111/j.2517-6161.1995.tb02031.x · Cited by 109,482 · cited 1×
“1 £ 10 4 to control for multiple testing [10], accounting for all comparisons across the five PheWASs.”
BackgroundSudlow, C., Gallacher, J., Allen, N., Beral, V., Burton, P., Danesh, J., Downey, P., Elliott, P., Green, J., Landray, M., et al. (2015) · PLOS Medicine · doi:10.1371/journal.pmed.1001779 · Cited by 12,728 · cited 2×
“Participants provided electronic consent to use their anonymised data and samples for healthrelated research, to be re-contacted for further sub-studies, and for the UK Biobank to access their health-related records [5].”
BackgroundMethodThe UK Biobank resource with deep phenotyping and genomic data
Bycroft, C., Freeman, C., Petkova, D., Band, G., Elliott, L. T., Sharp, K., Motyer, A., Vukcevic, D., Delaneau, O., O’Connell, J., et al. (2018) · Nature · doi:10.1038/s41586-018-0579-z · Cited by 8,876 · cited 3×
“Our analyses were restricted to 337,484 unrelated white British individuals (established by self-report and genetic data) [6] who had consistent information between self-reported and genetic sex (appendix p 35 figure S2).”
MethodInfluentialDenny, J. C., Bastarache, L. A., Ritchie, M. D., Carroll, R. J., Zink, R., Mosley, J. D., Field, J. R., Pulley, J. M., Ramirez, A. H., Bowton, E., et al. (2013) · Nature Biotechnology · doi:10.1038/nbt.2749 · Cited by 987 · cited 1×
“For each phecode, we coded individuals with the phecode-ofinterest as cases, whilst participants without a phecode within the same category were considered the control group [8].”
MethodWeisgraber, K. H., Innerarity, T. L., & Mahley, R. W. (1982) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)34954-8 · Cited by 673 · cited 1×
“The homozygous e2e2 genotype increased the odds for a distinct set of disease outcomes not associated with other genotypes, suggesting that these conditions stem from a homozygous loss of APOE function specific to the e2 variant, such as its inability to bind the LDL receptor [22].”
BackgroundR PheWAS: data analysis and plotting tools for phenome-wide association studies in the R environment
Carroll, R. J., Bastarache, L. A., & Denny, J. C. (2014) · Bioinformatics · doi:10.1093/bioinformatics/btu197 · Cited by 435
Wei, W., Bastarache, L. A., Carroll, R. J., Marlo, J. E., Osterman, T. J., Gamazon, E. R., Cox, N. J., Roden, D. M., & Denny, J. C. (2017) · PLoS ONE · doi:10.1371/journal.pone.0175508 · Cited by 364
Huebbe, P., & Rimbach, G. H. (2017) · Ageing Research Reviews · doi:10.1016/j.arr.2017.06.002 · Cited by 202 · cited 1×
“Chronologically, e4 is believed to be the ancestral allele from which the e3 and e2 variants sequentially evolved over 200,000 years ago [1].”
BackgroundOxidized LDL triggers changes in oxidative stress and inflammatory biomarkers in human macrophages
Lara-Guzmán, O. J., Gil-Izquierdo, Á., Medina, S., Osorio, E., Álvarez-Quintero, R., Zuluaga, N., Oger, C., Galano, J.-M., Durand, T., & Muñoz-Durango, K. (2018) · Redox Biology · doi:10.1016/j.redox.2017.11.017 · Cited by 194 · cited 7×
“As is typically reported, e2e3 and e2e4 were protective for hypercholesterolaemia compared to e3e3 (with lower levels of “bad” cholesterol indicators; total cholesterol, LDL and APOB). e2e3 also had increased levels of “good” cholesterol indicators (HDL-cholesterol and APOA) and was associated with reduced risk of IHD…”
BackgroundInfluentialTudorache, I. F., Trusca, V. G., & Gafencu, A. V. (2017) · Computational and Structural Biotechnology Journal · doi:10.1016/j.csbj.2017.05.003 · Cited by 186 · cited 1×
“The polymorphisms affect the binding affinities of APOE for lipid and the LDLR (appendix p 34 figure S1), resulting in various effects on biomarkers of lipid and cholesterol health, and differential risks of a variety of health outcomes [2].”
BackgroundKhan, T. A., Shah, T., Prieto‐Merino, D., Zhang, W., Price, J. F., Fowkes, G. R., Cooper, J. A., Talmud, P. J., Humphries, S. E., Sundström, J., et al. (2013) · International Journal of Epidemiology · doi:10.1093/ije/dyt034 · Cited by 178 · cited 3×
“While the low cholesterol and LDL indicators in the e2e2 group can generally be considered a favourable profile, the e2e2 genotype is known to be associated with the highest circulating APOE protein levels of all the genotypes [3,4], and APOE levels positively associate with coagulation markers [24] which may contribu…”
BackgroundResultTanne, D., Koren-Morag, N., Graff, E., & Goldbourt, U. (2001) · Circulation · doi:10.1161/hc4901.100384 · Cited by 158 · cited 1×
“This genotype also had the highest level of triglycerides; an independent risk factor for stroke [25].”
BackgroundPlasma levels of apolipoprotein Eand risk of dementia in the general population
Rasmussen, K. L., Tybjærg‐Hansen, A., Nordestgaard, B. G., & Frikke‐Schmidt, R. (2015) · Annals of Neurology · doi:10.1002/ana.24326 · Cited by 156 · cited 2×
“While the low cholesterol and LDL indicators in the e2e2 group can generally be considered a favourable profile, the e2e2 genotype is known to be associated with the highest circulating APOE protein levels of all the genotypes [3,4], and APOE levels positively associate with coagulation markers [24] which may contribu…”
BackgroundAPOE4 Protects the Cognitive Development in Children with Heavy Diarrhea Burdens in Northeast Brazil
Oriá, R. B., Patrick, P. D., Zhang, H., Lorntz, B., Costa, C. M. D. C., Brito, G. A. D. C., Barrett, L. J., Lima, A. Â. M., & Guerrant, R. L. (2004) · Pediatric Research · doi:10.1203/01.pdr.0000148719.82468.ca · Cited by 145 · cited 1×
“Indeed, possession of the e4 allele has previously been associated with benefits such as improved fitness during foetal development, infancy and youth [11], and endows carriers with the ability to thrive when faced with severe infections, such as has been observed in children with enteric infections and heavy diarrhoe…”
BackgroundVolcik, K. A., Barkley, R. A., Hutchinson, R. G., Mosley, T. H., HEISS, G. M., Sharrett, A. R., Ballantyne, C. M., & Boerwinkle, E. (2006) · American Journal of Epidemiology · doi:10.1093/aje/kwj202 · Cited by 135
Trumble, B. C., Stieglitz, J., Blackwell, A. D., Allayee, H., Beheim, B., Finch, C. E., Gurven, M., & Kaplan, H. (2017) · The FASEB Journal · doi:10.1096/fj.201601084r · Cited by 106
Metabolic biomarkers and gallstone disease – a population-based study
Shabanzadeh, D. M., Skaaby, T., Sørensen, L. T., Eugen‐Olsen, J., & Jørgensen, T. (2017) · Scandinavian Journal of Gastroenterology · doi:10.1080/00365521.2017.1365166 · Cited by 74 · cited 1×
“Reduced risk of gallstone disease may be a consequence of diminished T2D risk, consistent with a previous study that identified APOE e4, and lower levels of insulin resistance markers, as being associated with protection against gallstone disease in a Caucasian (Danish) population [17].”
ResultTejedor, M. T., García-Sobreviela, M. P., Ledesma, M., & Arbonés-Mainar, J. M. (2014) · PLoS ONE · doi:10.1371/journal.pone.0108605 · Cited by 48 · cited 1×
“The reduced risk of obesity in e4e4 homozygotes relative to e3e3 is consistent with previous reports that BMI and other measures of obesity increase across the APOE allelic spectrum in the direction e4 < e3 < e2 [14,15].”
BackgroundYin, Y.-W., Li, Q., Sun, Q., Hu, A., Liu, H., Wang, Q., & Hou, Z. (2013) · Metabolism · doi:10.1016/j.metabol.2013.12.008 · Cited by 46 · cited 10×
“For example, our study suggests e4-associated protection against T2D and gallstones, while meta-analyses of Asian and predominantly Asian populations have reported the reverse; e4-associated increased risk of T2D [30], and gallstone disease [31].”
ResultInfluentialImpact of apolipoprotein E genetic polymorphisms on liver disease: An essential review
Nascimento, J. C. R., Matos, G. A., Pereira, L. C., Mourão, A. E. C. C. B., Sampaio, A. M., Oriá, R. B., & Toniutto, P. (2019) · Annals of Hepatology · doi:10.1016/j.aohep.2019.07.011 · Cited by 44 · cited 1×
“Our observation of reduced odds of chronic liver disease and cirrhosis provides experimental support for the findings of a recent literature review suggesting the e4 allele has protective effects in the progression of liver cirrhosis [18].”
ResultSmith, C. J., Ashford, J. W., & Perfetti, T. A. (2019) · Journal of Alzheimer s Disease · doi:10.3233/jad-181089 · Cited by 40 · cited 1×
“Indeed, possession of the e4 allele has previously been associated with benefits such as improved fitness during foetal development, infancy and youth [11], and endows carriers with the ability to thrive when faced with severe infections, such as has been observed in children with enteric infections and heavy diarrhoe…”
BackgroundKoopal, C., Geerlings, M. I., Muller, M., de Borst, G. J., Algra, A., van der Graaf, Y., & Visseren, F. L. J. (2016) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2016.01.009 · Cited by 34 · cited 1×
“5-fold increase in prevalence of peripheral artery disease that has been reported to associate with the e2e2 genotype amongst patients with high risk of cardiovascular disease [23], and extend this risk to e2e2 carriers in the wider population.”
BackgroundApolipoprotein E (Apo E) gene polymorphisms and recurrent pregnancy loss: a meta-analysis
Li, J., Chen, Y., Wu, H., & Li, L. (2013) · Journal of Assisted Reproduction and Genetics · doi:10.1007/s10815-013-0128-5 · Cited by 34 · cited 1×
“The phecode encompassed cervical erosion and ectropion, stricture and stenosis, cervical incompetence, and requirement of pregnancy-related care for cervical abnormalities, suggesting this finding may be related to risk of recurrent pregnancy loss, that has previously been associated with the e2 and e4 alleles [26].”
BackgroundA Meta-Analysis of Apolipoprotein E Gene ε2/ε3/ε4 Polymorphism for Gallbladder Stone Disease
Xue, P., Niu, W., Jiang, Z., Zheng, M., & Fei, J. (2012) · PLoS ONE · doi:10.1371/journal.pone.0045849 · Cited by 26 · cited 1×
“For example, our study suggests e4-associated protection against T2D and gallstones, while meta-analyses of Asian and predominantly Asian populations have reported the reverse; e4-associated increased risk of T2D [30], and gallstone disease [31].”
ResultDecreased plasma C‐reactive protein levels in APOE ε4 allele carriers
Martiskainen, H., Takalo, M., Solomon, A., Stančáková, A., Marttinen, M., Natunen, T., Haapasalo, A., Herukka, S., Kuusisto, J., Soininen, H. S., et al. (2018) · Annals of Clinical and Translational Neurology · doi:10.1002/acn3.639 · Cited by 25 · cited 1×
“In line with previous findings of low plasma CRP levels in e4 carriers [21], we found that CRP levels decreased with each additional e4 allele.”
ResultHsu, Y., Liu, Y., Hannan, M. T., Maixner, W. D., Smith, S. B., Diatchenko, L. B., Golightly, Y. M., Menz, H. B., Kraus, V. B., Doherty, M., et al. (2015) · Journal of Medical Genetics · doi:10.1136/jmedgenet-2015-103142 · Cited by 25
Orsi, F. A., Lijfering, W. M., van der Laarse, A., Ruhaak, L. R., Rosendaal, F. R., Cannegieter, S. C., & Cobbaert, C. M. (2019) · Clinical Epidemiology · doi:10.2147/clep.s196266 · Cited by 24 · cited 1×
“While the low cholesterol and LDL indicators in the e2e2 group can generally be considered a favourable profile, the e2e2 genotype is known to be associated with the highest circulating APOE protein levels of all the genotypes [3,4], and APOE levels positively associate with coagulation markers [24] which may contribu…”
BackgroundKulminski, A. M., Barochia, A. V., Loika, Y., Raghavachari, N., Arbeev, K. G., Wojczynski, M. K., Thyagarajan, B., Vardarajan, B. N., Christensen, K., Yashin, A. I., et al. (2018) · PLoS ONE · doi:10.1371/journal.pone.0206873 · Cited by 16
Tao, T.-Q., Jiang, Y.-Q., Li, W., Li, Y., Du, J., & Gui, J.-C. (2018) · Journal of Foot and Ankle Surgery · doi:10.1053/j.jfas.2018.01.007 · Cited by 8 · cited 1×
“The e2e2 genotype was also associated with hallux valgus, suggesting the APOE e2 allele may represent another risk allele for this highly heritable foot disorder that has been linked to susceptibility loci near genes encoding Axin 2 (AXIN2), Esterase D (ESD) [27], vitamin D receptor (VDR) [28], and tumour necrosis fac…”
BackgroundApolipoprotein E is a pancreatic extracellular factor that maintains mature β-cell gene expression
Mahmoud, A. I., Galdos, F. X., Dinan, K. A., Jedrychowski, M. P., Davis, J. C., Vujić, A., Rachmin, I., Shigley, C., Pancoast, J. R., Lee, S., et al. (2018) · PLoS ONE · doi:10.1371/journal.pone.0204595 · Cited by 7 · cited 1×
“It could also be that other mechanisms are at play; for example, APOE protein within the extracellular matrix of pancreatic islets isolated from rats, directly stimulates expression of important genes for b-cell function [16], although the impact of different APOE isoforms on this stimulation in vivo (and in humans) i…”
BackgroundRelationship Between Genetic Polymorphisms of the TNF Gene and Hallux Valgus Susceptibility
Yang, J., Wang, J., Liang, X., Zhao, H., Lü, J., Ma, Q., & Tian, F. (2019) · Genetic Testing and Molecular Biomarkers · doi:10.1089/gtmb.2018.0269 · Cited by 5
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Apolipoprotein E in lipid metabolism and neurodegenerative disease
Yang, L. G., March, Z. M., Stephenson, R. A., & Narayan, P. S. (2023) · Trends in Endocrinology & Metabolism · doi:10.1016/j.tem.2023.05.002 · Cited by 286
“In fact, a recent study of samples from the UK Biobank discovered that the commonAPOE alleles were associated with the risk of a multitude of conditions including obesity, liver disease, chronic airway obstruction, and type 2 diabetes [29,59,60].”
Fernández-Calle, R., Konings, S. C., Frontiñán-Rubio, J., García-Revilla, J., Camprubí-Ferrer, L., Svensson, M., Martinson, I., Boza-Serrano, A., Venero, J. L., Nielsen, H. M., et al. (2022) · Molecular Neurodegeneration · doi:10.1186/s13024-022-00566-4 · Cited by 278
Identifying individuals with high risk of Alzheimer’s disease using polygenic risk scores
Leonenko, G., Baker, E. A., Stevenson‐Hoare, J. O., Sierksma, A. S. R., Fiers, M. W. E. J., Williams, J. H., Strooper, B. D., & Escott‐Price, V. (2021) · Nature Communications · doi:10.1038/s41467-021-24082-z · Cited by 233
Multifaceted roles of APOE in Alzheimer disease
Jackson, R. J., Hyman, B. T., & Serrano-Pozo, A. (2024) · Nature Reviews Neurology · doi:10.1038/s41582-024-00988-2 · Cited by 193
“By contrast, in the same registries, APOE ε2 has been associated with lower LDL cholesterol levels, increased triglyceride levels and increased risk of peripheral vascular disease 87,88 .”
The duality of amyloid-β: its role in normal and Alzheimer’s disease states
Azargoonjahromi, A. (2024) · Molecular Brain · doi:10.1186/s13041-024-01118-1 · Cited by 214
“Of note, homozygosity for the APOE ε4 allele further increases the risk of developing AD [268].”
Background
Metadata
- Authors
- Lumsden, A. L., Mulugeta, A., Zhou, A., & Hyppönen, E.
- Affiliations
- University of South Australia (AU)
- Corresponding author
- Hyppönen, Elina
- Venue
- eBioMedicine
- Publisher
- Elsevier BV
- Published
- 2020-09
- Volume
- 59
- Pages
- 102954
- ISSN
- 2352-3964 (ISSN-L)
- PMC
- PMC7452404
- OpenAlex
- W3069395596
- Cited by
- 317
- References
- 31
- Citations by year
- 2026: 54 · 2025: 72 · 2024: 82 · 2023: 59 · 2022: 33 · 2021: 17
- FWCI
- 3.88
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- EBioMedicine (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- UniSA Research Outputs Repository (University of South Australia) (submittedVersion, other-oa)
- Adelaide Research & Scholarship (AR&S) (University of Adelaide) (submittedVersion, cc-by-nc-nd)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- UK Biobank (GNT1123603)
- National Health and Medical Research Council (GNT1157281)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipoproteins and Cardiovascular Health
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Keywords
- apolipoprotein E, APOE genotype, APOE ε4, APOE ε2, Alzheimer's disease, hypercholesterolemia, ischemic heart disease, phenome-wide association study, disease risk, obesity, type 2 diabetes, peripheral vascular disease, thromboembolism, arterial aneurysm, peptic ulcer, hallux valgus, cardiovascular disease, genetic risk factors
- MeSH terms
- Adult, Aged, Alleles, Apolipoproteins E, Female, Genotype, United Kingdom, Humans, Male, Middle Aged, Phenotype, Population Surveillance, Registries, Risk Factors, Case-Control Studies, Biological Specimen Banks, Risk Assessment, Genetic Predisposition to Disease, Genetic Association Studies
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