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Journal of Medical Microbiology logo Journal of Medical Microbiology

Volume 74, Issue 1

The Apoprotein E4 isotype does not affect the severity of COVID-19 infection and other flu-like syndromes No Access

Graphical Abstract

Impact of e4 allele on flu-like syndromes

The ɛ4 allele has no influence on flu-like syndrome, including COVID-19. COVID-19 severity was associated with BMI, male sex, comorbidities and IL-4 levels.

Abstract

Apolipoprotein E (ApoE), especially the ApoE4 isotype, is suggested to influence the severity of respiratory viral infections; however, this association is still unclear.

The presence of allele ε4 impacts the development of flu-like syndromes.

This study aimed to evaluate the impact of the Apo E4 isoform on the severity and duration of flu-like syndromes, including the coronavirus disease COVID-19.

This study comprised 280 individuals presenting flu-like symptoms, all genotyped for ApoE isoforms. Data were collected on clinical course, comorbidities, nutritional status, biochemical and inflammatory markers, SARS-CoV-2 reverse transcription PCR results and disease severity (mild, moderate or severe) according to the World Health Organization criteria. The individuals were analysed as a whole and within subgroups based on the SARS-CoV-2-positive (COVID-19 group) or SARS-CoV-2-negative (flu-like syndrome group) test.

The frequency of the ε4 allele was similar across the whole population and in both the COVID-19 and flu-like syndrome subgroups (17 and 18%, respectively). No differences were seen in sex, age range, self-reported skin colour, body mass index (BMI), number of comorbidities, vaccination status, biochemical, cytokine and lipid profiles (except for total cholesterol) in the flu-like group when ε4 allele carriers and non-carriers were compared. In the COVID-19 group, the ε4 allele did not correlate with disease severity or duration, number of comorbidities or inflammatory biomarkers. While gender distribution was equal in the overall COVID-19 population, male gender strongly correlated with COVID-19 severity. Multivariate analysis showed that older individuals, male gender, higher BMI and the presence of comorbidities were linked to increased chances of developing moderate and severe disease. IL-4 was the only factor found to reduce the risk of severe COVID-19.

The presence of one ɛ4 allele showed no association with the duration and severity of flu-like syndromes, including COVID-19. Nonetheless, SARS-CoV-2-positive individuals tend to be older men with a higher BMI and a tendency to be overweight or with obesity. Regarding COVID-19 severity, BMI, male sex and the number of associated comorbidities were the factors that increased the chance of developing a more severe form of COVID-19.

  • Received:
  • Accepted:
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Keyword(s): apolipoprotein E , COVID-19 , cytokines , inflammation , obesity and viral infection
Funding
This study was supported by the:
  • Fundação de Amparo à Pesquisa do Estado de Minas Gerais (# APQ-01153-21)
  • Merck Sharp and Dohme United Kingdom - Investigator Initiated Studies Program (MISP#60383)"
  • Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (#0688/2020)
  • Conselho Nacional de Desenvolvimento Científico e Tecnológico (#407363/2021-1)
© 2024 The Authors
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/content/journal/jmm/10.1099/jmm.0.001951
2025-01-22
2025-11-11

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References

  1. Finch CE, Sapolsky RM. The evolution of Alzheimer disease, the reproductive schedule, and apoE isoforms. Neurobiol Aging 1999; 20:407–428 [View Article] [PubMed]
     [Google Scholar]
  2. Huebbe P, Rimbach G. Evolution of human apolipoprotein E (APOE) isoforms: gene structure, protein function and interaction with dietary factors. Ageing Res Rev 2017; 37:146–161 [View Article] [PubMed]
     [Google Scholar]
  3. Mahley RW, Weisgraber KH, Huang Y. Apolipoprotein E: structure determines function, from atherosclerosis to Alzheimer’s disease to AIDS. J Lipid Res 2009; 50:S183–S188 [View Article]
     [Google Scholar]
  4. Vance JM, Farrer LA, Huang Y, Cruchaga C, Hyman BT et al. Report of the APOE4 National Institute on Aging/Alzheimer Disease Sequencing Project Consortium Working Group: reducing APOE4 in Carriers is a Therapeutic Goal for Alzheimer’s Disease. Ann Neurol 2024; 95:625–634 [View Article] [PubMed]
     [Google Scholar]
  5. Liu YC, Kuo RL, Shih SR. COVID-19: The first documented coronavirus pandemic in history. Biomed J 2020; 43:328–333 [View Article] [PubMed]
     [Google Scholar]
  6. Severe Covid-19 GWAS Group Ellinghaus D, Degenhardt F, Bujanda L, Buti M et al. Genomewide association study of severe Covid-19 with respiratory failure. N Engl J Med 2020; 383:1522–1534 [View Article] [PubMed]
     [Google Scholar]
  7. Kurki SN, Kantonen J, Kaivola K, Hokkanen L, Mäyränpää MI et al. APOE ε4 associates with increased risk of severe COVID-19, cerebral microhaemorrhages and post-COVID mental fatigue: a Finnish biobank, autopsy and clinical study. Acta Neuropathol Commun 2021; 9:199 [View Article] [PubMed]
     [Google Scholar]
  8. Kuo C-L, Pilling LC, Atkins JL, Masoli JAH, Delgado J et al. APOE e4 genotype predicts severe COVID-19 in the UK Biobank Community Cohort. J Gerontol A Biol Sci Med Sci 2020; 75:2231–2232 [View Article] [PubMed]
     [Google Scholar]
  9. Kuo C-L, Pilling LC, Atkins JL, Masoli JAH, Delgado J et al. ApoE e4e4 genotype and mortality with COVID-19 in UK Biobank. J Gerontol A Biol Sci Med Sci 2020; 75:1801–1803 [View Article]
     [Google Scholar]
  10. Zhang LN, Li MJ, Shang YH, Zhao FF, Huang HC et al. Independent and correlated role of apolipoprotein E ɛ4 genotype and herpes simplex virus type 1 in Alzheimer’s Disease. J Alzheimers Dis 2020; 77:15–31 [View Article] [PubMed]
     [Google Scholar]
  11. Burt TD, Agan BK, Marconi VC, He W, Kulkarni H et al. Apolipoprotein (apo) E4 enhances HIV-1 cell entry in vitro, and the APOE epsilon4/epsilon4 genotype accelerates HIV disease progression. Proc Natl Acad Sci U S A 2008; 105:8718–8723 [View Article] [PubMed]
     [Google Scholar]
  12. Chen F, Ke Q, Wei W, Cui L, Wang Y. Apolipoprotein E and viral infection: risks and mechanisms. Mol Ther Nucleic Acids 2023; 33:529–542 [View Article] [PubMed]
     [Google Scholar]
  13. Gao P, Ji M, Liu X, Chen X, Liu H et al. Apolipoprotein E mediates cell resistance to influenza virus infection. Sci Adv 2022; 8:eabm6668 [View Article] [PubMed]
     [Google Scholar]
  14. Zhao Y, Zhao Z, Wang Y, Zhou Y, Ma Y et al. Single-cell RNA expression profiling of ACE2, the receptor of SARS-CoV-2. Am J Respir Crit Care Med 2020; 202:756–759 [View Article] [PubMed]
     [Google Scholar]
  15. Chen F, Chen Y, Ke Q, Wang Y, Gong Z et al. ApoE4 associated with severe COVID-19 outcomes via downregulation of ACE2 and imbalanced RAS pathway. J Transl Med 2023; 21:103 [View Article] [PubMed]
     [Google Scholar]
  16. Chaves JCS, Milton LA, Stewart R, Senapati T, Rantanen LM et al. Differential cytokine responses of APOE3 and APOE4 blood-brain barrier cell types to SARS-CoV-2 spike proteins. J Neuroimmune Pharmacol 2024; 19:22 [View Article] [PubMed]
     [Google Scholar]
  17. Fernández-de-Las-Peñas C, Arendt-Nielsen L, Díaz-Gil G, Gómez-Esquer F, Gil-Crujera A et al. Apolipoprotein E (ApoE) ε4 genotype (ApoE rs429358-ApoE rs7412 polymorphisms) is not associated with long COVID symptoms in previously hospitalized COVID-19 survivors. Genes 2023; 14:1420 [View Article] [PubMed]
     [Google Scholar]
  18. Oliveira DN, Tavares-Júnior JWL, Feitosa WLQ, Cunha LCV, Gomes CMP et al. Long-COVID olfactory dysfunction: allele E4 of apolipoprotein E as a possible protective factor. Arq Neuropsiquiatr 2024; 82:1–7 [View Article] [PubMed]
     [Google Scholar]
  19. Organization. WH Novel coronavirus COVID-19 therapeutic trial synopsis. Geneva, Switzerland; 2020
  20. Lu X, Wang L, Sakthivel SK, Whitaker B, Murray J et al. US CDC real-time reverse transcription PCR panel for detection of severe acute respiratory syndrome coronavirus 2. Emerg Infect Dis 2020; 26:1654–1665 [View Article] [PubMed]
     [Google Scholar]
  21. Dancey C, Reidy J. Statistics without Maths for Psychology Pearson Education; 2020
     [Google Scholar]
  22. Corbo RM, Scacchi R. Apolipoprotein E (APOE) allele distribution in the world. Is APOE*4 a “thrifty” allele?. Ann Hum Genet 1999; 63:301–310 [View Article] [PubMed]
     [Google Scholar]
  23. Souza DRS, Nakachima L, Biagioni RB, Nakazone MA, Pinhel MAS et al. Relevance of apolipoprotein E4 for the lipid profile of Brazilian patients with coronary artery disease. Braz J Med Biol Res 2007; 40:189–197 [View Article] [PubMed]
     [Google Scholar]
  24. Demarchi DA, Salzano FM, Altuna ME, Fiegenbaum M, Hill K et al. APOE polymorphism distribution among Native Americans and related populations. Ann Hum Biol 2005; 32:351–365 [View Article] [PubMed]
     [Google Scholar]
  25. Arrifano G, Alvarez-Leite J, Souza-Monteiro J, Augusto-Oliveira M, Paraense R et al. In the Heart of the Amazon: noncommunicable diseases and apolipoprotein E4 genotype in the riverine population. IJERPH 2018; 15:1957 [View Article]
     [Google Scholar]
  26. Fuzikawa AK, Peixoto SV, Taufer M, Moriguchi EH, Lima-Costa MF. Apolipoprotein E polymorphism distribution in an elderly Brazilian population: the Bambuí Health and Aging Study. Braz J Med Biol Res 2007; 40:1429–1434 [View Article] [PubMed]
     [Google Scholar]
  27. Lumsden AL, Mulugeta A, Zhou A, Hyppönen E. Apolipoprotein E (APOE) genotype-associated disease risks: a phenome-wide, registry-based, case-control study utilising the UK Biobank. EBioMedicine 2020; 59:102954 [View Article] [PubMed]
     [Google Scholar]
  28. Goldstein MR, Poland GA, Graeber ACW. Does apolipoprotein E genotype predict COVID-19 severity?. QJM 2020; 113:529–530 [View Article] [PubMed]
     [Google Scholar]
  29. Tavares-Júnior JWL, Oliveira DN, da Silva JBS, Feitosa WLQ, Sousa AVM et al. Long-covid cognitive impairment: cognitive assessment and apolipoprotein E (APOE) genotyping correlation in a Brazilian cohort. Front Psychiatry 2022; 13:947583 [View Article] [PubMed]
     [Google Scholar]
  30. Kasparian K, Graykowski D, Cudaback E. Commentary: APOE e4 genotype predicts severe COVID-19 in the UK Biobank Community Cohort. Front Immunol 2020; 11:1939 [View Article] [PubMed]
     [Google Scholar]
  31. Conti P, Younes A. Coronavirus COV-19/SARS-COV-2 affects women less than men: clinical response to viral infection. J Biol Regul Homeost Agents 2020; 34:339–343 [View Article] [PubMed]
     [Google Scholar]
  32. Takahashi T, Ellingson MK, Wong P, Israelow B, Lucas C et al. Sex differences in immune responses that underlie COVID-19 disease outcomes. Nature 2020; 588:315–320 [View Article]
     [Google Scholar]
  33. Caussy C, Pattou F, Wallet F, Simon C, Chalopin S et al. Prevalence of obesity among adult inpatients with COVID-19 in France. Lancet Diabetes Endocrinol 2020; 8:562–564 [View Article] [PubMed]
     [Google Scholar]
  34. Klang E, Kassim G, Soffer S, Freeman R, Levin MA et al. Severe obesity as an independent risk factor for COVID‐19 mortality in hospitalized patients younger than 50. Obesity 2020; 28:1595–1599 [View Article]
     [Google Scholar]
  35. Anderson MR, Geleris J, Anderson DR, Zucker J, Nobel YR et al. Body mass index and risk for intubation or death in SARS-CoV-2 infection : a retrospective cohort study. Ann Intern Med 2020; 173:782–790 [View Article] [PubMed]
     [Google Scholar]
  36. Goyal P, Ringel JB, Rajan M, Choi JJ, Pinheiro LC et al. Obesity and COVID-19 in New York City: a retrospective cohort study. Ann Intern Med 2020; 173:855–858 [View Article] [PubMed]
     [Google Scholar]
  37. Tartof SY, Qian L, Hong V, Wei R, Nadjafi RF et al. Obesity and mortality among patients diagnosed with COVID-19: results from an integrated health care organization. Ann Intern Med 2020; 173:773–781 [View Article] [PubMed]
     [Google Scholar]
  38. Kruglikov IL, Scherer PE. The role of adipocytes and adipocyte-like cells in the severity of COVID-19 infections. Obesity 2020; 28:1187–1190 [View Article] [PubMed]
     [Google Scholar]
  39. Kass DA. COVID-19 and severe obesity: a big problem?. Ann Intern Med 2020; 173:840–841 [View Article] [PubMed]
     [Google Scholar]
  40. Gallo Marin B, Aghagoli G, Lavine K, Yang L, Siff EJ et al. Predictors of COVID-19 severity: a literature review. Rev Med Virol 2021; 31:1–10 [View Article] [PubMed]
     [Google Scholar]
  41. Williamson EJ, Walker AJ, Bhaskaran K, Bacon S, Bates C et al. Factors associated with COVID-19-related death using OpenSAFELY. Nature 2020; 584:430–436 [View Article] [PubMed]
     [Google Scholar]
  42. Chatterjee S, Nalla LV, Sharma M, Sharma N, Singh AA et al. Association of COVID-19 with comorbidities: an update. ACS Pharmacol Transl Sci 2023; 6:334–354 [View Article] [PubMed]
     [Google Scholar]
  43. Russell CD, Lone NI, Baillie JK. Comorbidities, multimorbidity and COVID-19. Nat Med 2023; 29:334–343 [View Article] [PubMed]
     [Google Scholar]
  44. Ozsurekci Y, Aykac K, Er AG, Halacli B, Arasli M et al. Predictive value of cytokine/chemokine responses for the disease severity and management in children and adult cases with COVID-19. J Med Virol 2021; 93:2828–2837 [View Article] [PubMed]
     [Google Scholar]
  45. Liu Y, Chen D, Hou J, Li H, Cao D et al. An inter-correlated cytokine network identified at the center of cytokine storm predicted COVID-19 prognosis. Cytokine 2021; 138:155365 [View Article] [PubMed]
     [Google Scholar]
  46. Chang Y, Bai M, You Q. Associations between serum interleukins (IL-1). Biomed Res Int 20222755246 [View Article]
     [Google Scholar]
  47. Merza MY, Hwaiz RA, Hamad BK, Mohammad KA, Hama HA et al. Analysis of cytokines in SARS-CoV-2 or COVID-19 patients in Erbil city, Kurdistan Region of Iraq. PLoS One 2021; 16:e0250330 [View Article] [PubMed]
     [Google Scholar]
  48. Bourhis M, Idir A, Machraoui S, Hachimi A, Elouardi Y et al. Cytokine and chemokine profiles in the sera of COVID-19 patients with different stages of severity. Cytokine 2024; 180:156653 [View Article] [PubMed]
     [Google Scholar]
  49. Vaz de Paula CB, de Azevedo MLV, Nagashima S, Martins APC, Malaquias MAS et al. IL-4/IL-13 remodeling pathway of COVID-19 lung injury. Sci Rep 2020; 10:18689 [View Article] [PubMed]
     [Google Scholar]
  50. Cabaro S, D’Esposito V, Di Matola T, Sale S, Cennamo M et al. Cytokine signature and COVID-19 prediction models in the two waves of pandemics. Sci Rep 2021; 11:20793 [View Article] [PubMed]
     [Google Scholar]
  51. Gadotti AC, de Castro Deus M, Telles JP, Wind R, Goes M et al. IFN-γ is an independent risk factor associated with mortality in patients with moderate and severe COVID-19 infection. Virus Res 2020; 289:198171 [View Article] [PubMed]
     [Google Scholar]
  52. Kozak K, Pavlyshyn H, Kamyshnyi O, Shevchuk O, Korda M et al. The relationship between COVID-19 severity in children and immunoregulatory gene polymorphism. Viruses 2023; 15:2093 [View Article] [PubMed]
     [Google Scholar]
  53. Deb P, Zannat KE, Talukder S, Bhuiyan AH, Jilani MSA et al. Association of HLA gene polymorphism with susceptibility, severity, and mortality of COVID-19: a systematic review. HLA 2022; 99:281–312 [View Article] [PubMed]
     [Google Scholar]
  54. Bakaros E, Voulgaridi I, Paliatsa V, Gatselis N, Germanidis G et al. Innate immune gene polymorphisms and COVID-19 prognosis. Viruses 2023; 15:1784 [View Article] [PubMed]
     [Google Scholar]
  55. Li Y, Chen X-Y, Gu W-M, Qian H-M, Tian Y et al. A meta-analysis of tumor necrosis factor (TNF) gene polymorphism and susceptibility to influenza A (H1N1). Comput Biol Chem 2020; 89:107385 [View Article] [PubMed]
     [Google Scholar]
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The Apoprotein E4 isotype does not affect the severity of COVID-19 infection and other flu-like syndromes
J. Med. Microbiol. 74, 001951 (2025); https://doi.org/10.1099/jmm.0.001951
/content/journal/jmm/10.1099/jmm.0.001951
/content/journal/jmm/10.1099/jmm.0.001951
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