key: cord-0735678-0c9l0bv6 authors: Kuo, C.-L.; Pilling, L. C.; Atkins, J. L.; Masoli, J. A.; Delgado, J.; Kuchel, G. A.; Melzer, D. title: APOE E4 GENOTYPE PREDICTS SEVERE COVID-19 IN THE UK BIOBANK COMMUNITY COHORT date: 2020-05-11 journal: nan DOI: 10.1101/2020.05.07.20094409 sha: a6f083f9abd608db6cb2fbf83f3609e384456c16 doc_id: 735678 cord_uid: 0c9l0bv6 The novel respiratory disease COVID-19 produces varying symptoms, with fever, cough, and shortness of breath being common. In older adults, we found that pre-existing dementia is a major risk factor (OR = 3.07, 95% CI: 1.71 to 5.50) for COVID-19 hospitalization in the UK Biobank (UKB). In another UK study of 16,749 patients hospitalized for COVID-19, dementia was among the common comorbidities and was associated with higher mortality. Additionally, impaired consciousness, including delirium, is common in severe cases. The ApoE e4 genotype is associated with both dementia and delirium, with the e4e4 (homozygous) genotype associated with high risk of dementia. We therefore aimed to test associations between ApoE e4 alleles and COVID-19 severity, using the UKB data. The novel respiratory disease COVID-19 produces varying symptoms, with fever, cough, and shortness of breath being common. In older adults, we found that pre-existing dementia is a major risk factor (OR = 3.07, 95% CI: 1.71 to 5.50) for COVID-19 hospitalization in the UK Biobank (UKB) [1] . In another UK study of 16,749 patients hospitalized for COVID-19 [2] , dementia was among the common comorbidities and was associated with higher mortality. Additionally, impaired consciousness, including delirium, is common in severe cases [3] . The ApoE e4 genotype is associated with both dementia and delirium [4] , with the e4e4 (homozygous) genotype associated with high risk of dementia. We therefore aimed to test associations between ApoE e4 alleles and COVID-19 severity, using the UKB data. UKB is a community cohort currently aged 48 to 86 [5] . COVID-19 laboratory test results for UKB participants in England are available from March 16 to April 26, 2020, the peak period of COVID-19 incidence in the current outbreak [6] . Because testing for older adults during the above period was essentially restricted to hospital in-patients with clinical signs of infection, test positivity is a marker of severe COVID-19 [7] . We analyzed UKB data from genetically European ancestry participants [8] A logistic regression model was used to compare e3e4 or e4e4 genotypes to e3e3 for COVID-19 positivity status, adjusted for: sex; age at the COVID-19 test or age on 26 th April, . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 11, 2020. As ApoE e4e4 prevalence is higher in people of African descent, we analyzed data for UKB self-reported Black participants: e4e4 was present in 5.2% of Blacks versus 2.3% of Whites. Blacks were more likely to get severe COVID-19 than Whites (e4e4 OR= 3.96, 95% CI: 2.92 to 5.35), which reduced to 3.80 (95% CI: 2.81 to 5.15) after ApoE adjustment (e4e4 p = 6.34×10 -6 ), additional to sex, age at test, genotyping array type, and assessment center. In conclusion, ApoE e4 allele increases risks of being hospitalized with COVID-19, independent of pre-existing dementia, cardiovascular disease, and type-2 diabetes. ApoE not only affects lipoprotein function (and subsequent cardio-metabolic diseases) but also moderates macrophage pro-/anti-inflammatory phenotypes [9] . The novel coronavirus SARS-. CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 11, 2020. . https://doi.org/10.1101/2020.05.07.20094409 doi: medRxiv preprint CoV-2 causing COVID-19 uses the ACE2 receptor for cell entry. ACE2 is highly expressed in type II alveolar cells in the lungs, where ApoE is one of highly co-expressed genes [10] . ApoE e4 allele frequency is higher in people of African ancestry than in Europeans, and preliminary results suggest that ApoE e4 prevalence makes a modest contribution to the excess incidence of COVID-19 in Blacks. Further investigation is needed to understand biological mechanisms linking ApoE genotypes to COVID-19 severity. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 11, 2020. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted May 11, 2020. . https://doi.org/10.1101/2020.05.07.20094409 doi: medRxiv preprint Preexisting comorbidities predicting severe COVID-19 in older adults in the UK Biobank community cohort Features of 16,749 hospitalised UK patients with COVID-19 using the ISARIC WHO Clinical Characterisation Protocol. medRxiv Neurological Manifestations of Hospitalized Patients with COVID-19 in Wuhan, China: A Retrospective Case Series Study ApoE e2 and aging-related outcomes in 379,000 UK Biobank participants. medRxiv The UK Biobank resource with deep phenotyping and genomic data COVID-19) in the UK COVID-19): Using data to track the virus Common conditions associated with hereditary haemochromatosis genetic variants: Cohort study in UK Biobank Apolipoprotein E -A Multifunctional Protein with Implications in Various Pathologies as a Result of Its Structural Features Single-cell RNA expression profiling of ACE2, the putative receptor of Wuhan 2019-nCov. bioRxiv . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 11, 2020. CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 11, 2020. . https://doi.org/10.1101/2020.05.07.20094409 doi: medRxiv preprint