key: cord-0818624-k19v38gz
authors: Kuo, Chia-Ling; Pilling, Luke C; Atkins, Janice L; Masoli, Jane A H; Delgado, João; Kuchel, George A; Melzer, David
title: APOE e4 Genotype Predicts Severe COVID-19 in the UK Biobank Community Cohort
date: 2020-05-26
journal: J Gerontol A Biol Sci Med Sci
DOI: 10.1093/gerona/glaa131
sha: 48f3ea162a3d5ed03cf8f4f29f499dd334e0f05a
doc_id: 818624
cord_uid: k19v38gz

nan

The novel respiratory disease COVID-19 produces varying symptoms, with fever, cough, and shortness of breath being common. In older adults, we found that preexisting dementia is a major risk factor (odds ratio [OR] = 3.07, 95% CI: 1.71 to 5.50) for COVID-19 severity 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 a 14-fold increase in risk of Alzheimer's disease (5) compared to the common e3e3 genotype, in populations with European ancestries. 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 (6) . 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. During this period, COVID-19 testing was largely restricted to hospital inpatients with clinical signs of infection, and therefore test positivity is a marker of severe COVID-19 infection (7) .

We analyzed UKB data from genetically European ancestry participants (8) (n = 451,367, 90% of sample) attending baseline assessment centers in England (n = 398,073), excluding participants who died before the epidemic (n = 15,885). Single nucleotide polymorphism (SNP) data for rs429358 and rs7412 was used to determine ApoE genotypes: ApoE e4e4 homozygotes (n = 9,022, 3%), e3e4 (n = 90,469, 28%), and e3e3 (most common genotype, n = 223,457, 69%) genotype groups (final n = 322,948). Mean age was 68 years (SD = 8) with 176,951 females (55%). There were 622 positive COVID-19 patients (Table 1) including 37 with e4e4 (positivity rate: 410/100,000) and 401 with e3e3 (179 per 100,000). 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 April 26, 2020 (the last test date); baseline UKB assessment center in England; genotyping array type; and the top five genetic principal components (accounting for possible population admixture).

ApoE e4e4 homozygotes were more likely to be COVID-19 test positives (OR = 2.31, 95% CI: 1.65 to 3.24, p = 1.19 × 10 -6 ) compared to e3e3 homozygotes ( Of 622 included participants who tested positive for COVID-19, 417 (67%) were noted to the laboratory to be inpatients when the sample was taken: unfortunately, data on later admission to hospital is not available (7) . Including only those known to have been inpatients when tested made little difference to the excess risk associated with ApoE e4e4 status (OR = 2.32, 95% CI: 1.54 to 3.29), compared to OR = 2.31 (95% CI: 1.65 to 3.24) using all the tested samples.

In conclusion, the ApoE e4e4 allele increases risks of severe COVID-19 infection, independent of preexisting dementia, cardiovascular disease, and type-2 diabetes. ApoE e4 not only affects lipoprotein function (and subsequent cardio-metabolic diseases) but also moderates macrophage pro-/anti-inflammatory phenotypes (9) . The novel coronavirus SARS-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 the highly co-expressed genes (10) . Further investigation is needed to understand the biological mechanisms linking ApoE genotypes to COVID-19 severity. 

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Features of 16,749 hospitalised UK patients with COVID-19 using the ISARIC WHO clinical characterisation protocol. medRxiv

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