key: cord-1046628-dod8k0xa
authors: Goldstein, Mark R; Poland, Gregory A; Graeber, Charles W
title: Does apolipoprotein E genotype predict COVID-19 severity?
date: 2020-04-27
journal: QJM
DOI: 10.1093/qjmed/hcaa142
sha: b766057262ececb9b740b75ede651a0d8bbb1caf
doc_id: 1046628
cord_uid: dod8k0xa

nan

A challenge facing the medical community caring for coronavirus disease 2019 (COVID-19) patients is predicting who will eventually progress to severe illness and even death, which is usually from acute respiratory distress syndrome (ARDS) [1] . A major driving force for the development of ARDS is a cytokine storm, which is an uncontrolled release of pro-inflammatory cytokines and chemokines by immune effector cells in response to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [2] . Risk factors associated with subsequent death include older age, hypertension, diabetes, ischemic heart disease, obesity and chronic lung disease; however, sometimes there are no obvious risk factors [3] . We hypothesize that the apolipoprotein E4 (apoE4) genotype may predict the propensity to manifest rapid and severe illness with COVID-19.

Although ApoE has been classically associated with lipoprotein metabolism and atherosclerosis, it is also associated with the risk the susceptibility to viral, bacterial and parasitic infections [4] . Notably, apoE exists in three isoforms (apoE2, apoE3, apoE4) giving rise to three homozygous and three heterozygous phenotypes; in the general population, the three alleles differ in frequency (ε2: 5-10%, ε3: 65-70%, ε4: 15-20%) [4] .

Interestingly, individuals of African decent may have twice the frequency of the ε4 allele (30-40%) compared to individuals of European and Asian decent [5] . It has been shown that possessing one or two copies of apoE4, versus two copies of apoE3, is associated with an augmented in vivo innate immune response to an intravenous lipopolysaccharide challenge, as manifested by higher hyperthermia and cytokine levels [6] . An example of the modulation of viral infections by apoE, is that the apoE4 isoform has been shown to increase HIV-1 cell entry in vitro, and possessing two copies of apoE4 results in a more rapid HIV disease progression [7] . Of interest, apoE4 has also been associated with some of the comorbid risk factors associated with severe COVID-19, such as atherosclerosis and hypertension [4, 8] .

It is also noteworthy that apoE is expressed by many cell types in the lung, including macrophages and both type I and type II alveolar epithelial cells [9] ; while the functional receptor for SARS-CoV-2, angiotensin-converting enzyme 2 (ACE2), is highly expressed on type II alveolar cells [10] . Moreover, the local pulmonary apoE concentration acts as a danger signal in asthmatics, which activates the inflammasome and subsequently interleukin (IL)-1β production by macrophages [9] . Therefore, it is possible that having one or two copies of apoE4 predisposes one to be at high risk to progress to severe illness from SARS-CoV-2, by virtue of a sequence of robust innate immune response, followed by cytokine storm, and resulting ARDS.

Furthermore, apoE polymorphism may explain in part why African-Americans appear to be disproportionally affected with severe illness from COVID-19, in addition to other well known socioeconomic inequalities and risk factors. The apoE genotype is easily obtained by buccal swab analysis or blood test, and investigators should determine if having a copy of apoE4 does indeed predict more severe COVID-19 and death. If so, this group could be targeted more aggressively from the outset of the disease. 

challenges and recommendations

Molecular immune pathogenesis and diagnosis of COVID-19

Clinical characteristics of patients who died of coronavirus disease 2019 in China

Apolipoprotein E: structure determines function, from atherosclerosis to Alzheimer's disease to AIDS

Apolipoprotein E (APOE) allele distribution in the world. Is APOE*4 a 'thrifty' allele?

APOε4 is associated with enhanced in vivo innate immune responses in human subjects

Apolipoprotein (apo) E4 enhances HIV-1 cell entry in vitro, and the APOE ε4/ε4 genotype accelerates HIV disease progression

The relationship between apolipoprotein E ε2/ε3/ε4 polymorphisms and hypertension: a meta-analysis of six studies comprising 1812 cases and 1762 controls

Apolipoprotein E is a concentration-dependent pulmonary danger signal that activates the NLRP3 inflammasome and IL-1β secretion by bronchoalveolar fluid macrophages from asthmatic subjects

Single-cell RNA expression profiling of ACE2, the putative receptor of Wuhan 2019-nCoV. bioRxiv preprint first posted online