ACE2 expression and patient demographics
While our study profiles the expression of the coronavirus receptors from various tissue samples, whether and how much receptor expression varies among individuals across various factors like age, disease states, genetic diversity, lifestyle, and environmental factors are not well understood. For instance, in order to understand variation of expression with age we explored ACE2 expression using GTEx samples. Interestingly, ACE2 expression levels in colon (transverse) samples were higher in younger individuals in comparison to older individuals (Figure 2—figure supplement 19A). In contrast, ACE2 expression levels in the esophagus (gastroesophageal junction) were lower in younger individuals in comparison to older individuals (Figure 2—figure supplement 19B). These patterns of ACE2 expression need to be tested more rigorously on larger sample sizes across diverse ethnicities to establish statistical significance. If ACE2 were found to be expressed more significantly in the colon of younger individuals, taken together with recent reports of sustained fecal shedding of SARS-CoV-2 (Xu et al., 2020a; Gu et al., 2020), the emerging epidemiological hypothesis of younger individuals having fewer respiratory complications in general and serving as facile vectors in transmission of COVID-19 requires more deeper investigation.
The recent reports of hypertension as a comorbidity in COVID-19 patients (Fang et al., 2020) and specifically the use of ACE inhibitors as antihypertensives contributing to mortality encourages a hypothesis-free examination of the FDA adverse event reporting system (FAERS; see Materials and Methods). Examining the differential patterns of adverse event reports between ACE inhibitors and beta blockers - both antihypertensive drug classes, with the former known to increase ACE2 expression in select cardiovascular tissues (Ferrario et al., 2005) - shows that use of ACE inhibitors is associated with a higher risk of respiratory edema (Figure 2—figure supplement 19C). Any reports of patients on beta blockers also were removed from the ACE inhibitors set, and vice versa, for this analysis. The increased adverse events of epiglottic edema, epiglottis, pneumopericardium, upper airway obstruction, eosinophilic oesophagitis, edema mucosal, edema of the mouth, tracheal edema, palatal edema, and allergic edema associated with ACE inhibitors compared to beta blockers suggests that a thorough investigation of all 10 million plus adverse event reports is necessary, to triangulate any drug-induced side effects that also appear as comorbidities from the emerging evidence of COVID-19 mortality. Availability of single-cell RNAseq data from healthy, pathological, and drug-treated tissues would enable us to profile the age-associated and treatment-based expression levels of ACE2 across cell populations. These observations underline that investments are needed to conduct comprehensive scRNAseq profiling of tissue samples from across different demographics and pathologies pertinent to COVID-19, as such effort will hold tremendous potential to reveal under-appreciated fingerprints of coronavirus transmission patterns, tissue tropism, and mortality.