Mining transcriptomics and clinical data reveals ACE2 expression modulators and identifies cardiomyopathy as a risk factor for mortality in COVID-19 patients

Angiotensin-converting enzyme 2 (ACE2) is the cell-entry receptor for SARS-CoV-2. It plays critical roles in both the transmission and the pathogenesis of the coronavirus disease 2019 (COVID-19). Comprehensive profiling of ACE2 expression patterns will help researchers to reveal risk factors of severe COVID-19 illness. While the expression of ACE2 in healthy human tissues has been well characterized, it is not known which diseases and drugs might modulate the ACE2 expression. In this study, we developed GENEVA (GENe Expression Variance Analysis), a semi-automated framework for exploring massive amounts of RNA-seq datasets. We applied GENEVA to 28,6650 publicly available RNA-seq samples to identify any previously studied experimental conditions that could directly or indirectly modulate ACE2 expression. We identified multiple drugs, genetic perturbations, and diseases that modulate the expression of ACE2, including cardiomyopathy, HNF1A overexpression, and drug treatments with RAD140 and Itraconazole. Our unbiased meta-analysis of seven datasets confirms ACE2 up-regulation in all cardiomyopathy categories. Using electronic health records data from 3936 COVID19 patients, we demonstrate that patients with pre-existing cardiomyopathy have an increased mortality risk than age-matched patients with other cardiovascular conditions. GENEVA is applicable to any genes of interest and is freely accessible at <ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="uri" xlink:href="http://genevatool.org">http://genevatool.org</ext-link>.