The Genetic Dissection of Expression Variation in the Heart of Murine Genetic Reference Population.

A high inflammatory and cytokine burden that induces vascular inflammation, myocarditis, cardiac arrhythmias, and myocardial injury is associated with a lethal outcome in COVID-19. The SARS-CoV-2 virus utilizes the ACE2 receptor for cell entry in a similar way to SARS-CoV. This study investigates the regulation, gene network, and associated pathways of ACE2 that may be involved in inflammatory and cardiovascular complications of COVID-19. Cardiovascular traits were determined in the one of the largest mouse genetic reference populations: BXD recombinant inbred strains using blood pressure, electrocardiography, and echocardiography measurements. Expression quantitative trait locus (eQTL) mapping, genetic correlation, and functional enrichment analysis were used to identify regulation, gene pathway, and co-expression networks. A wide range of variation was found in expression of among the BXD strains. Levels of expression are negatively correlated with cardiovascular traits, including systolic and diastolic blood pressure and P wave duration and amplitude. co-expressed genes are significantly involved in cardiac- and inflammatory-related pathways. The eQTL mapping revealed that is a candidate upstream regulator for . Moreover, the protein-protein interaction (PPI) network analysis inferred several potential key regulators (, and ) for co-expressed genes in the heart. is associated with blood pressure, atrial morphology, and sinoatrial conduction in BXD mice. co-varies with , and and is enriched in the RAS, TGFβ, TNFα, and p38α signaling pathways, involved in inflammation and cardiac damage. We suggest that all these novel Ace2-associated genes and pathways may be targeted for preventive, diagnostic, and therapeutic purposes in cardiovascular damage in patients with systemic inflammation, including COVID-19 patients.