Role of ACE, ACE2 gene variants and serum ACE/ACE2 ratio in COVID-19 severity

Abstract Background: As the outbreak of COVID-19 progresses, prognostic markers for identification of high-risk individuals are of urgent medical need. The Angiotensin system is implicated in the pathogenesis of COVID19 as ACE2 is the cellular receptor for SARS-COV-2 virus, and expression of the ACE2 gene could regulate the individual´s susceptibility to infection. In addition, the balance between ACE and ACE2 activity could play a role in the severity of COVID19. Methods: 180 COVID-19 patients were divided into three groups (60 patients as mild, 60 patients as moderate and 60 patients as severe). Enzyme levels of ACE and ACE2 were measured by ELISA. ACE I/D (rs4646994) was assayed by PCR and ACE2 ( rs2285666) gene variant was determined by Real-Time PCR. Results: ACE/ACE2 ratio was significantly lower in mild group versus moderate to severe group (P <0.001). GG (wild) genotype and G allele of ACE2 were more frequent in mild group, AA (variant) genotype and A allele were more frequent in severe group ( P value 50y) (OR 10.4, 95% CI 3.8-28.4, P<0.001), Comorbidities (OR 8.2, 95% CI 1.6-42.1, P 0.012) and higher ACE/ACE2 ratio (OR 8.3 95% CI 3.7-18.6 P<0.001) were independent significant predictors of severity. Haplotype analysis revealed Patients with D allele of ACE gene combined with A allele of ACE2 gene will have nearly double the risk of having severe COVID infection (OR=1.9, CI 1.1-3.5 P=0.024). Conclusion: Old age (>50 years), presence of co‐morbidities and high ACE/ACE2 ratio are recognized as pivotal predictors for COVID-19 severity.