Effect of ACE1 (Angiotensin Converting Enzyme 1) Polymorphism Rs1799752 on Protein Levels of ACE2, the SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2) Entry Receptor, in Alveolar Lung Epithelium

Abstract

Rationale One of the striking features of the Coronavirus Disease 19 (COVID-19) pandemic is the considerable variation in disease presentation and severity amongst patients, ethnic groups, and countries. Genetic factors could contribute to this variation. The Angiotensin-Converting Enzyme 1 (ACE1) gene is characterized by a genetic deletion/insertion (D/I) of an alu repeat and this polymorphism (rs1799752) shows an important geographical variation. Recently, we showed that COVID-19 incidence was inversely correlated to the presence of the ACE1 D-allele frequency. Also, a significant correlation between COVID-19 related mortality and the prevalence of the D-allele was observed. ACE1 is a homologue of ACE2, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) host cell entry receptor. Since ACE1 and ACE2 levels are strongly regulated by common genetic variants in their genes, ACE2 levels may also be influenced by this polymorphism. Therefore, this genetic D/I in ACE1 might influence infectivity and pathogenicity of SARS-CoV-2. Methods ACE2 protein expression was visualized by immunohistochemistry on lung tissue sections from 67 subjects and quantified in alveolar epithelium. DNA was extracted from lung tissue and the prevalence of the three genotypes of rs1799752 (II, DI, DD) in ACE1 was determined using Taqman® SNP Genotyping assays. Results Significantly higher levels of ACE2 protein in alveolar lung epithelium were observed when subjects were homozygous for the insertion (II), compared to subjects homozygous for the deletion (DD). Importantly, this correlation remained significant, even after adjusting for age, sex, BMI, COPD, smoking, and diabetes. Therefore, homozygosity of the insertion (II) is an independent determinant for increased lung ACE2 levels and is not driven by higher frequencies of the insertion in certain patient groups. Conclusion In conclusion, we suggest a genetic D/I polymorphism in ACE1 to correlate with alveolar protein expression of ACE2, the SARS-CoV-2 entry receptor, thereby potentially affecting infectivity and pathogenicity of SARS-CoV-2. The geographical variance in the ACE1 II genotype might contribute to the varying prevalence, morbidity, and mortality due to COVID-19.