COVID-19 susceptibility: potential of ACE2 polymorphisms

Angiotensin-converting enzyme 2 (ACE2) is a metallopeptidase that primarily functions as a negative regulator of renin angiotensin system (RAS) by converting angiotensin II (Ang II) to angiotensin 1-7. Contrary to this, another RAS component, angiotensin-converting enzyme (ACE) catalyzes synthesis of Ang II from angiotensin I (Ang I) that functions as active compound in blood pressure regulation. This indicates importance of ACE/ACE2 level in regulating blood pressure by targeting Ang II. An outbreak of severe acute respiratory syndrome (SARS) highlighted the additional role of ACE2 as a receptor for SARS coronavirus (SARS-CoV) infection.

ACE2 is a functional receptor for SARS-CoV and SARS-CoV-2. Activation of spike (S)-protein by either type II transmembrane serine proteases (TTSPs) or cathepsin-mediated cleavage initiates receptor binding and viral entry. In addition to TTSPs, ACE2 can also be trimmed by ADAM 17 (a disintegrin and metalloproteinase 17) that competes for the same receptor. Cleavage by TTSPs activates ACE2 receptor for binding, whereas ADAM17 releases extracellular fragment called soluble ACE2 (sACE2). Structural studies of both ACE2 and S-protein have found critical sites involved in binding mechanism. In addition to studies on structural motifs, few single-nucleotide polymorphism (SNPs) studies have been done to find an association between genetic variants and SARS susceptibility. Though no association was found in those reports, but seeing the non-reproducibility of SNP studies among different ethnic groups, screening of ACE2 SNPs in individual population can be undertaken.

Thus, screening for novel SNPs focussing on recently identified critical regions of ACE2 can be targeted to monitor susceptibility towards coronavirus disease 2019 (COVID-19).