ACE2 genetic variants may influence coronavirus disease progression

ACE2 genetic variants may influence coronavirus disease progression

Coronavirus pandemic affecting the Earth's movement For their study, the team used the gnomAD database – a resource cataloging genetic coding variants for 141,456 adults. They assessed entries on ACE2 in the database and downloaded files predicting missense variants in the protein. The database cataloged 242 coding missense variants, 15 of which were predicted to be located at or close to the ACE2 binding site for SSARS-CoV-2 spike protein. On aggregating the frequency of these variants, the team estimated that they occur in approximately 3.9 per 1,000 males and 8.5 per 1,000 females. However, the distribution of these rare alleles is not even across subpopulations, and the only common one was rs41303171 (thought to encode p.Asn720Asp), which occurred in 1.7% of males and 3.2% of females in the database. Although the occurrence of this allele was frequent enough to be identified in genome-wide association studies, it does not lie in the ACE2 domain thought to be bound by SARS-CoV-2 and was therefore not considered a worthwhile candidate for this interaction. The second most common variant was rs4646116 (thought to encode p.Lys26Arg), which was predicted to lie next to the ACE2-Spike protein interface. Frequency of the variants On considering the ACE2 missense variants overall, the researchers say their estimated prevalence was 3.9 per 1,000 males and 8.5 per 1,000 females. On calculating the prevalence of individual variants, the estimated prevalence of rs4646116 (p.Lys26Arg) was 1 in 70 among Ashkenazi Jewish males and 1 in 172 among non-Finnish European males. The frequency of this allele was higher among females. This allele occurred at a very low frequency among other populations and was absent among Korean and Japanese participants. The remaining variants all occurred very infrequently. The researchers say their proof-of-principle study warrants further in vitro studies looking at viral binding and replication in cells made to express human variant ACE2 proteins. Potential therapeutic targets Furthermore, “given recent data that human recombinant soluble ACE2 (hrsACE2) can block early stages of SARS-CoV-2 infections,” says the team “any naturally-occurring human ACE2 variant that bound more tightly to the viral spike protein might serve as a better ‘decoy’ for the viral protein and would be a candidate for novel hrsACE2 molecules with therapeutic potential.” The researchers also point out that since three pathogenic coronaviruses (SARS-CoV, MERS-CoV, and SARS-CoV2 ) have emerged over the last 20 years and two of them access human host cells via ACE2, it is possible “that additional coronaviruses that bind to ACE2 are likely to emerge in the future.” “Thus, knowledge of this specific host-pathogen interaction at the molecular level is important to have at this time,” concludes the team. Journal reference: ACE 2 Coding Variants: A Potential X-linked Risk Factor for COVID-19 Disease William T Gibson, Daniel M Evans, Jianghong An, Steven JM Jones bioRxiv 2020.04.05.026633; doi: https://doi.org/10.1101/2020.04.05.026633



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