The team's results, posted as a preprint in BioRxiv earlier this month, proposed a handful of ACE2 variants suspected of boosting SARS-CoV-2 binding and, potentially, host susceptibility, along with several variants predicted to dial down ACE2 interactions with the viral spike protein that may be protective.

"What we can conclude is that this new virus has evolved new modality to interact with the ACE2 receptor," Jura noted. "Unfortunately, it seems like there are polymorphisms in the human population that will make some individuals more susceptible to binding this virus because these mutations are enhancing this unique part of the interface."

Seshagiri noted that such insights might make it possible to design potential therapeutic versions of ACE2 that are particularly adept at binding coronavirus spike proteins, thereby preventing the viruses from interacting with an individual's own ACE2 receptors, for example.

In a recent Cell paper, a team from Sweden, Spain, Austria, and Canada proposed its own strategy for engineering soluble, clinical-grade forms of the human ACE2 protein that appeared to dial down early-stage infections by SARS-CoV-2 in otherwise susceptible cell types.

"We are not the first to come up with the idea of saying ACE2 could be a therapeutic," he said, though he suggested that engineering soluble forms of the receptors protein that bind well to SARS-CoV-2 may serve as a strategy for "future proofing" against the emergence of these and other related viruses down the road.

The researchers plan to profile ACE2 polymorphisms in still more human samples for the final version of the study, which will likely be submitted for peer review in the coming weeks, Seshagiri said.

He and MedGenome CEO Rayman Mathoda noted that the diagnostic company, which is active in India and other emerging markets, is also a founding member of a GenomeAsia 100K project.

"We've made a very intentional effort to build on a data-focused set of efforts, where we take our proprietary data as we grow, but build in other data source," Mathoda said.

The investigators are not alone in attempting to establish a baseline understanding of ACE2 variation across and within populations.

At the University of Siena in northern Italy, Alessandra Renieri and her colleagues have been delving into ACE2 genetic variation using available exome sequences for some 7,000 healthy participants in the Network of Italian Genomes project. As they reported in a preprint posted to MedRxiv in early April, the investigators saw significant variation in ACE2 in that retrospective dataset, including both common and rare, missense variants predicted to influence the protein's stability and its interactions with the coronavirus viral spike.

"There is pretty wide genetic variability," Renieri said. "There are both polymorphisms, so variants found in a percentage of the population, and there are also rare variants a lot of rare variants."

It may be possible for the individual centers participating in the Network of Italian Genomes to recontact individuals in the future to try to find out who became infected with SARS-CoV-2 and to assess ACE2 variation alongside clinical outcomes, Renieri noted, though she cautioned that "ACE2 is just one of the many genes that could be involved."

For the reCOVID project, members of the team are seeking funding through the European Commission's Innovative Medicines Initiative IMI2 call for proposals to do functional analyses on ACE2 and other genes, for example, in the hopes of developing candidate therapeutics.

Renieri is also part of a team that been working since mid-March to prospectively collect samples from 2,000 COVID-19 patients at least 21 different hospitals in Italy as part of the GEN-COVID study, part of the COVID-19 Host Genetics Initiative.

For that project, researchers in Italy will use whole-exome sequencing to assess patient samples collected in conjunction with very detailed clinical information, she explained, while collaborators in Finland will genotype the samples for a related genome-wide association study.

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A gene that could unlock the mysteries of COVID-19 - ModernHealthcare.com