Genetic variants may help explain variability in COVID-19 severity, study finds

Although underlying medical conditions play an important role, many aspects of why the severity of COVID-19 can differ significantly from person to person have remained unclear.

A new study identifies dozens of genomic variations that can drive these hard-to-predict differences in clinical outcomes. According to work by scientists at the University of Pennsylvania, genomic variants of four genes essential for SARS-CoV-2 infection, including the ACE2 gene, were targets of natural selection and associated with problems of health observed in COVID-19 patients.

The investigation, which used genomic data from various global populations, suggests that these variants may have evolved in response to past encounters with viruses similar to SARS-CoV-2. The team published the results in the journal Proceedings of the National Academy of Sciences.

This study exemplifies my lab’s approach to genomic studies: we use what happens in nature and the signatures of natural selection to identify functionally important variants that impact health and disease. Nature has already done much of the screening and can give us clues as to which parts of a gene like ACE2 are important for infection.”

Sarah Tishkoff, corresponding co-author of the work and Penn University Integrates Knowledge Professor with appointments at the Perelman School of Medicine and the School of Arts & Sciences

While other groups have conducted genome-wide association studies to identify genetic variants associated with COVID-19 severity, this is the first to include ethnically diverse Africans and a very comprehensive dataset. diversified from the Penn Medicine BioBank. The inclusion of these often overlooked groups has revealed new variants that may be clinically significant.

Selection signals

Even before COVID-19 was declared a pandemic, Giorgio Sirugo of the Perelman School of Medicine hypothesized that there was a genetic basis for susceptibility or protection against more severe outcomes.

“The idea is really classic, that infectious diseases have a genetic component of the host”, explains Sirugo, corresponding co-author of the article. He contacted Tishkoff and other colleagues to begin addressing the issue with a population genetics approach.

The researchers focused on a handful of genes known to play a role in how SARS-CoV-2 enters cells: ACE2, TMPRSS2, DPP4 and LY6E. They used genomic data from 2,012 Africans of various ethnicities, including people who practice traditional hunter-gatherer, herder and agricultural lifestyles, as well as 15,977 people of European and African descent from the Penn Medicine BioBank, all of which had associated electronic health record data. available.

Looking for variations in these genes that showed evidence of being selected for during evolution, the researchers found 41 variants in the ACE2 gene that affected the amino acid sequence of the protein. Although these variants were rare when the team looked at the aggregated global population, among a population of Central African hunter-gatherers, three variants were common.

“It really stuck with us,” says Tishkoff. “This is a group that lives in a tropical environment and continues to forage for bushmeat, spending a lot of time in the forest. They are probably exposed to all kinds of viruses introduced by animals. And, well sure, SARS-CoV -2 is believed to have jumped from animals to humans, so even if this population would not have been exposed to this exact virus in the past, they could have been exposed to types of similar viruses.

In other words, these variants could have evolved because they offered a protective effect against viruses with similarities to SARS-CoV-2. These variants showed signs of positive selection, more evidence that they confer a fitness advantage.

Signs of natural selection were not only present in the parts of the genome that code for ACE2 and other genes, but also in what are called regulatory regions, which affect how and where these genes are expressed. . Many of these variants appeared to have been subjected to what is known as purifying selection, which occurs when evolutionary forces select the removal of variants with negative fitness impacts.

“We saw significant signals of natural selection in the regulatory regions of ACE2,” says Chao Zhang, postdoctoral fellow in Tishkoff’s lab and co-lead author. “I personally think this is going to be very important in thinking about clinical outcomes.”

“From an African and specifically Central African perspective, the discovery of three non-synonymous variants to ACE2 in indigenous Cameroonian populations is significant,” says Alfred K. Njamnshi, co-author and professor of neurology and neuroscience at the University Cameroonian from Yaoundé. “The regulatory variants found at ACE2 suggest targets of recent natural selection in some African populations, and this may have important implications for disease risk or resistance that warrant further investigation.”

Rare variants also likely play a role in health outcomes, the team notes, which explains individual variation in disease severity. In East Asian populations, they found variations in the ACE2 regulatory region that may increase ACE2 expression, which could influence the degree to which SARS-CoV-2 infects people. host cells.

“To be sure, we need to test the function of this variant and see if we can get any indications that changes in this region are related to susceptibility and severity of COVID infection,” says Yuanqing Feng, a another postdoc from the Tishkoff lab who shared the first paternity. On paper.

These variations in non-coding regions of the genome could also influence the organs in which genes are expressed, a relevant feature given the known effects of COVID-19 on the heart, brain, lungs, kidneys and other organs. . Moreover, the ACE2 receptor does not only play a role in binding to the SARS-CoV-2 spike protein; it is also involved in blood pressure regulation, and therefore variants may affect health outside of simple COVID infection.

Beyond ACE2, signals of natural selection were also apparent in the coding and regulatory regions of the TMPRSS2 gene, including variations that appear to have evolved after early human populations split from other great apes. “There are a lot of human-specific substitutions in this protein, which is really intriguing,” says Tishkoff, suggesting that natural selection acted on these sites during post-divergence human evolutionary history. with the ancestor of chimpanzees more than 5 million years ago. . The team also identified dozens of additional variants in the DPP4 and LY6E genes.

Genome-health links

To understand the clinical relevance of these variants, the researchers used data from Penn Medicine BioBank. The analysis was conducted largely before the pandemic swept across the United States, and therefore COVID-19 disease results were not part of patients’ medical records at the time. But because the biobank data contains genetic sequencing information, the researchers were able to look at the genetic variants they had just identified and see if there were any links to medical conditions thought to be relevant to COVID infection. -19.

“With our data, we can look at the variants that have been identified by Sarah’s team and relate them to clinical data,” says Anurag Verma of Penn’s Perelman School of Medicine, co-first author of the paper.

The team found that certain variants of the coding regions they had identified were indeed associated with conditions related or overlapping with COVID-19, including respiratory disorders, respiratory syncytial virus infection and liver disease.

Building on these initial findings, the researchers say further exploration of key genetic variants could reveal a lot about how proteins function in the context of COVID-19 or other diseases.

“From a medical perspective, you could identify new therapeutic targets, or even provide personalized medicine based on a person’s variants,” says Sirugo.

The team stresses the importance of seeking genome studies in diverse populations, as some of the newly identified variants that could be clinically significant have only been identified in African populations that had not been studied in this way before. .

“This is a deeply important and unique aspect of this study,” says Tishkoff.


Journal reference:

Zhang, C. et al. (2022) Impact of natural selection on global patterns of genetic variation and association with clinical phenotypes at genes implicated in SARS-CoV-2 infection. Proceedings of the National Academy of Sciences.

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