MAY 23, 2022 6:40 AM PDT

The Genetics Underlying Susceptibility to Severe COVID-19

WRITTEN BY: Carmen Leitch

Since the onset of the pandemic, researchers and clinicians have been trying to determine why COVID-19 is more severe in some people. It's not unusual for underlying medical conditions to complicate respiratory infections, and COVID-19 is no exception. Scientists have also found that some genetic variants can predispose people to serious COVID-19 cases as well. Investigators have now identified variants in four genes that may increase a carrier's risk of more severe SARS-CoV-2 infection, and these genes are related to how the virus infects cells. For example, some of those variants are found in the gene that encodes for the ACE2 receptor, which the virus uses to enter cells. This research suggested that past encounters with similar viruses may have influenced the evolution of these human genes.

Transmission electron micrograph of a SARS-CoV-2 virus particle (UK B.1.1.7 variant), isolated from a patient sample and cultivated in cell culture. Image captured at the NIAID Integrated Research Facility (IRF) in Fort Detrick, Maryland. Credit: NIAID
 
The findings have been reported in the Proceedings of National Academy of Sciences.

While other groups have looked for genetic variants that predispose people to more severe COVID-19 infections, the researchers noted that the population in this analysis is very diverse. Another recently reported study has also used diverse groups to identify variants that can protect against severe COVID-19.

“This study exemplifies my lab’s approach to genomic studies: We use what happens in nature and signatures of natural selection to identify functionally important variants that impact health and disease,” said co-corresponding study author Sarah Tishkoff, a University of Pennsylvania Professor, among other appointments.

In this study, the researchers focused on ACE2, TMPRSS2, DPP4, and LY6E, genes that have all been shown to encode for molecules that are relevant to how SARS-CoV-2 enters cells. Genetic and health data from about 18,000 people was analyzed in this work, including individuals with diverse lifestyles and heritage.

The researchers looked for evidence of genetic selection in those genes over time. IN the ACE2 gene, there were 41 variants that impacted the protein sequence - the amino acids that compose the ACE2 receptor were changed by those genetic variations. Among the global population, these variants were rare. But three of the variants were commonly found among Central African hunter-gatherers.

These individuals live in the tropics, and spend lots of time in the forest, noted Tishkoff, so they are probably exposed to many viruses, some of which are zoonotic; they could pass to humans. SARS-CoV-2 is also thought to be a zoonotic virus, and while these people would not have previously been exposed to SARS-CoV-2, they may have been in contact with something similar, Tishkoff continued. The genetic variants identified in these people could be beneficial, and were selected through evolution.

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

Some variants were also found in regulatory genetic regions that impact the expression of other genes. Other rare variants were identified in East Asian populations that could be increasing the expression of ACE2, and impacting SARS-CoV-2 infection, though more work would be needed to test the impact of that variant. Dozens of variants were also found in TMPRSS2, DPP4, and LY6E genes. Some genetic variants have previously been associated with other respiratory disorders.

Further study of these variants could help researchers learn more about how to prevent or treat SARS-CoV-2 infection.

Sources: University of Pennsylvania, Proceedings of the National Academy of Sciences

About the Author
BS
Experienced research scientist and technical expert with authorships on over 30 peer-reviewed publications, traveler to over 70 countries, published photographer and internationally-exhibited painter, volunteer trained in disaster-response, CPR and DV counseling.
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