Virus World

Immune genes could play a part in the risk of needing intensive care when infected with SARS-CoV-2. An analysis of DNA from more than 24,000 people who had COVID-19 and required treatment in intensive care has yielded more than a dozen new genetic links to the risk of developing extreme illness from the disease. The study, which was published on 17 May in Nature1 and has more than 2,000 authors, highlights the role of the immune system in fuelling the later stages of particularly severe COVID-19. The results could one day contribute to the development of therapies for COVID-19 — and potentially other diseases that cause acute respiratory distress or sepsis. “These are likely to be processes that are active in other conditions,” says Kenneth Baillie, an intensive-care specialist at the University of Edinburgh, UK, and lead author on the study. “Everything that we’ve done in COVID will, I think, be relevant to other groups of patients that we haven’t identified yet.”

Team effort

Much of the data were collected from people who were infected with SARS-CoV-2 during the first waves of the pandemic in the United Kingdom. At that time, many intensive-care staff members were terrified of spending time on the ward, says Baillie. A coronavirus outbreak in 2003 caused by the related virus SARS-CoV had a mortality rate of about 10% and had hit health-care workers particularly hard. “We were nervous,” says Baillie. “Certainly, in the first wave of the pandemic, and for some people in subsequent waves, it seemed like a considerable personal risk.” Despite their fear and the frenzy of providing care at the onset of the pandemic, scores of health-care workers took on the added burden of enrolling participants in studies that investigate how genetics might have contributed to disease severity. Many of the participants were on ventilators, and enrolling them meant long discussions with relatives who were going through some of the most difficult times of their lives, says Baillie. The result was an effort called GenOMICC, which researchers hope will help to improve treatment options for COVID-19 and other conditions in future pandemics. Baillie and his colleagues analysed data from more than 24,000 people and combined this information with data sets from around the world. They found 49 DNA sequences that are associated with becoming critically ill from COVID-19. Sixteen of these had not been reported previously. Among these sequences are some that could affect the activity of genes and proteins involved in the immune system. Raging immune cells have long been implicated in causing some of the tissue damage seen in late-stage, severe cases of COVID-19. Baillie and his colleagues found genetic links to inflammatory responses and the activation of immune cells — processes that can damage the lungs and reduce their capacity to send oxygen to the body’s tissues. “It definitely expands our understanding of the genetic determinants of severe COVID,” says Brent Richards, a human geneticist at McGill University in Montreal, Canada. Richards is an investigator on another project called the COVID-19 Host Genetics Initiative, a global effort in which scientists from more than 54 countries share data. The diversity of that effort will provide a crucial counterpart to the GenOMICC study, which is predominantly drawn from participants of European descent, says Richards.

Reliable results

In addition to the new findings, it is important that the UK study has replicated many of the findings by other groups, says Alexander Hoischen, a geneticist at Radboud University Medical Center in Nijmegen, the Netherlands. Replication of results across different data sets is crucial when trying to tease apart the possible contribution of common genetic variants to disease. Even so, it will take a great deal of work to show that these variants contribute directly to critical illness — a necessary step to turn these initial findings into new therapies. “That is still a long trajectory,” says Hoischen. But putting together these large consortia of investigators and taking the first steps are considerable triumphs, he adds. In the early days of the pandemic, it was unclear how participation in such large endeavours would benefit the careers of individual scientists. “Many of them acted as purely human beings,” he says, instead of worrying about their careers. “It illustrates the degree of solidarity that we really witnessed in COVID times.”

Cited research published in Nature (May 17, 2023):

https://doi.org/10.1038/s41586-023-06034-3 

Researchers in British Columbia have identified a set of gene variants that are likely to influence disease progression from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection to COVID-19 disease. They have identified a rare set of variants in specific amino acid residues on the protein angiotensin-converting enzyme 2 (ACE2) that affect the viral spike protein’s ability to bind to and enter human cells. A spike protein is a key structural protein on the surface of SARS-CoV and SARS-CoV2 (the causative agent in COVID-19) virions that enables interaction with human cell receptors and fusion with the host cell membrane....

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 SARS-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.

Preprint of the original study available at bioRxiV (April 14, 2020):

https://www.biorxiv.org/content/10.1101/2020.04.05.026633v1

Geneticists have turned up intriguing links between DNA and the disease. Patients with Type A blood, for example, seem to be at greater risk. Why do some people infected with the coronavirus suffer only mild symptoms, while others become deathly ill? Geneticists have been scouring our DNA for clues. Now, a study by European scientists is the first to document a strong statistical link between genetic variations and Covid-19, the illness caused by the coronavirus. Variations at two spots in the human genome are associated with an increased risk of respiratory failure in patients with Covid-19, the researchers found. One of these spots includes the gene that determines blood types.  Having Type A blood was linked to a 50 percent increase in the likelihood that a patient would need to get oxygen or to go on a ventilator, according to the new study.

The study was equally striking for the genes that failed to turn up. The coronavirus attaches to a protein called ACE2 on the surface of human cells in order to enter them, for example. But genetic variants in ACE2 did not appear to make a difference in the risk of severe Covid-19. The findings suggest that relatively unexplored factors may be playing a large role who develops life-threatening Covid-19. “There are new kids on the block now,” said Andre Franke, a molecular geneticist at the University of Kiel in Germany and a co-author of the new study, which is currently going through peer review....

COVID-19, caused by the new pandemic coronavirus, is strangely—and tragically—selective. Only some infected people get sick, and although most of the critically ill are elderly or have complicating problems such as heart disease, some killed by the disease are previously healthy and even relatively young. Researchers are now gearing up to scour the patients’ genomes for DNA variations that explain this mystery. The findings could be used to identify those most at risk of serious illness and those who might be protected, and they might also guide the search for new treatments. 

The projects range from ongoing studies with DNA for many thousands of participants, some now getting infected with the coronavirus, to new efforts that are collecting DNA from COVID-19 patients in hard-hit places such as Italy. The goal is to compare the DNA of people who have serious cases of COVID-19 (which stands for coronavirus disease 2019)—but no underlying disease like diabetes, heart or lung disease—with those with mild or no disease. “We see huge differences in clinical outcomes and across countries. How much of that is explained by genetic susceptibility is a very open question,” says geneticist Andrea Ganna of the University of Helsinki’s Institute for Molecular Medicine Finland (FIMM).

It’s hard to predict what will pop out from these gene hunts, some researchers say. But there are obvious suspects, such as the gene coding for the cell surface protein angiotensin-converting enzyme 2 (ACE2), which the coronavirus uses to enter airway cells. Variations in the ACE2 gene that alter the receptor could make it easier or harder for the virus to get into cells, says immunologist Philip Murphy of the National Institute of Allergy and Infectious Diseases, whose lab identified a relatively common mutation in another human cell surface protein, CCR5, that makes some people highly resistant to HIV.