The body’s response to SARS-CoV-2 infection range from imperceptible to death, raising an obvious question: what makes the difference? If we could identify the factors that make COVID-19 so dangerous for some people, we could do our best to address these factors and provide extra protections for those who are at highest risk. But aside from the obvious—health disparities associated with poverty and race seem to be at play here, too—we’ve had trouble identifying the factors that make a difference.
A recently published study takes a look at one potential influence: genetics. In a large study of UK COVID-19 patients, researchers have found a number of genes that appear to be associated with severe cases, most of them involved in immune function. But the results don’t clarify how immune function is linked to the disease’s progression.
All in the genes
The work took place in the UK, one of the countries involved in the GenOMICC (Genetics Of Mortality In Critical Care) project, which has already been exploring the genetics underlying hospitalization for communicable diseases. For the new study, the researchers worked with over 200 intensive care units in the UK to identify study participants. All told, they managed to get genetic data for over 2,700 critical COVID-19 patients. These were matched with people in the UK’s Biobank who had similar demographics in order to provide a control population. The one weakness of this design is that some people in the Biobank may be susceptible to severe COVID-19 but simply haven’t been infected yet, which would tend to weaken any genetic signals.
The research team performed two analyses to look for genes associated with severe COVID-19. The first was a standard genomewide association analysis, in which the entire genome was scanned for variants that occurred more often in those who had severe illness. The researchers broke out different ethnic groups for this analysis, since informative variants occasionally differ between them. The only group that was large enough to do a full analysis was made up of people of European descent, which limited the number of cases to 1,676.
Using this group, the analysis pulled out 15 different locations throughout the genome. To revalidate the study, however, the researchers also swapped in different control groups taken from other genetic resources. In addition, they used other sources of cases, including 23andMe, which has registered over 1,100 cases among its members. These reanalyses eliminated seven of the 15 original genome sites, leaving eight that had replicated.
The second analysis the team did was look at the activity of genes, as measured by their being transcribed into RNA copies, a key step in making proteins. The researchers checked for RNA production in the lung and blood, and they compared those results to the location of the genetic factors that had been identified in the other part of the study.
Immune links
Overall, the genes that came out of this analysis fall into two groups. One involves genes that are involved in the initial response to viral infection, part of what’s called the innate immune system. One of these is the receptor for an immune signaling molecule (interferons) that are induced when cells detect the presence of a virus. Problems with interferon signaling had already been associated with severe COVID-19 cases, so this is an important validation of the work. The other gene that fell into this category is part of a pathway that results in activating an enzyme that chews up double-stranded RNA, which is the genetic material of some viruses and a key intermediate in the process of producing new coronaviruses.
The other group of genes generally fall on inflammatory immune pathways. One is an enzyme that has several relevant effects, including activating some immune signaling molecules and assisting T cells in identifying infected cells. Another is part of a signaling pathway involved in regulating immune activities (the JAK/STAT pathway). And other variants altered the activity of a collection of receptors for chemokines, key immune signaling molecules.
While finding out that immune-system activity is involved in the severity of an infection might seem like a “duh” moment, the results are both more and less informative than they might appear. It’s actually quite interesting that nothing other than immune-related genes came out of this screen, suggesting that genetic factors may not play a large role in how infections proceed or which tissues end up damaged. It’s also informative, given that some things that had come out of other screens, like the A/B/O blood type, didn’t come out of this one.
But knowing the immune response is involved doesn’t necessarily tell us what it’s doing. Do severe health problems come from an anemic immune response that lets the virus run wild? Or do they come because the immune system revs into overdrive and starts damaging tissues? Given the two groups of genes identified here, it could even be a bit of both—a weak early response, followed by an overactive inflammatory one later in the infection.
Still, identifying genes that are worth further study is an important early step. The progress of COVID-19, with its erratic collection of symptoms, has very variable recovery periods. Figuring out the details there, which this work might contribute to, could help us make much more informed treatment decisions.
Nature, 2020. DOI: 10.1038/ s41586-020-03065-y (About DOIs).
https://arstechnica.com/?p=1730434