Some brush off COVID-19 with ease
Genetics may hold key to fighting the disease
Researchers are diving deep into human genetics, hoping to find clues that might explain why many people brush off COVID-19 without even knowing they have it, while others are hospitalized or even die from the disease.
For inspiration, geneticists are looking to HIV. The absence of one gene called CCR5 makes people unlikely to catch HIV even if exposed. Other genes allow some people’s immune systems to control the virus once infected, escaping its ill effects.
There may not be such powerful genetic twists with SARS-CoV-2, the virus that causes COVID-19. But researchers hope by identifying genes that seem to be involved in different reactions to the disease they will learn more about which patients need the most aggressive treatment, and which drugs may be most effective.
If researchers can identify a protective genetic factor, for example, they can begin to track down a drug that will have the same effect; if they fi nd one that increases risk, they can look for a drug that reduces or blocks it.
“If you have evidence for a (genetic) target, the odds are twice as high that a pharmaceutical compound directed against this target will succeed in a clinical study,” said Andre Franke, a molecular geneticist at the University of Kiel in Germany. “That’s why genetics are so important, because they provide you a first insight into the disease architecture” and the harm it causes.
Genetics likely contribute to both a person’s symptoms of disease and their susceptibility, said Dr. Lisa Strug, a statistical geneticist at the University of Toronto. When some entire families are wiped out by the virus, while others escape without serious harm, it is an indication that genetics is at play, she said.
An individual’s response to a virus is the interplay between the virus it
self, external risk factors and their own characteristics, she said. Once exposed to the virus, genes affect how much virus is produced and shed, and how their immune system responds to the virus.
Knowing someone’s genetic risk for a severe response also will help prioritize who should be first in line to get a vaccine once one is developed, Strug said.
“If you know who’s at greatest risk for severe symptoms, it gives you a model of how to deploy vaccine strategies,” she said.
Genes can point to treatments
Genes have played a role in infectious disease that geneticists have examined, said Mark Daly, director of the Institute of Molecular Medicine Finland, and codirector of the Program in Medical and Population Genetics at the Broad Institute of Harvard and MIT.
But different genes are involved in each disease. Someone who may easily brush off one disease could be flattened by another, Daly said, adding that he thinks it highly unlikely that someone might have immunity to many or all diseases.
It’s unclear which genes will be important to the seriousness of a COVID-19 infection, and how much of a role each will play.
“This is an entirely unexplored question,” he said.
It’s still in the very early days for understanding the genetics behind people’s response to COVID-19. A new study that should be completed in about a week will add more detail.
So far, the most obvious gene involved in the different reactions people have to COVID-19, sits on chromosome 3, and affects the entry of the virus into cells. People with one genetic variant seem to be less likely infected and less likely to show severe consequences from infection, according to an unpublished study.
Assuming this genetic connection is confirmed, researchers could look for a drug that creates the same benefit as the mutation. Many drug companies and scientists are already screening vast numbers of drugs – some already approved and readily available – to see if they can help patients. Identifying the genes will speed this process, Daly said.
In that study, which included samples from 900 COVID-19 patients in Italy and Spain, researchers focused on areas of the genome they thought would most likely be involved in the disease response.
“The results were quite surprising to me,” said Franke, who helped lead the study. “All the candidate genes that we suspected, they didn’t show up in our analysis.”
Is the blood type gene a factor?
The researchers did find an association with the ABO gene, which controls blood type and had been identified in previous COVID-19 studies from China and the US.
The study found people with O blood type are protected and were less likely to get infected. This association makes some sense, Franke said, because the A blood group is associated with an increased risk of blood clots, and blood clots are one of the leading causes of death for COVID-19 patients. People with the blood group O also may be able to better detect viruses than people with other blood types, he added.
The study was made public on June 2 without the usual scientific review process, but it has been accepted for publication and is now undergoing such review, Franke said.
If blood type turns out to be involved in the seriousness of a patient’s response to COVID-19, it could be one factor used to decide whether a hospitalized patient needed relatively aggressive care, added Franke, who plans to dig deeper into the genetics of other blood groups.
Daly said his early data hasn’t confirmed the relationship with the ABO gene, but it seems likely that it will pop up again after more research.
Strug said even if a relationship is confirmed, she doesn’t think it will have a huge effect on the seriousness of someone’s illness. Factors like a patient’s age and preexisting conditions such as heart disease and diabetes likely will remain far more predictive of their outcome, she said. But, she added, such a relationship could inform the understanding of the disease course and suggest directions for the development of new drugs.
Different ways to track key genes
To get a picture of the genes involved in a particular response, researchers need to screen the genes of hundreds, thousands or even tens of thousands of people.
It’s the complexity of the disease and people’s reaction to it that demand such large sample sizes, Daly said. A large group will allow for variations in patient age, sex, preexisting conditions and immune status, among other factors.
That much genetic screening takes time, so most of the studies so far have been small.
Daly helps lead a group of more than 1,000 scientists at 150 institutions all over the world who are collaborating to get the volume and diversity of records they need to truly understand the effects of COVID-19.
He said he hopes to have 5,000 to 10,000 cases analyzed within the next week or so, and tens of thousands by the end of the summer. “With each successive round, we will gain further insights,” he said.
He and his collaborators are particularly interested in the genetic differences between people who escaped serious infection and those whose infections were so serious they were hospitalized or required intensive care.
In some studies, like Franke’s, researchers start with hypotheses of which genes they think will be involved, and target those specific genes. Unfortunately, as was the case in his study, they aren’t always right.
Strug thinks an “agnostic approach,” where researchers look instead at the whole genome, will be more likely to lead to useful information. These socalled genome-wide association studies look for genetic variations among the participants. The price has come down so far, that for each participant it only costs about $20-$50, Daly said.
But still, he’s not sure where the money will come from to analyze the thousands of genetic samples he hopes to get. He and his colleagues decided to pursue the work now and worry about grant funding and other financial sources later.
“Everyone realized we had to act now,” Daly said.
Italian researcher Alessandra Renieri, director of the Medical Genetics Unit at the University Hospital of Siena, is taking a different approach. She is looking at a combined model of common and rare genetic variations. Rare, but strong-acting mutations might explain why some young people get very ill.
Renieri recently presented results for 150 patients with COVID-19, but she now has results on 500. In a handful, she found a mutation in a gene called JAK2 that is involved in the immune overreaction called a cytokine storm that has contributed to many of the COVID-19 deaths. Those people should be treated with a drug that inhibits JAK2, she said.
“It’s not the same in the others,” Renieri added. “If they do not have these kinds of mutations, the treatment should be different. This is the main message we can leave to the scientific world.”
Daly said he looks forward to the findings of his new study, and plans to make the results public right away, so other researchers can quickly put them to work.
“I am quite enthusiastic that over the next week to week-and-a-half, we’ll have the first really reasonably wellpowered genetic study,” he said Monday. “Hopefully, it will lead to some useful insights.”
“If you know who’s at greatest risk for severe symptoms, it gives you a model of how to deploy vaccine strategies.” Dr. Lisa Strug, a statistical geneticist at the University of Toronto
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