Genetic flashpoints: Why Covid-19 hits some people harder than others

``Such studies are a little akin to panning for gold. We know our genetic makeup contributes to why some people are more susceptible to viral infections. By sifting through the DNA of enough people, researchers hope to discover a eureka moment explaining why, said Mark Daly, a study co-author who is the director of the Institute for Molecular Medicine Finland at the University of Helsinki and a geneticist at Harvard University..


Throughout the pandemic, one crucial question has perplexed scientists worldwide: Why do some people become so sick from Covid-19 while others show no symptoms at all?

Now, a peek deep into the human genome by a global initiative with more than 3,000 researchers from 25 countries is providing some answers. There are 13 locations in the genome strongly linked to either susceptibility to the virus or severe cases, the researchers reported Thursday in the journal Nature.

The research began in March 2020 as scientists struggled to understand how the virus operates. It culminated in the largest genome-wide association study ever conducted, with researchers sifting through the genetic material of almost 50,000 infected people and two million uninfected. The goal: Identify which bits of human DNA correlate with  people getting very sick from the virus.

The results may help pinpoint “some clear biological markers that could be used to repurpose existing drugs or drugs in the pipeline,” said Mark Daly, a study co-author who is the director of the Institute for Molecular Medicine Finland at the University of Helsinki and a geneticist at Harvard University.

The Nature report summarizes information from 46 studies and three meta-analyses investigating the role of human genetics in Sars-CoV-2 infections and Covid-19 severity.

``Such studies are a little akin to panning for gold. We know our genetic makeup contributes to why some people are more susceptible to viral infections. By sifting through the DNA of enough people, researchers hope to discover a eureka moment explaining why, said Daly.

Treating sick Covid patients more efficiently could also take the pressure off of hospital systems, sending patients home sooner, especially in countries still battling significant outbreaks. The results of genetic studies like this can offer drugmakers a starting point to develop new therapies in addition to identifying potential treatments already on the market.

Several of the 13 significant genetic locations identified in the research had previously been linked to other illnesses, including lung cancer and autoimmune diseases.

TYK2 Gene
One gene that appears strongly connected to disease severity with Covid-19 is known as TYK2. In healthy people, it helps control the body’s pathways for immune signaling and inflammatory signaling.

Previously, a variant of the TYK2 gene linked by the researchers to Covid-19 was found to be associated with a reduced risk for autoimmune diseases but an increased risk of tuberculosis. Researchers suggested that since the variant has previously been shown to reduce the function of the gene, the same mechanism may be interfering with the body’s ability to effectively fight Covid.

Another gene the study identified, FOXP4, is linked to lung cancer. The FOXP4 variant increases that gene’s expression, suggesting that inhibiting the gene might be a strategy for treating Covid.

Not every genetic location of interest that the researchers identified had a link that clearly explained its association with Covid. Far more study will be needed to untangle all the complexities between the virus and human DNA.

Diversity Importance
Of the genetic locations identified so far by the researchers, two had higher frequencies among patients of Asian ancestry than in those of European ancestry, underscoring how crucial diversity is in genetic research.

Genetics has long offered the promise of personalized insights that could explain who gets sick and how to treat them. The pandemic has only heightened interest in that promise. Last year, the consumer genomics firm 23andMe published research bolstering evidence that blood type can affect a person’s susceptibility to Covid-19 by looking at a gene that influences blood type.
 


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