Got severely ill from COVID? Genetics may have made that more likely, MCG researchers find

Scientists may finally have found genetic clues for why some patients get sicker from COVID-19 and similar patients do not, according to findings from an international consortium hosted at Medical College of Georgia at Augusta University.

"This is a huge effort across the globe trying to figure that out," said Dr. Ravindra Kolhe, who helped form the consortium of 30 labs working on the problem. It includes researchers at Harvard Medical School, M.D. Anderson Cancer Center, Howard Hughes Medical Institute and labs in Germany and the Netherlands.

Work began almost as soon as the pandemic began to find genetic clues to why COVID-19 affected some patients more. Even after sequencing as many as 50,000 patients there was no convincing evidence of a genetic predisposition for severe disease. Those previous efforts looked for much smaller flaws in the genetic code, akin to typos in words inside a very long book.

But the consortium looked at the bigger picture, much like a flyover of the genomes, seeking out larger scale aberrations known as structural variants. It is similar to how scientists found genetic changes that allow Sherpas in Nepal, for instance, to adapt to lower oxygen environments at high altitude, Kolhe said.

The scientists sought to explain why some patients with a lot of virus showed no symptoms while others with a smaller amount got very sick, Kolhe said.

"It was something not related to the virus but something related to the (person)," he said.

The consortium identified rare genetic changes in three key areas:  a genetic flaw that weakens the initial defense against the virus, a heightened ability for the virus to access the cell and a change that promotes easier spread from cell to cell.

Their work identified changes in five immune-related genes involved in what is known as innate immunity, "the first line of defense against the invading pathogen," according to their study. These involved the ability to recognize the virus and marshal a response with a key virus attacking protein.

Another weakness was changes in genes that normally help cells keep viruses and bacteria out, particularly in the skin. But this change allowed the virus "to actually transmit from cell to cell a lot faster” and spread quicker in patients, Kolhe said.

A third major area was a gene normally associated with T-cell activation and immune response. But changes in that gene produce an overabundance of enzyme that the virus can actually use as a second doorway into host cells. That same gene, which was inherited from the Neanderthals, was implicated in an unrelated study for greater risk from a previous strain of the SARS virus, but now also increasing risk for this one.

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The MCG-led researchers were very cautious about publishing their findings because they know the "extreme scrutiny" they will get from the scientific community. But the hope is to build on these findings to create a screening test that can be administered to more vulnerable patients, such as cancer patients, to see if they can identify those at most risk, Kolhe said.

"The end goal is to understand why people are getting sicker and if we can create a screening tool, that will be the icing on this cake," he said.