Younger Men May be at Risk for Severe COVID-19 with Rare Genetic Variant

Levels of interferon gene activity were much lower in those with the missense mutation.

A recent study conducted by investigators from the University of Siena, in collaboration with the University of Pavia, has discovered that a genetic variant found in young men with COVID-19 may put them at risk for a more severe form of the disease. Data from the study was published in the journal eLife.

"Although older age and the presence of long-term conditions such as cardiovascular disease or diabetes are known risk factors, they alone do not fully explain differences in severity," Chiara Fallerini, first author on the study said. "Some younger men without pre-existing medical conditions are more likely to be hospitalized, admitted to intensive care and to die of COVID-19, which suggests that some factors must cause a deficiency in their immune system."

Investigators behind the study analyzed a subset of 156 males who were younger than 60 years old from a large multicenter study in Italy, called GEN-COVID. The study is a network of over 40 hospitals that collect and share data.

They then analyzed genes on the X chromosome of men with both mild and severe cases of COVID-19, and found that the gene TLR7 was linked to the severity of disease. Of the 156 men that were studied, 79 of them had a missense mutation in the gene and had a life-threating case of COVID-19.

The investigators then treated white blood cells of recovered patients with a therapy that is known to switch the TLR7 gene on, and found that the gene was dampened down in immune cells from patients with mutations, compared to the TLR7 activity seen in normal immune cells.

Additionally, they discovered lower levels of interferon in the cells containing the mutation compared to normal white blood cells, which confirms the mutations directly impact the control of interferon as part of the innate immune response.

"Our results show that young men with severe COVID-19 who have lost function in their interferon-regulating genes represent a small but important subset of more vulnerable COVID-19 patients," Elisa Frullanti, co-senior author on the study said.