It has long been known that in addition to age, gender and previous illnesses, genes also have an influence on how severely a person gets Covid-19. Now researchers have identified a gene variant on the third chromosome that can double the risk of death from corona infection. The exchange of just one DNA base causes the defense reaction of mucosal cells in the lungs and airways to be weakened, the team found out. Carriers of this gene variant are around 15 percent of Europeans and 60 percent of people in South Asia. The good news, however, is that the vaccination also protects these people.
How seriously a person gets sick with Covid-19 and whether they die of infection with the Sars-CoV-2 coronavirus depends on a number of different factors. In the course of the pandemic, it has been shown that older people, men, people who are very overweight and previous illnesses such as diabetes, high blood pressure and heart and lung diseases are at a particularly high risk of a severe course of Covid-19. However, scientists have already uncovered some genetic factors that impair the body’s immune response and promote the excessive inflammation typical of severe courses. This also includes a gene variant that we inherited from the Neanderthals and a gene location associated with blood groups.
Search on chromosome 3
Damien Downes from the University of Oxford and his colleagues have now identified another risk gene. Some time ago, scientists used genome-wide comparative studies (GWAS) to determine that a certain DNA segment on the third chromosome can double the risk of death for corona patients under 65 years of age. However, what kind of gene is behind it and how it influences the death rate from Covid-19 remained unclear. “The reason it was so difficult to pin down is that this genetic signal affects the genome’s’ dark matter ‘,” explains Dowes’ colleague Jim Hughes. “The increased risk is not due to a protein-coding gene, but to a gene variant that acts as a switch. Such a switch gene is far more difficult to identify. “
In order to track down the risk gene, the scientists evaluated the data of several genome-wide comparative studies with the help of artificial intelligence. Because such switch genes are often only active in certain tissues and cells, they used the algorithm to search for suspicious gene variants based on cell types. In addition, the team performed genetic tests with cultures of various potentially affected cell types. Through these analyzes, the research team was able to identify 28 gene variants that were possible candidates for the risk gene they were looking for. The cell tests already showed that none of these candidate genes was present in defense cells of the immune system, including T killer cells, dendritic cells or B cells. Instead, the gene variants were mainly found in the lung tissue.
Defense of the mucous membrane cells impaired
After the scientists had examined various lung cells more closely, they were finally able to identify the gene variant they were looking for: “The data showed that a gene LZTFL1, which has not yet been investigated, is causing the effect,” reports Downes. In the risk allele baptized rs17713054, the DNA base guanine (G) in this gene has been replaced by an adenine (A). According to the team, the mucous membrane cells of the airways and lungs are primarily affected by this genetic change. The risk gene variant has the effect that an inhibiting factor for the cell’s own defense reaction is strengthened in these cells. As a result, the affected cells are less able to fight off infection with the SARS-CoV-2 coronavirus. “The genetic factor that we discovered explains why some people become so seriously ill after a corona infection,” says co-author James Davies of the University of Oxford.
According to studies, around 15 percent of Europeans are carriers of this risk gene variant, compared with only around two percent of people of African descent. In South Asia, on the other hand, up to 60 percent of the population carry this gene variant in their genome. According to the researchers, this – along with socio-economic factors – could explain why, for example, so many people in India became victims of Covid-19. Comforting, however: Because this gene variant does not hinder the function of the immune system, the vaccination against Covid-19 also works with the carriers of the risk gene. “Even if we cannot change our genes, our results show that people with this risk gene particularly benefit from a vaccination,” says Davies. “Because the genetic signal affects the lungs and not the immune system, the vaccine can largely offset the increased risk.”
Source: Damien Downes (University of Oxford, UK) et al., Nature Genetics, doi: 10.1038 / s41588-021-00955-3