University of Oxford researchers have identified the gene responsible for doubling the risk of respiratory failure from COVID-19.
Sixty percent of people with South Asian ancestry carry the high-risk genetic signal, which could partly explain the excess deaths seen in some UK communities, and the impact of COVID-19 in South Asia.
Previous work had already identified a stretch of DNA on chromosome 3 which doubled the risk of adults under 65 dying from COVID. However, scientists did not know how this genetic signal worked to increase the risk, nor the exact genetic change that was responsible.
In a study published in Nature Genetics, a team lead by Professors James Davies and Jim Hughes from the University’s MRC Weatherall Institute of Molecular Medicine used cutting-edge technology to work out which gene was causing the effect, and how it was doing so.
The research team were supported by the NIHR Oxford Biomedical Research Centre.
Prof Hughes said: “The reason this has proved so difficult to work out, is that the previously identified genetic signal affects the ‘dark matter’ of the genome. We found that the increased risk is not because of a difference in gene coding for a protein, but because of a difference in the DNA that makes a switch to turn a gene on. It’s much harder to detect the gene which is affected by this kind of indirect switch effect.”
The team trained an artificial intelligence algorithm to analyse huge quantities of genetic data from hundreds of types of cells from all parts of the body, to show that the genetic signal is likely to affect cells in the lung.
Then, using a newly developed technique, the researchers could zoom down on the DNA at the genetic signal. This examines the way that the billions of DNA letters fold up to fit inside a cell to pinpoint accurately the specific gene that was being controlled by the sequence causing the greater risk of developing severe COVID-19.
Several genes were suspected of being responsible, but the data showed that a relatively unstudied gene called LZTFL1 caused the effect.
The researchers found that the higher risk version of the gene probably prevents the cells that line airways and the lungs from responding to the virus properly. But importantly it does not affect the immune system, so the researchers expect people carrying this version of the gene to respond normally to vaccines.
The researchers are also hopeful that drugs and other therapies could target the pathway preventing the lung lining from transforming to less specialised cells, raising the possibility of new treatments customised for those most likely to develop severe symptoms.
Study co-lead Prof James Davies, who worked as an NHS Consultant in Intensive Care Medicine during the pandemic, said: “The genetic factor we have found explains why some people get very seriously ill after coronavirus infection. It shows that the way in which the lung responds to the infection is critical. This is important because most treatments have focussed on changing the way in which the immune system reacts to the virus.”
Sixty percent of people with South Asian ancestry carried this higher-risk version of the gene compared to 15 percent of those with European ancestry – explaining in part the higher death rates and hospitalisations in the former group.
The study also found that two percent of people with Afro-Caribbean ancestry carried the higher risk genotype, meaning that this genetic factor does not completely explain the higher death rates reported for black and minority ethnic communities.
Prof Davies explained: “Socioeconomic factors are also likely to be important in explaining why some communities have been particularly badly affected by the COVID-19 pandemic.
“Although we cannot change our genetics, our results show that the people with the higher-risk gene are likely to particularly benefit from vaccination. Since the genetic signal affects the lung rather than the immune system it means that the increased risk should be cancelled out by the vaccine.”
Read the full paper.