Scientists at Oxford University have found evidence that variation in a single gene, LZTFL1, doubles the risk of respiratory failure from COVID-19. Sixty percent of people with South Asian ancestry carry a genetic signal for this effect, partly explaining the excess deaths seen in some U.K. communities, and the impact of COVID-19 in the Indian subcontinent.
The study was published in Nature Genetics, by a team lead by Professors James Davies and Jim Hughes at the University of Oxford’s MRC Weatherall Institute of Molecular Medicine.
Previous work has identified a stretch of DNA on chromosome 3, the 3p21.31 region, which doubles the risk of adults under 65 of dying from COVID.
This team of scientists wanted to know the exact gene(s) involved and more about how this genetic signal worked to increase the risk. Using chromosome conformation capture and gene-expression analysis, they showed the rs17713054-affected enhancer upregulates the interacting gene, leucine zipper transcription factor like 1 (LZTFL1).
Damien Downes, who led the laboratory work from the Hughes research group, said: ‘Surprisingly, as several other genes were suspected, the data showed that a relatively unstudied gene called LZTFL1 causes the effect.”
Hughes, Professor of Gene Regulation, 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 analyze genetic data from hundreds of types of cells from all parts of the body.
The researchers also found that the higher risk version of the gene probably prevents the cells lining airways and the lungs from responding to the virus properly. But importantly it doesn’t affect the immune system, so the researchers expect people carrying this version of the gene to respond normally to vaccines.
They applied selective spatial transcriptomic analysis of lung biopsies from patients with COVID-19 to find signals associated with epithelial–mesenchymal transition (EMT), a viral response pathway regulated by LZTFL1. They concluded that “Pulmonary epithelial cells undergoing EMT, rather than immune cells, are likely responsible for the 3p21.31-associated risk. Since the 3p21.31 effect is conferred by a gain-of-function, LZTFL1 may represent a therapeutic target.”
The researchers are hopeful that drugs and other therapies could target the pathway preventing the lung lining from transforming to less specialized cells, raising the possibility of new treatments customized for those most likely to develop severe symptoms.
Davies, who is an Associate Professor of Genomics at Oxford University’s Radcliffe Department of Medicine, 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 focused on changing the way in which the immune system reacts to the virus.”
He added that, “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.”