Switching Response behind increased Respiratory Risk from COVID

A gene responsible for doubling the risk of respiratory failure from COVID-19 has been identified by researchers at the University of Oxford’s MRC Weatherall Institute of Molecular Medicine.

Led by Professor James Davies and Professor Jim Hughes, the team studied how a stretch of DNA on chromosome 3 known to double the risk of adults aged under 65 dying from COVID worked to increase this risk and how it was doing so.

Study co-lead Prof Jim 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.’

Using an artificial intelligence algorithm trained to analyse huge quantities of genetic data of cells from all over the body, to indicate that the genetic signal is likely to affect cells in the lung, the researchers then zoomed down on the DNA at the genetic signal. This examined how billions of DNA letters fold up to fit inside a cell to pinpoint the specific gene that was being controlled by the sequence, thus causing the greater risk of developing severe COVID-19.

Dr 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.’

While this higher risk version of the gene probably interferes with cells lining the airways and lungs, the researchers pointed out that it doesn’t affect the immune system, so expected that people carrying this version of the gene would respond normally to vaccines. They were also hopeful that the findings would lead to the possibility of other customised drug and therapy treatments for those more at risk.

Study co-lead Prof James Davies, who worked as an NHS Consultant in Intensive Care Medicine during the pandemic and 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 focussed on changing the way in which the immune system reacts to the virus.’

Sixty percent of people with South Asian ancestry carry 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 2 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: ‘The higher risk DNA code is found more commonly in some black and minority ethnic communities but not in others. 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.’

Published in Nature Genetics

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