The gene, leucine zipper transcription factor-like 1, doubles the risk of respiratory failure and death from COVID-19

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A gene that doubles the risk of respiratory failure and death from COVID-19, and is present in 60% of South Asians but only 15% of Europeans, has been identified. The gene may explain the excess deaths in some ethnic groups over others.

Researchers from Oxford University led by James Davies, Consultant in Intensive Care Medicine and Associate Professor of Genomics, and Jim Hughes, Professor of Gene Regulation, both from the University of Oxford’s Medical Research Council (MRC) Weatherall Institute of Molecular Medicine, used an artificial intelligence algorithm to analyse huge quantities of genetic data from hundreds of types of cells to show that the gene, leucine zipper transcription factor-like 1 (LZTFL1), is associated with lung function rather than the immune system. The study findings are published in Nature Genetics.

An area of DNA on chromosome 3 (the 3p21.31 region) has previously been found to double mortality from COVID-19 in adults under the age of 60 years, and to double the risk of respiratory failure overall. However, until now, researchers did not understand how this genetic signal increased the risk.   

‘Switch’

‘The previously identified genetic signal affects the ”dark matter” of the genome’, explained Professor Hughes in a news release. ‘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 [enhancer] to turn a gene on. It’s much harder to detect the gene which is affected by this kind of indirect switch effect.’

Machine learning and molecular biology platforms were used to analyse huge quantities of genetic data from hundreds of COVID-19-relevant cell types, including blood, brain, muscle, endothelium, epithelium, and lung, among many others, to find key cells types associated with risk level for COVID-19 outcomes.

Researchers found that the genetic signal is likely to affect cells in the lung. By examining DNA at the site of the genetic signal (the LZTFL1 gene) controlled by the so-called ‘switch’, they identified the gene responsible for the greater risk of developing severe COVID-19.

The team found that the higher-risk version of the gene probably prevents the cells lining the airways and lungs from responding to the virus properly. In biopsies of lung tissue from patients with COVID-19, they identified a viral response pathway linked to LZTFL1 called epithelial–mesenchymal transition.

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.

Ethnicity risks

Professor Davies commented: ‘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.’

The higher mortality and more severe disease in certain ethnic groups may be, in part, explained by this finding. Around 60% of people with South Asian ancestry have the high-risk version of the gene, compared with only 15% of those with European ancestry. However, only 2% of people of people with African-Caribbean ancestry carried the higher-risk genotype, which suggests that other factors, and possibly other genes, may be at play in the higher mortality seen in some ethnic groups. 

Commenting on the finding via the Science Media Centre, Dr Raghib Ali, Senior Clinical Research Associate, MRC Epidemiology Unit, University of Cambridge and independent expert adviser on COVID-19 and ethnicity to the Race Disparity Unit, Cabinet Office, said: ‘Although the higher death rate we have seen in ethnic minorities is primarily due to their higher risk of infection, which in turn is driven by their higher likelihood of living in densely populated urban areas, in larger and multi-generational households (especially among South Asians), and to work in public-facing roles, including health and social care (especially Black groups), there has been an unexplained residual excess risk in South Asians, even after taking these risk factors into account.’

He added that other studies have also shown that South Asians—Bangladeshis in particular, but not Black groups—have worse survival than White people. ‘This study, as well as others, shows that this may be due to them being more likely to carry this gene, which increases their risk of death once infected.’

Professor Davies said: ‘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.’

The study authors also added that the finding ‘raises the possibility that LZTFL1 could be a potential therapeutic target for the treatment or prevention of COVID-19’.

Published in the November 2021 edition of Nature Genetics.

This article originally appeared on Medscape, part of the Medscape Professional Network.

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