Scientists uncover why certain genotype increases risk of dying from COVID-19

A mechanism has been uncovered which explains why genetic variation at a particular site on the third chromosome in humans makes people twice as likely to die from COVID-19.

Scientists have found those with a particular genotype at this site have greater expression of a relatively unknown gene called LZTFL1, also found on the third chromosome. Increased expression of this gene raises the risk of fatal respiratory failure in those under 65 years of age. The study, carried out at the University of Oxford, used genome databases to compare the prevalence of this genotype among people of different heritages. The high-risk variant found on this part of the genome which controls the regulation of LZTFL1, was found in the genomes of 60 percent of people of South-Asian descent, 15 percent of people of European descent, two percent of people of Afro-Caribbean descent and 1.8 percent of people of East-Asian descent.

'If you have the high-risk genotype and you get very unwell with COVID, there's a 50 percent chance that that wouldn't have happened to you had you had the lower risk genotype,' Dr James Davies, who co-led the study, said.

The gene affects the endothelial lining of the lungs and trachea, helping COVID-19 particles to bind to these cells through the endothelial cell surface proteins called ACE-2. Since this gene affects pulmonary epithelial cells and does not affect the body's immune system, the efficacy of COVID-19 vaccines remains undiminished, and these findings reinforce the importance of vaccinating carriers of this genotype against COVID-19 as the increased risk 'should be cancelled out by the vaccine' according to Dr Davies.

This research, published in Nature, could lead to better treatments for COVID-19 targeting the LZTFL1 gene. Moreover, these findings may help to identify which sections of society are most at risk from developing severe COVID-19, ensuring that they are offered preventative measures such as vaccines, at an earlier stage.

'The discrepancy between the risk of serious disease and death in different ethnic groups has previously been attributed in part to socio-economic differences, but it was clear that this was not a complete explanation' said Professor Frances Flinter, emeritus professor of Clinical Genetics at Guy's and St Thomas' NHS Foundation Trust, who was not involved in the study.

She continued: 'It is particularly important to offer vaccination to communities that are at greater risk of serious COVID-19 infection as a consequence of carrying this genetic predisposition, as their increased risk should be cancelled out by vaccination. These results are important as they also identify a potential new drug target, which could be particularly useful for those at risk of serious disease.'

However, this research does not implicate the riskier genotype in the higher death rate reported in black communities, as only two percent of those with Afro-Caribbean ancestry carried this. Furthermore, this research was conducted from a database of nearly 200,000 genomes, of which 85 percent were from people of European descent, highlighting the need for this discovery to be confirmed using genetic data from COVID patients from a larger proportion of ethnic groups and further shows the under-representation of people from ethnic minority backgrounds in genetic databases.