November 4, 2021

expert reaction to study looking at a gene, LZTFL1, and risk of severe COVID-19 disease

A study published in Nature Genetics identifies the gene LZTFL1 involved with risk of severe COVID-19 disease.

This Roundup accompanied an SMC Briefing.

Prof Kenneth Baillie, Professor of Experimental Medicine, University of Edinburgh, said:

“This is a nice approach to explaining a plausible mechanism of action for our first and strongest human genetic association with Covid-19 as first reported last year. (Ellinghaus et al, NEJM June 2020).”

Dr Simon Biddie, Clinical lecturer in Intensive Care Medicine, MRC Human Genetics Units, Institute of Genetics and Cancer, University of Edinburgh, said:

“This study provides compelling evidence to suggest roles for LZFTL1 in the lung parenchyma in severe COVID-19 that warrants urgent further investigation.  The candidate SNP will need further experimental verification to provide direct evidence for regulation of LZTFL1, using for example genome engineering approaches.”

Prof Frances Flinter, Emeritus Professor of Clinical Genetics, Guy’s & St Thomas’ NHS Foundation Trust, said:

“This is a very interesting publication.  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.  Evidence that a relatively unstudied gene, LZTFL1, has emerged as a candidate causal gene, which is potentially responsible for some of the twofold increased risk of respiratory failure from COVID-19 in some populations, provides a big step forward in our understanding of the variable susceptibility of some individuals to serious disease and death.  Sixty percent of people with South Asian ancestry carried a higher-risk version of the gene compared with 15 percent of those with European ancestry – explaining in part the higher rate of hospitalisation and death in the former group.

“The study also found that 2 percent of people with Afro-Caribbean ancestry carried the higher risk genotype, so this genetic factor does not completely explain the increased death rates reported in black and minority ethnic communities.

“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.”

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:

“This is an important study which contributes to our ongoing efforts to understand the causes of the higher death rates from Covid in some ethnic groups and specifically as to why their outcomes or survival from Covid are worse after infection.

“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.

“Other studies from Public Health England, ISARIC and ICNARC have also shown that South Asians (and Bangladeshis in particular) – but not Black groups – have worse survival than Whites and this study, as well as others, show that this may be due to  them being more likely to carry this gene which increases their risk of death once infected.

“Vaccine uptake has been high in South Asian groups but this study reinforces the importance of taking the booster doses now to maximise their protection and reduce their risk as immunity is now waning.”

‘Identification of LZTFL1 as a candidate effector gene at a COVID-19 risk locus’ by Damien J. Downes et al. was published in Nature Genetics at 16:00 UK time on Thursday 4 November 2021.

DOI: 10.1038/s41588-021-00955-3

All our previous output on this subject can be seen at this weblink:

www.sciencemediacentre.org/tag/covid-19

Declared interests

Prof Frances Flinter: “I work as a prescriber in a Covid vaccination centre.”

None others received.