Lest we forget

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The COVID-19 pandemic has had an extraordinary impact on ethnic minorities in the UK. Most of us had ascribed this excess mortality to the social determinants of health. However, the study below suggests some of the excess mortality may be related to genetic factors. 

A gene that acts as a switch to turn on a defence mechanism that prevents the SARS-CoV-2 from entering epithelial cells in the lung may be an important factor. With the high-risk version of the gene, these defence mechanisms are blunted, allowing the virus to enter, infect and damage cells in the lung for a longer time period after exposure and infection. 

Having the high-risk version of this gene doubles your risk of respiratory failure and death from COVID-19 and could explain why people of South Asian origin are more vulnerable to the disease. The high-risk gene is carried by ~60% of people with south Asian backgrounds, compared to only 15% of those from a white European background. 

I wonder if my friend and colleague Dr Peter Tun, who died last April from COVID-19, carried this gene variant?

Downes et al. Identification of LZTFL1 as a candidate effector gene at a COVID-19 risk locus. Nature Genetics. 4-Nov-2021.

The severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) disease (COVID-19) pandemic has caused millions of deaths worldwide. Genome-wide association studies identified the 3p21.31 region as conferring a twofold increased risk of respiratory failure. Here, using a combined multiomics and machine learning approach, we identify the gain-of-function risk A allele of an SNP, rs17713054G>A, as a probable causative variant. We show with chromosome conformation capture and gene-expression analysis that the rs17713054-affected enhancer upregulates the interacting gene, leucine zipper transcription factor like 1 (LZTFL1). Selective spatial transcriptomic analysis of lung biopsies from patients with COVID-19 shows the presence of signals associated with epithelial–mesenchymal transition (EMT), a viral response pathway that is regulated by LZTFL1. We conclude 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.

Conflicts of Interest

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General Disclaimer: Please note that the opinions expressed here are those of Professor Giovannoni and do not necessarily reflect the positions of the Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust and are not meant to be interpreted as personal clinical advice. 

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