LZTFL1 gene doubles your chance of dying of covid: Found in 60% of south Asians and 15% of Europeans, but not in east Asians or Africans

LZTFL1 gene doubles your chance of dying of covid: Found in 60% of south Asians and 15% of Europeans, but not in east Asians or Africans. By Damien Downes et al.

The 3p21.31 risk haplotype … confers a twofold increased risk of respiratory failure from COVID-19 and an over twofold increased risk of mortality for individuals under 60. Additionally, the risk variants at this locus are carried by >60% of individuals with South Asian ancestry, compared to 15% of European ancestry groups, partially explaining the ongoing higher death rate in this population in the UK. …

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.

Megan Hinton:

Researchers have discovered the gene which puts people at double the risk of respiratory failure from coronavirus.

The gene is found in around 60 per cent of people with South Asian ancestry, according to a new study. …

The study also found that around 15 percent of the European population carried the gene …

Study co-lead James Davies .. said: “If you have the high-risk genotype and you get very unwell with Covid, there’s a 50 per cent chance that that wouldn’t have happened to you had you had the lower risk genotype.” …

The study, published in Nature Genetics, also found that the gene does not alter immune cell function. Because the effect is in the biology of the lungs, people with the higher risk version of the genes should respond fully to vaccination, the scientists say.

Study co-lead James Davies, quoted by the Radcliffe Dept of Medicine:

‘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.’


They estimate the risky version of the gene is present in about 2% of people from African-Caribbean backgrounds and 1.8% of people of East Asian decent. …

When cells lining the lung interact with coronavirus, one of their defence strategies is to turn into less specialised cells and become less welcoming to the virus. This despecialisation process reduces the amount on the surface of cells of a key protein called ACE-2, which is key to coronavirus attaching itself to cells.

But for people with the risky version of the LZTFL1 gene this process does not work as well, and lung cells are left vulnerable to invasion of the virus.

So, this gene is rarely found around Wuhan.