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In Nature genetics ; h5-index 174.0

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.

Downes Damien J, Cross Amy R, Hua Peng, Roberts Nigel, Schwessinger Ron, Cutler Antony J, Munis Altar M, Brown Jill, Mielczarek Olga, de Andrea Carlos E, Melero Ignacio, Gill Deborah R, Hyde Stephen C, Knight Julian C, Todd John A, Sansom Stephen N, Issa Fadi, Davies James O J, Hughes Jim R