Detalle Publicación


Identification of LZTFL1 as a candidate effector gene at a COVID-19 risk locus

Autores: Downes, D. J.; Cross, A. R.; Hua, P.; Roberts, N.; Schwessinger, R.; Cutler, A. J.; Munis, A. M.; Brown, J.; Mielczarek, O.; De Andrea, Carlos Eduardo; Melero Bermejo, Ignacio; Gill, D. R.; Hyde, S. C.; Knight, J. C.; Todd, J. A.; Sansom, S, N.; Issa, F.; Davies, J. O. J. (Autor de correspondencia); Hughes J. R. (Autor de correspondencia); COvid-19 Multi-omics Blood ATlas (COMBAT) Consorti
Título de la revista: NATURE GENETICS
ISSN: 1061-4036
Volumen: 53
Número: 11
Páginas: 1606 - 1615
Fecha de publicación: 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. SNP rs17713054 in the 3p21.31 COVID-19 risk locus is identified as a probable causative variant for disease association. Chromatin conformation and gene expression data indicate that LZTFL1 is impacted by rs17713054 in pulmonary epithelial cells.