RRC ID 68659
Author Downes DJ, Cross AR, Hua P, Roberts N, Schwessinger R, Cutler AJ, Munis AM, Brown J, Mielczarek O, de Andrea CE, Melero I, COvid-19 Multi-omics Blood ATlas (COMBAT) Consortium, Gill DR, Hyde SC, Knight JC, Todd JA, Sansom SN, Issa F, Davies JOJ, Hughes JR.
Title Identification of LZTFL1 as a candidate effector gene at a COVID-19 risk locus.
Journal Nat Genet
Abstract 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.
Volume 53(11)
Pages 1606-1615
Published 2021-11-1
DOI 10.1038/s41588-021-00955-3
PII 10.1038/s41588-021-00955-3
PMID 34737427
PMC PMC7611960
MeSH COVID-19 / complications* COVID-19 / transmission COVID-19 / virology Case-Control Studies Chromosomes, Human, Pair 3 / genetics* Epithelial Cells / metabolism Epithelial Cells / pathology Epithelial Cells / virology Epithelial-Mesenchymal Transition* Female Genome-Wide Association Study Humans Lung / metabolism Lung / pathology Lung / virology* Male Polymorphism, Single Nucleotide* SARS-CoV-2 / isolation & purification* Transcription Factors / genetics* Transcription Factors / metabolism
IF 27.605
Human and Animal Cells HUDEP-2(RCB4557)