Identification of LZTFL1 as a candidate effector gene at a COVID-19 risk locus.
Nat Genet
; 53(11): 1606-1615, 2021 11.
Article
in English
| MEDLINE | ID: covidwho-1503871
ABSTRACT
The severe acute respiratory syndrome coronavirus 2 (SARSCoV2) 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.
Full text:
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Collection:
International databases
Database:
MEDLINE
Main subject:
Transcription Factors
/
Chromosomes, Human, Pair 3
/
Polymorphism, Single Nucleotide
/
Epithelial-Mesenchymal Transition
/
SARS-CoV-2
/
COVID-19
/
Lung
Type of study:
Experimental Studies
/
Observational study
/
Prognostic study
Topics:
Long Covid
/
Variants
Limits:
Female
/
Humans
/
Male
Language:
English
Journal:
Nat Genet
Journal subject:
Genetics, Medical
Year:
2021
Document Type:
Article
Affiliation country:
S41588-021-00955-3
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