Identification of LZTFL1 as a candidate effector gene at a COVID-19 risk locus.
Nat Genet
; 53(11): 1606-1615, 2021 11.
Article
en En
| MEDLINE
| ID: mdl-34737427
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.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Factores de Transcripción
/
Cromosomas Humanos Par 3
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Polimorfismo de Nucleótido Simple
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Transición Epitelial-Mesenquimal
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SARS-CoV-2
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COVID-19
/
Pulmón
Tipo de estudio:
Diagnostic_studies
/
Etiology_studies
/
Observational_studies
/
Prognostic_studies
/
Risk_factors_studies
Límite:
Female
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Humans
/
Male
Idioma:
En
Revista:
Nat Genet
Asunto de la revista:
GENETICA MEDICA
Año:
2021
Tipo del documento:
Article
País de afiliación:
Reino Unido