tetano
Editor, Senior Moderator
Nat Genet
. 2021 Nov 4.
doi: 10.1038/s41588-021-00955-3. Online ahead of print.
Identification of LZTFL1 as a candidate effector gene at a COVID-19 risk locus
Damien J Downes[SUP] 1 [/SUP], Amy R Cross[SUP] #[/SUP][SUP] 2 [/SUP], Peng Hua[SUP] #[/SUP][SUP] 1 [/SUP], Nigel Roberts[SUP] 1 [/SUP], Ron Schwessinger[SUP] 1 3 [/SUP], Antony J Cutler[SUP] 4 5 [/SUP], Altar M Munis[SUP] 6 [/SUP], Jill Brown[SUP] 1 [/SUP], Olga Mielczarek[SUP] 4 [/SUP], Carlos E de Andrea[SUP] 7 [/SUP], Ignacio Melero[SUP] 8 [/SUP], COvid-19 Multi-omics Blood ATlas (COMBAT) Consortium; Deborah R Gill[SUP] 6 [/SUP], Stephen C Hyde[SUP] 6 [/SUP], Julian C Knight[SUP] 4 9 10 [/SUP], John A Todd[SUP] 4 [/SUP], Stephen N Sansom[SUP] 11 [/SUP], Fadi Issa[SUP] 2 12 [/SUP], James O J Davies[SUP] 13 14 [/SUP], Jim R Hughes[SUP] 15 16 [/SUP]
Affiliations
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.
. 2021 Nov 4.
doi: 10.1038/s41588-021-00955-3. Online ahead of print.
Identification of LZTFL1 as a candidate effector gene at a COVID-19 risk locus
Damien J Downes[SUP] 1 [/SUP], Amy R Cross[SUP] #[/SUP][SUP] 2 [/SUP], Peng Hua[SUP] #[/SUP][SUP] 1 [/SUP], Nigel Roberts[SUP] 1 [/SUP], Ron Schwessinger[SUP] 1 3 [/SUP], Antony J Cutler[SUP] 4 5 [/SUP], Altar M Munis[SUP] 6 [/SUP], Jill Brown[SUP] 1 [/SUP], Olga Mielczarek[SUP] 4 [/SUP], Carlos E de Andrea[SUP] 7 [/SUP], Ignacio Melero[SUP] 8 [/SUP], COvid-19 Multi-omics Blood ATlas (COMBAT) Consortium; Deborah R Gill[SUP] 6 [/SUP], Stephen C Hyde[SUP] 6 [/SUP], Julian C Knight[SUP] 4 9 10 [/SUP], John A Todd[SUP] 4 [/SUP], Stephen N Sansom[SUP] 11 [/SUP], Fadi Issa[SUP] 2 12 [/SUP], James O J Davies[SUP] 13 14 [/SUP], Jim R Hughes[SUP] 15 16 [/SUP]
Affiliations
- PMID: 34737427
- DOI: 10.1038/s41588-021-00955-3
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.