Reference - Detail
| 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 |
| Altmetric score |
オルトメトリクス指標項目
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| The most frequently cited source | X(Twitter) |
| Total number of mentions | 1145 |
| Altmetric score changes over past 6months | 0.0 |
| Resource | |
| Human and Animal Cells | HUDEP-2(RCB4557) |