Identification of LZTFL1 as a candidate effector gene at a COVID-19 risk locus
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 mac...
| Main Authors: | , , , , , , , , , , , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
Springer Nature
2021
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| _version_ | 1797107669115338752 |
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| author | Downes, DJ Cross, AR Hua, P Roberts, N Schwessinger, R Cutler, AJ Munis, AM Brown, J Mielczarek, O de Andrea, CE Melero, I Gill, DR Hyde, SC Knight, JC Todd, JA Sansom, SN Issa, F Davies, JOJ Hughes, JR |
| author_facet | Downes, DJ Cross, AR Hua, P Roberts, N Schwessinger, R Cutler, AJ Munis, AM Brown, J Mielczarek, O de Andrea, CE Melero, I Gill, DR Hyde, SC Knight, JC Todd, JA Sansom, SN Issa, F Davies, JOJ Hughes, JR |
| author_sort | Downes, DJ |
| collection | OXFORD |
| description | 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. |
| first_indexed | 2024-03-07T07:18:56Z |
| format | Journal article |
| id | oxford-uuid:d2902d1a-f49b-45ed-a325-6e704bae01e8 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T07:18:56Z |
| publishDate | 2021 |
| publisher | Springer Nature |
| record_format | dspace |
| spelling | oxford-uuid:d2902d1a-f49b-45ed-a325-6e704bae01e82022-09-09T16:08:09ZIdentification of LZTFL1 as a candidate effector gene at a COVID-19 risk locusJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:d2902d1a-f49b-45ed-a325-6e704bae01e8EnglishSymplectic ElementsSpringer Nature2021Downes, DJCross, ARHua, PRoberts, NSchwessinger, RCutler, AJMunis, AMBrown, JMielczarek, Ode Andrea, CEMelero, IGill, DRHyde, SCKnight, JCTodd, JASansom, SNIssa, FDavies, JOJHughes, JRThe 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. |
| spellingShingle | Downes, DJ Cross, AR Hua, P Roberts, N Schwessinger, R Cutler, AJ Munis, AM Brown, J Mielczarek, O de Andrea, CE Melero, I Gill, DR Hyde, SC Knight, JC Todd, JA Sansom, SN Issa, F Davies, JOJ Hughes, JR Identification of LZTFL1 as a candidate effector gene at a COVID-19 risk locus |
| title | Identification of LZTFL1 as a candidate effector gene at a COVID-19 risk locus |
| title_full | Identification of LZTFL1 as a candidate effector gene at a COVID-19 risk locus |
| title_fullStr | Identification of LZTFL1 as a candidate effector gene at a COVID-19 risk locus |
| title_full_unstemmed | Identification of LZTFL1 as a candidate effector gene at a COVID-19 risk locus |
| title_short | Identification of LZTFL1 as a candidate effector gene at a COVID-19 risk locus |
| title_sort | identification of lztfl1 as a candidate effector gene at a covid 19 risk locus |
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