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Статья
Mendelian randomisation identifies alternative splicing of the FAS death receptor as a mediator of severe COVID-19
L. Klarić,
J. Gisby,
A. Papadaki,
M. Muckian,
E. Macdonald-Dunlop,
J. Zhao,
A. Tokolyi,
E. Persyn,
E. Pairo-Castineira,
A. Morris,
A. Kalnapenkis,
A. Richmond,
A. Landini,
Å. Hedman,
B. Prins,
D. Zanetti,
E. Wheeler,
C. Kooperberg,
C. Yao,
J. Petrie,
J. Fu,
L. Folkersen,
M. Walker,
M. Magnusson,
N. Eriksson,
N. Mattsson-Carlgren,
P. Timmers,
S. Hwang,
S. Enroth,
S. Gustafsson,
U. Võsa,
Y. Chen,
A. Siegbahn,
A. Reiner,
Å. Johansson,
B. Thorand,
B. Gigante,
C. Hayward,
C. Herder,
C. Gieger,
C. Langenberg,
D. Levy,
D. Zhernakova,
J. Smith,
H. Campbell,
J. Sundström,
J. Danesh,
K. Michaëlsson,
K. Suhre,
L. Lind,
L. Wallentin,
L. Padyukov,
M. Landén,
N. Wareham,
A. Göteson,
O. Hansson,
R. Strawbridge,
T. Assimes,
T. Esko,
U. Gyllensten,
J. Baillie,
D. Paul,
P. Joshi,
A. Butterworth,
A. Mälarstig,
N. Pirastu,
J. Wilson,
J. Peters,
2021
Severe COVID-19 is characterised by immunopathology and epithelial injury. Proteomic studies have identified circulating proteins that are biomarkers of severe COVID-19, but cannot distinguish correlation from causation. To address this, we performed Mendelian randomisation (MR) to identify proteins that mediate severe COVID-19. Using protein quantitative trait loci (pQTL) data from the SCALLOP consortium, involving meta-analysis of up to 26,494 individuals, and COVID-19 genome-wide association data from the Host Genetics Initiative, we performed MR for 157 COVID-19 severity protein biomarkers. We identified significant MR results for five proteins: FAS, TNFRSF10A, CCL2, EPHB4 and LGALS9. Further evaluation of these candidates using sensitivity analyses and colocalization testing provided strong evidence to implicate the apoptosis-associated cytokine receptor FAS as a causal mediator of severe COVID-19. This effect was specific to severe disease. Using RNA-seq data from 4,778 individuals, we demonstrate that the pQTL at the FAS locus results from genetically influenced alternate splicing causing skipping of exon 6. We show that the risk allele for very severe COVID-19 increases the proportion of transcripts lacking exon 6, and thereby increases soluble FAS. Soluble FAS acts as a decoy receptor for FAS-ligand, inhibiting apoptosis induced through membrane-bound FAS. In summary, we demonstrate a novel genetic mechanism that contributes to risk of severe of COVID-19, highlighting a pathway that may be a promising therapeutic target.
Цитирование
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Версии
- 1. Version of Record от 2021-04-07
Метаданные
Об авторах
-
L. Klarić
University of Edinburgh -
J. Gisby
Imperial College London -
A. Papadaki
Imperial College London -
M. Muckian
University of Edinburgh -
E. Macdonald-Dunlop
University of Edinburgh -
J. Zhao
University of Cambridge -
A. Tokolyi
Wellcome Trust Sanger Institute -
E. Persyn
British Heart Foundation -
E. Pairo-Castineira
Western General Hospital; University of Edinburgh -
A. Morris
University of Manchester -
A. Kalnapenkis
University of Tartu -
A. Richmond
Western General Hospital -
A. Landini
University of Edinburgh -
Å. Hedman
Karolinska Institutet -
B. Prins
British Heart Foundation -
D. Zanetti
Stanford University -
E. Wheeler
University of Cambridge -
C. Kooperberg
Fred Hutchinson Cancer Research Center -
C. Yao
National Institutes of Health -
J. Petrie
University of Glasgow -
J. Fu
University Medical Center Groningen - L. Folkersen
-
M. Walker
Newcastle University - M. Magnusson
-
N. Eriksson
Uppsala University - N. Mattsson-Carlgren
-
P. Timmers
Western General Hospital; University of Edinburgh -
S. Hwang
National Institutes of Health -
S. Enroth
Uppsala University -
S. Gustafsson
Uppsala University -
U. Võsa
University of Tartu -
Y. Chen
Karolinska Institutet -
A. Siegbahn
Uppsala University -
A. Reiner
Fred Hutchinson Cancer Research Center -
Å. Johansson
Uppsala University - B. Thorand
-
B. Gigante
Karolinska Institutet -
C. Hayward
Western General Hospital -
C. Herder
University of Düsseldorf - C. Gieger
-
C. Langenberg
University of Cambridge; Charité -
D. Levy
National Institutes of Health -
D. Zhernakova
University Medical Center Groningen; Saint Petersburg State University of Information Technologies, Mechanics and Optics - J. Smith
-
H. Campbell
University of Edinburgh -
J. Sundström
Uppsala University; The George Institute for Global Health -
J. Danesh
University of Cambridge; Wellcome Trust Sanger Institute; British Heart Foundation -
K. Michaëlsson
Uppsala University -
K. Suhre
Cornell University -
L. Lind
Uppsala University - L. Wallentin
-
L. Padyukov
Karolinska University Hospital; Karolinska Institutet -
M. Landén
Karolinska Institutet; University of Gothenburg -
N. Wareham
University of Cambridge -
A. Göteson
University of Gothenburg - O. Hansson
-
R. Strawbridge
University of Cambridge; Karolinska Institutet; University of Glasgow -
T. Assimes
Stanford University -
T. Esko
University of Tartu -
U. Gyllensten
Uppsala University -
J. Baillie
Western General Hospital; University of Edinburgh -
D. Paul
British Heart Foundation; National Institute for Health Research -
P. Joshi
University of Edinburgh -
A. Butterworth
University of Cambridge; British Heart Foundation; National Institute for Health Research -
A. Mälarstig
Pfizer; Karolinska Institutet -
N. Pirastu
University of Edinburgh -
J. Wilson
Western General Hospital; University of Edinburgh -
J. Peters
University of Cambridge
Предметная рубрика
- COVID-19
Название журнала
- medRxiv : the preprint server for health sciences
Тип документа
- preprint
Источник
- lens
