Imperial College London
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DrJamesPeters

Faculty of Medicine, Department of Immunology and Inflammation

Clinical Reader in Rheumatology
 
 
 
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j.peters

 
 
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ICTEM buildingHammersmith Campus

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Summary

 

Publications

Citation

BibTex format

@article{Klaric:2021:10.1101/2021.04.01.21254789,
author = {Klaric, L and Gisby, JS and Papadaki, A and Muckian, MD and Macdonald-Dunlop, E and Zhao, JH and Tokolyi, A and Persyn, E and Pairo-Castineira, E and Morris, AP and Kalnapenkis, A and Richmond, A and Landini, A and Hedman, ÅK and Prins, B and Zanetti, D and Wheeler, E and Kooperberg, C and Yao, C and Petrie, JR and Fu, J and Folkersen, L and Walker, M and Magnusson, M and Eriksson, N and Mattsson-Carlgren, N and Timmers, PRHJ and Hwang, S-J and Enroth, S and Gustafsson, S and Vosa, U and Chen, Y and Siegbahn, A and Reiner, A and Johansson, Å and Thorand, B and Gigante, B and Hayward, C and Herder, C and Gieger, C and Langenberg, C and Levy, D and Zhernakova, DV and Smith, JG and Campbell, H and Sundstrom, J and Danesh, J and Michaëlsson, K and Suhre, K and Lind, L and Wallentin, L and Padyukov, L and Landén, M and Wareham, NJ and Göteson, A and Hansson, O and Eriksson, P and Strawbridge, RJ and Assimes, TL and Esko, T and Gyllensten, U and Baillie, JK and Paul, DS and Joshi, PK and But},
doi = {10.1101/2021.04.01.21254789},
journal = {medRxiv},
title = {Mendelian randomisation identifies alternative splicing of the FAS death receptor as a mediator of severe COVID-19.},
url = {http://dx.doi.org/10.1101/2021.04.01.21254789},
year = {2021}
}
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TY  - JOUR
AB  - 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.
AU  - Klaric,L
AU  - Gisby,JS
AU  - Papadaki,A
AU  - Muckian,MD
AU  - Macdonald-Dunlop,E
AU  - Zhao,JH
AU  - Tokolyi,A
AU  - Persyn,E
AU  - Pairo-Castineira,E
AU  - Morris,AP
AU  - Kalnapenkis,A
AU  - Richmond,A
AU  - Landini,A
AU  - Hedman,ÅK
AU  - Prins,B
AU  - Zanetti,D
AU  - Wheeler,E
AU  - Kooperberg,C
AU  - Yao,C
AU  - Petrie,JR
AU  - Fu,J
AU  - Folkersen,L
AU  - Walker,M
AU  - Magnusson,M
AU  - Eriksson,N
AU  - Mattsson-Carlgren,N
AU  - Timmers,PRHJ
AU  - Hwang,S-J
AU  - Enroth,S
AU  - Gustafsson,S
AU  - Vosa,U
AU  - Chen,Y
AU  - Siegbahn,A
AU  - Reiner,A
AU  - Johansson,Å
AU  - Thorand,B
AU  - Gigante,B
AU  - Hayward,C
AU  - Herder,C
AU  - Gieger,C
AU  - Langenberg,C
AU  - Levy,D
AU  - Zhernakova,DV
AU  - Smith,JG
AU  - Campbell,H
AU  - Sundstrom,J
AU  - Danesh,J
AU  - Michaëlsson,K
AU  - Suhre,K
AU  - Lind,L
AU  - Wallentin,L
AU  - Padyukov,L
AU  - Landén,M
AU  - Wareham,NJ
AU  - Göteson,A
AU  - Hansson,O
AU  - Eriksson,P
AU  - Strawbridge,RJ
AU  - Assimes,TL
AU  - Esko,T
AU  - Gyllensten,U
AU  - Baillie,JK
AU  - Paul,DS
AU  - Joshi,PK
AU  - Butterworth,AS
AU  - Mälarstig,A
AU  - Pirastu,N
AU  - Wilson,JF
AU  - Peters,JE
DO  - 10.1101/2021.04.01.21254789
PY  - 2021///
TI  - Mendelian randomisation identifies alternative splicing of the FAS death receptor as a mediator of severe COVID-19.
T2  - medRxiv
UR  - http://dx.doi.org/10.1101/2021.04.01.21254789
UR  - https://www.ncbi.nlm.nih.gov/pubmed/33851187
ER  -
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