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@article{Pairo-Castineira:2021:10.1038/s41586-020-03065-y,
author = {Pairo-Castineira, E and Clohisey, S and Klaric, L and Bretherick, AD and Rawlik, K and Pasko, D and Walker, S and Parkinson, N and Fourman, MH and Russell, CD and Furniss, J and Richmond, A and Gountouna, E and Wrobel, N and Harrison, D and Wang, B and Wu, Y and Meynert, A and Griffiths, F and Oosthuyzen, W and Kousathanas, A and Moutsianas, L and Yang, Z and Zhai, R and Zheng, C and Grimes, G and Beale, R and Millar, J and Shih, B and Keating, S and Zechner, M and Haley, C and Porteous, DJ and Hayward, C and Yang, J and Knight, J and Summers, C and Shankar-Hari, M and Klenerman, P and Turtle, L and Ho, A and Moore, SC and Hinds, C and Horby, P and Nichol, A and Maslove, D and Ling, L and McAuley, D and Montgomery, H and Walsh, T and Pereira, A and Renieri, A and GenOMICC, Investigators and ISARICC, Investigators and COVID-19, Human Genetics Initiative and 23andMe, Investigators and BRACOVID, Investigators and Gen-COVID, Investigators and Shen, X and Ponting, CP and Fawkes, A and Tenes},
doi = {10.1038/s41586-020-03065-y},
journal = {Nature},
pages = {92--98},
title = {Genetic mechanisms of critical illness in Covid-19},
url = {http://dx.doi.org/10.1038/s41586-020-03065-y},
volume = {591},
year = {2021}
}

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TY  - JOUR
AB  - Host-mediated lung inflammation is present,1 and drives mortality,2 in critical illness caused by Covid-19. Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development.3 Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study(GWAS) in 2244 critically ill Covid-19 patients from 208 UK intensive care units (ICUs). We identify and replicate novel genome-wide significant associations, on chr12q24.13 (rs10735079, p=1.65 [Formula: see text] 10-8) in a gene cluster encoding antiviral restriction enzyme activators (OAS1, OAS2, OAS3), on chr19p13.2 (rs2109069, p=2.3 [Formula: see text] 10-12) near the gene encoding tyrosine kinase 2 (TYK2), on chr19p13.3 (rs2109069, p=3.98 [Formula: see text] 10-12) within the gene encoding dipeptidyl peptidase 9 (DPP9), and on chr21q22.1 (rs2236757, p=4.99 [Formula: see text] 10-8) in the interferon receptor gene IFNAR2. We identify potential targets for repurposing of licensed medications: using Mendelian randomisation we found evidence in support of a causal link from low expression of IFNAR2, and high expression of TYK2, to life-threatening disease; transcriptome-wide association in lung tissue revealed that high expression of the monocyte/macrophage chemotactic receptor CCR2 is associated with severe Covid-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms, and mediators of inflammatory organ damage in Covid-19. Both mechanisms may be amenable to targeted treatment with existing drugs. Large-scale randomised clinical trials will be essential before any change to clinical practice.
AU  - Pairo-Castineira,E
AU  - Clohisey,S
AU  - Klaric,L
AU  - Bretherick,AD
AU  - Rawlik,K
AU  - Pasko,D
AU  - Walker,S
AU  - Parkinson,N
AU  - Fourman,MH
AU  - Russell,CD
AU  - Furniss,J
AU  - Richmond,A
AU  - Gountouna,E
AU  - Wrobel,N
AU  - Harrison,D
AU  - Wang,B
AU  - Wu,Y
AU  - Meynert,A
AU  - Griffiths,F
AU  - Oosthuyzen,W
AU  - Kousathanas,A
AU  - Moutsianas,L
AU  - Yang,Z
AU  - Zhai,R
AU  - Zheng,C
AU  - Grimes,G
AU  - Beale,R
AU  - Millar,J
AU  - Shih,B
AU  - Keating,S
AU  - Zechner,M
AU  - Haley,C
AU  - Porteous,DJ
AU  - Hayward,C
AU  - Yang,J
AU  - Knight,J
AU  - Summers,C
AU  - Shankar-Hari,M
AU  - Klenerman,P
AU  - Turtle,L
AU  - Ho,A
AU  - Moore,SC
AU  - Hinds,C
AU  - Horby,P
AU  - Nichol,A
AU  - Maslove,D
AU  - Ling,L
AU  - McAuley,D
AU  - Montgomery,H
AU  - Walsh,T
AU  - Pereira,A
AU  - Renieri,A
AU  - GenOMICC,Investigators
AU  - ISARICC,Investigators
AU  - COVID-19,Human Genetics Initiative
AU  - 23andMe,Investigators
AU  - BRACOVID,Investigators
AU  - Gen-COVID,Investigators
AU  - Shen,X
AU  - Ponting,CP
AU  - Fawkes,A
AU  - Tenesa,A
AU  - Caulfield,M
AU  - Scott,R
AU  - Rowan,K
AU  - Murphy,L
AU  - Openshaw,PJM
AU  - Semple,MG
AU  - Law,A
AU  - Vitart,V
AU  - Wilson,JF
AU  - Baillie,JK
DO  - 10.1038/s41586-020-03065-y
EP  - 98
PY  - 2021///
SN  - 0028-0836
SP  - 92
TI  - Genetic mechanisms of critical illness in Covid-19
T2  - Nature
UR  - http://dx.doi.org/10.1038/s41586-020-03065-y
UR  - https://www.ncbi.nlm.nih.gov/pubmed/33307546
UR  - http://hdl.handle.net/10044/1/85822
VL  - 591
ER  -

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