BibTex format
@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}
}
RIS format (EndNote, RefMan)
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 -
