Genetic mechanisms of critical illness in COVID-19 #MMPMID33307546
Pairo-Castineira E; Clohisey S; Klaric L; Bretherick AD; Rawlik K; Pasko D; Walker S; Parkinson N; Fourman MH; Russell CD; Furniss J; Richmond A; Gountouna E; Wrobel N; Harrison D; Wang B; Wu Y; Meynert A; Griffiths F; Oosthuyzen W; Kousathanas A; Moutsianas L; Yang Z; Zhai R; Zheng C; Grimes G; Beale R; Millar J; Shih B; Keating S; Zechner M; Haley C; Porteous DJ; Hayward C; Yang J; Knight J; Summers C; Shankar-Hari M; Klenerman P; Turtle L; Ho A; Moore SC; Hinds C; Horby P; Nichol A; Maslove D; Ling L; McAuley D; Montgomery H; Walsh T; Pereira AC; Renieri A; Shen X; Ponting CP; Fawkes A; Tenesa A; Caulfield M; Scott R; Rowan K; Murphy L; Openshaw PJM; Semple MG; Law A; Vitart V; Wilson JF; Baillie JK
Nature 2021[Mar]; 591 (7848): 92-98 PMID33307546show ga
Host-mediated lung inflammation is present(1), and drives mortality(2), in the critical illness caused by coronavirus disease 2019 (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 in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units. We have identified and replicated the following new genome-wide significant associations: on chromosome 12q24.13 (rs10735079, P = 1.65 x 10(-8)) in a gene cluster that encodes antiviral restriction enzyme activators (OAS1, OAS2 and OAS3); on chromosome 19p13.2 (rs74956615, P = 2.3 x 10(-8)) near the gene that encodes tyrosine kinase 2 (TYK2); on chromosome 19p13.3 (rs2109069, P = 3.98 x 10(-12)) within the gene that encodes dipeptidyl peptidase 9 (DPP9); and on chromosome 21q22.1 (rs2236757, P = 4.99 x 10(-8)) in the interferon receptor gene IFNAR2. We identified potential targets for repurposing of licensed medications: using Mendelian randomization, we found evidence that low expression of IFNAR2, or high expression of TYK2, are associated with life-threatening disease; and 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. However, large-scale randomized clinical trials will be essential before any change to clinical practice.
Nature 2021 ; 591 (7848): 92-98
