Publication Date:
2021
Short description:
Pairo-Castineira, E., Clohisey, S., Klaric, L., Bretherick, A. D., Rawlik, K., Pasko, D., Walker, S., Parkinson, N., Fourman, M. H., Russell, C. D., 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, D. J., Hayward, C., Yang, J., Knight, J., Summers, C., Shankar-Hari, M., Klenerman, P., Turtle, L., Ho, A., Moore, S. C., Hinds, C., Horby, P., Nichol, A., Maslove, D., Ling, L., Mcauley, D., Montgomery, H., Walsh, T., Pereira, A. C., Renieri, A., Millar, J., Walsh, T., Ponting, C., Meikle, J., Finernan, P., Mcmaster, E., Law, A., Baillie, J. K., Paterson, T., Wackett, T., Armstrong, R., Clark, R., Coutts, A., Donnelly, L., Gilchrist, T., Hafezi, K., Macgillivray, L., Maclean, A., Mccafferty, S., Morrice, K., Weaver, J., Boz, C., Golightly, A., Ward, M., Mal, H., Szoor-Mcelhinney, H., Brown, A., Hendry, R., Stenhouse, A., Cullum, L., Law, D., Law, S., Law, R., Swets, M., Day, N., Taneski, F., Duncan, E., Parkinson, N., Collier, D., Wood, S., Zak, A., Borra, C., Matharu, M., May, P., Alldis, Z., Mitchelmore, O., Bowles, R., Easthope, A., Bibi, F., Lancoma-Malcolm, I., Gurasashvili, J., Pheby, J., Shiel, J., Bolton, M., Patel, M., Taylor, M., Zongo, O., Ebano, P., Harding, P., Astin-Chamberlain, R., Choudhury, Y., Cox, A., Kallon, D., Burton, M., Hall, R., Blowes, S., Prime, Z., Biddle, J., Prysyazhna, O., Newman, T., Tierney, C., Kassam, J., Ostermann, M., Campos, S., Bociek, A., Lim, R., Grau, N., Jones, T. O., Whitton, C., Marotti, M., Arbane, G., Bonner, S., Hugill, K., Reid, J., Welters, I., Waugh, V., Williams, K., Shaw, D., Roman, J. F., Martinez, M. L., Johnson, E., Waite, A., Johnston, B., Hamilton, D., Mulla, S., Mcphail, M., Smith, J., Baillie, J. K., Barclay, L., Hope, D., Mcculloch, C., Mcquillan, L., Clark, S., Singleton, J., Priestley, K., Rea, N., Callaghan, M., Campbell, R., Andrew, G., Marshall, L., Mckechnie, S., Hutton, P., Bashyal, A., Davidson, N., Polgarova, P., Stroud, K., Pathan, N., Elston, K., Agrawal, S., Battle, C., Newey, L., Rees, T., Harford, R., Brinkworth, E., Williams, M., Murphy, C., White, I., Croft, M., Bandla, N., Gellamucho, M., Tomlinson, J., Turner, H., Davies, M., Quinn, A., Hussain, I., Thompson, C., Parker, H., Bradley, R., Griffiths, R., Scriven, J., Nilsson, A., Bates, M., Dasgin, J., Gill, J., Puxty, A., Cathcart, S., Salutous, D., Turner, L., Duffy, K., Puxty, K., Joseph, A., Herdman-Grant, R., Simms, R., Swain, A., Naranjo, A., Crowe, R., Sollesta, K., Loveridge, A., Baptista, D., Morino, E., Davey, M., Golden, D., Jones, J., Moreno Cuesta, J., Haldeos, A., Bakthavatsalam, D., Vincent, R., Elhassan, M., Xavier, K., Ganesan, A., Purohit, D., Abdelrazik, M., Morgan, J., Akeroyd, L., Bano, S., Lawton, T., Warren, D., Bromley, M., Sellick, K., Gurr, L., Wilkinson, B., Nagarajan, V., Szedlak, P., Cupitt, J., Stoddard, E., Benham, L., Preston, S., Laha, S., Slawson, N., Bradshaw, Z., Brown, J., Caswell, M., Melling, S., Bamford, P., Faulkner, M., Cawley, K., Jeffrey, H., London, E., Sainsbury, H., Nagra, I., Nasir, F., Dunmore, C., Jones, R., Abraheem, A., Al-Moasseb, M., Girach, R., Padden, G., Egan, J., Brantwood, C., Alexander, P., Bradley-Potts, J., Allen, S., Felton, T., Manna, S., Farnell-Ward, S., Leaver, S., Queiroz, J., Maccacari, E., Dawson, D., Delgado, C. C., Saluzzio, R. P., Ezeobu, O., Ding, L., Sicat, C., Kanu, R., Durrant, G., Texeira, J., Harrison, A., Samakomva, T., Scriven, J., Willis, H., Hopkins, B., Thrasyvoulou, L., Jackson, M., Zaki, A., Tibke, C., Bennett, S., Woodyatt, W., Kent, A., Goodwin, E., Brandwood, C., Clark, R., Smith, L., Rooney, K., Thomson, N., Rodden, N., Hughes, E., Mcglynn, D., Clark, C., Clark, P., Abel, L., Sundaram, R., Gemmell, L., Brett, M., Hornsby, J., Macgoey, P., Price, R., Digby, B., O'Neil, P., Mcconnell, P.
abstract:
Host-mediated lung inflammation is present1, and drives mortality2, in the critical illness caused by coronavirus disease 2019 (COVID-19). Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development3. 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 × 10−8) in a gene cluster that encodes antiviral restriction enzyme activators (OAS1, OAS2 and OAS3); on chromosome 19p13.2 (rs74956615, P = 2.3 × 10−8) near the gene that encodes tyrosine kinase 2 (TYK2); on chromosome 19p13.3 (rs2109069, P = 3.98 × 10−12) within the gene that encodes dipeptidyl peptidase 9 (DPP9); and on chromosome 21q22.1 (rs2236757, P = 4.99 × 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.
Iris type:
Editoriale in rivista
Keywords:
COVID-19
List of contributors:
Pairo-Castineira, E.; Clohisey, S.; Klaric, L.; Bretherick, A. D.; Rawlik, K.; Pasko, D.; Walker, S.; Parkinson, N.; Fourman, M. H.; Russell, C. D.; 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, D. J.; Hayward, C.; Yang, J.; Knight, J.; Summers, C.; Shankar-Hari, M.; Klenerman, P.; Turtle, L.; Ho, A.; Moore, S. C.; Hinds, C.; Horby, P.; Nichol, A.; Maslove, D.; Ling, L.; Mcauley, D.; Montgomery, H.; Walsh, T.; Pereira, A. C.; Renieri, A.; Millar, J.; Walsh, T.; Ponting, C.; Meikle, J.; Finernan, P.; Mcmaster, E.; Law, A.; Baillie, J. K.; Paterson, T.; Wackett, T.; Armstrong, R.; Clark, R.; Coutts, A.; Donnelly, L.; Gilchrist, T.; Hafezi, K.; Macgillivray, L.; Maclean, A.; Mccafferty, S.; Morrice, K.; Weaver, J.; Boz, C.; Golightly, A.; Ward, M.; Mal, H.; Szoor-McElhinney, H.; Brown, A.; Hendry, R.; Stenhouse, A.; Cullum, L.; Law, D.; Law, S.; Law, R.; Swets, M.; Day, N.; Taneski, F.; Duncan, E.; Parkinson, N.; Collier, D.; Wood, S.; Zak, A.; Borra, C.; Matharu, M.; May, P.; Alldis, Z.; Mitchelmore, O.; Bowles, R.; Easthope, A.; Bibi, F.; Lancoma-Malcolm, I.; Gurasashvili, J.; Pheby, J.; Shiel, J.; Bolton, M.; Patel, M.; Taylor, M.; Zongo, O.; Ebano, P.; Harding, P.; Astin-Chamberlain, R.; Choudhury, Y.; Cox, A.; Kallon, D.; Burton, M.; Hall, R.; Blowes, S.; Prime, Z.; Biddle, J.; Prysyazhna, O.; Newman, T.; Tierney, C.; Kassam, J.; Ostermann, M.; Campos, S.; Bociek, A.; Lim, R.; Grau, N.; Jones, T. O.; Whitton, C.; Marotti, M.; Arbane, G.; Bonner, S.; Hugill, K.; Reid, J.; Welters, I.; Waugh, V.; Williams, K.; Shaw, D.; Roman, J. F.; Martinez, M. L.; Johnson, E.; Waite, A.; Johnston, B.; Hamilton, D.; Mulla, S.; Mcphail, M.; Smith, J.; Baillie, J. K.; Barclay, L.; Hope, D.; Mcculloch, C.; Mcquillan, L.; Clark, S.; Singleton, J.; Priestley, K.; Rea, N.; Callaghan, M.; Campbell, R.; Andrew, G.; Marshall, L.; Mckechnie, S.; Hutton, P.; Bashyal, A.; Davidson, N.; Polgarova, P.; Stroud, K.; Pathan, N.; Elston, K.; Agrawal, S.; Battle, C.; Newey, L.; Rees, T.; Harford, R.; Brinkworth, E.; Williams, M.; Murphy, C.; White, I.; Croft, M.; Bandla, N.; Gellamucho, M.; Tomlinson, J.; Turner, H.; Davies, M.; Quinn, A.; Hussain, I.; Thompson, C.; Parker, H.; Bradley, R.; Griffiths, R.; Scriven, J.; Nilsson, A.; Bates, M.; Dasgin, J.; Gill, J.; Puxty, A.; Cathcart, S.; Salutous, D.; Turner, L.; Duffy, K.; Puxty, K.; Joseph, A.; Herdman-Grant, R.; Simms, R.; Swain, A.; Naranjo, A.; Crowe, R.; Sollesta, K.; Loveridge, A.; Baptista, D.; Morino, E.; Davey, M.; Golden, D.; Jones, J.; Moreno Cuesta, J.; Haldeos, A.; Bakthavatsalam, D.; Vincent, R.; Elhassan, M.; Xavier, K.; Ganesan, A.; Purohit, D.; Abdelrazik, M.; Morgan, J.; Akeroyd, L.; Bano, S.; Lawton, T.; Warren, D.; Bromley, M.; Sellick, K.; Gurr, L.; Wilkinson, B.; Nagarajan, V.; Szedlak, P.; Cupitt, J.; Stoddard, E.; Benham, L.; Preston, S.; Laha, S.; Slawson, N.; Bradshaw, Z.; Brown, J.; Caswell, M.; Melling, S.; Bamford, P.; Faulkner, M.; Cawley, K.; Jeffrey, H.; London, E.; Sainsbury, H.; Nagra, I.; Nasir, F.; Dunmore, C.; Jones, R.; Abraheem, A.; Al-Moasseb, M.; Girach, R.; Padden, G.; Egan, J.; Brantwood, C.; Alexander, P.; Bradley-Potts, J.; Allen, S.; Felton, T.; Manna, S.; Farnell-Ward, S.; Leaver, S.; Queiroz, J.; Maccacari, E.; Dawson, D.; Delgado, C. C.; Saluzzio, R. P.; Ezeobu, O.; Ding, L.; Sicat, C.; Kanu, R.; Durrant, G.; Texeira, J.; Harrison, A.; Samakomva, T.; Scriven, J.; Willis, H.; Hopkins, B.; Thrasyvoulou, L.; Jackson, M.; Zaki, A.; Tibke, C.; Bennett, S.; Woodyatt, W.; Kent, A.; Goodwin, E.; Brandwood, C.; Clark, R.; Smith, L.; Rooney, K.; Thomson, N.; Rodden, N.; Hughes, E.; Mcglynn, D.; Clark, C.; Clark, P.; Abel, L.; Sundaram, R.; Gemmell, L.; Brett, M.; Hornsby, J.; Macgoey, P.; Price, R.; Digby, B.; O'Neil, P.; Mcconnell, P.
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