17 research outputs found
Whole-genome sequencing reveals host factors underlying critical COVID-19
- Author
- Abd Elghafar M. S.
- Abdel-Aziz M.
- Abdelrazik M.
- Abdollahi H.
- Abdullah T.
- Abecasis G. R.
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- Publication venue
- 'Springer Science and Business Media LLC'
- Publication date
- 01/01/2022
- Field of study
Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2–4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease
Whole-genome sequencing reveals host factors underlying critical COVID-19
- Author
- Abd Elghafar M.S.
- Abdel-Aziz M.
- Abdelrazik M.
- Abdollahi H.
- Abdullah T.
- Abecasis G.R.
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- Zöllner S.
- Åsvold B.O.
- Publication venue
- Springer Science and Business Media LLC
- Publication date
- 07/07/2022
- Field of study
Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2,3,4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease
Dimethyl fumarate in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial
- Author
- Abbas M.
- Abdul Rasheed A.
- Abdul A.
- Abdul-Kadir R.
- Abdusamad K.
- Abernethy K.
- Aboelela H.
- Abouzaid M.
- Abraham M.
- Abraham T.
- Abrams J.
- Abu H.
- Abu-Arafeh A.
- Acton C.
- Adam F.
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- Adedeji O.
- Adegoke K.
- Adewunmi E.
- Adeyemo T.
- Agbeko R.
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- Ahmed I.
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- Akili S.
- Al Aaraj A.
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- Al-Asadi A.
- Al-Khalil M.
- Al-Ramadhani B.
- Al-Saadi Z.
- Al-Shahi Salman R.
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- Albert P.
- Alegria A.
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- Publication venue
- Springer Science and Business Media LLC
- Publication date
- 31/01/2024
- Field of study
Dimethyl fumarate (DMF) inhibits inflammasome-mediated inflammation and has been proposed as a treatment for patients hospitalised with COVID-19. This randomised, controlled, open-label platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing multiple treatments in patients hospitalised for COVID-19 (NCT04381936, ISRCTN50189673). In this assessment of DMF performed at 27 UK hospitals, adults were randomly allocated (1:1) to either usual standard of care alone or usual standard of care plus DMF. The primary outcome was clinical status on day 5 measured on a seven-point ordinal scale. Secondary outcomes were time to sustained improvement in clinical status, time to discharge, day 5 peripheral blood oxygenation, day 5 C-reactive protein, and improvement in day 10 clinical status. Between 2 March 2021 and 18 November 2021, 713 patients were enroled in the DMF evaluation, of whom 356 were randomly allocated to receive usual care plus DMF, and 357 to usual care alone. 95% of patients received corticosteroids as part of routine care. There was no evidence of a beneficial effect of DMF on clinical status at day 5 (common odds ratio of unfavourable outcome 1.12; 95% CI 0.86-1.47; p = 0.40). There was no significant effect of DMF on any secondary outcome
Dimethyl fumarate in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial
- Author
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- Publication date
- Field of study
Dimethyl fumarate (DMF) inhibits inflammasome-mediated inflammation and has been proposed as a treatment for patients hospitalised with COVID-19. This randomised, controlled, open-label platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing multiple treatments in patients hospitalised for COVID-19 (NCT04381936, ISRCTN50189673). In this assessment of DMF performed at 27 UK hospitals, adults were randomly allocated (1:1) to either usual standard of care alone or usual standard of care plus DMF. The primary outcome was clinical status on day 5 measured on a seven-point ordinal scale. Secondary outcomes were time to sustained improvement in clinical status, time to discharge, day 5 peripheral blood oxygenation, day 5 C-reactive protein, and improvement in day 10 clinical status. Between 2 March 2021 and 18 November 2021, 713 patients were enroled in the DMF evaluation, of whom 356 were randomly allocated to receive usual care plus DMF, and 357 to usual care alone. 95% of patients received corticosteroids as part of routine care. There was no evidence of a beneficial effect of DMF on clinical status at day 5 (common odds ratio of unfavourable outcome 1.12; 95% CI 0.86-1.47; p = 0.40). There was no significant effect of DMF on any secondary outcome
Effect of remote ischaemic conditioning on clinical outcomes in patients with acute myocardial infarction (CONDI-2/ERIC-PPCI): a single-blind randomised controlled trial.
- Author
- Aarøe Jens
- Abbass Hakam
- Abella-Ovalle Luis
- Adam Zul
- Agyemang Michael
- Ahlehof Ole
- Ahlehoff Ole
- Ahmad Yousif
- Al-Lamee Rasha
- Alberdi Lucía
- Aleti Shilpa
- Ali Danish
- Allen Kezia
- Alvares Wilson
- Alzuhairi Karam
- Amed Nadifa
- Anantharam Brijesh
- Andersen Grethe
- Andersen Henning Rud
- Anderson Michelle
- Andiapen Mervyn
- Andrews Michelle
- Ankersen Jens Peter
- Ansell Valerie
- Arango Amalia
- Armstrong Elissa
- Astarci Josenir
- Atkinson Emma
- Austin Rosalynn
- Avanzas Pablo
- Aziz Ahmed
- Azkhalil Mohammed
- Bales Emily
- Banerjee Prithwish
- Barclay Justin
- Barker Deborah
- Barker Joann
- Barmby David
- Bates Rachel
- Baucutt Karen
- Been Martin
- Beirnes Charmaine
- Bell Sheila
- Bennett Amy
- Bennett Lorraine
- Bernardo-Alba Pablo
- Berry Alan
- Berry Colin
- Besana Rissa
- Bhatre Gurbir
- Bhatti Rishma
- Bidle Amanda
- Bijsterveld Petra
- Bose Tuhina
- Boyle Georgina
- Brady Rebecca
- Braybrook Christine
- Breeze Jonathan
- Brennan Oliver
- Brett Sarah
- Brogan Richard
- Brown Janette
- Bucciarelli-Ducci Chiara
- Buchanan Louise
- Buelga-Díaz Covadonga
- Bueno Hector
- Bulluck Heerajnarain
- Burd Amanda
- Burnett Gillian
- Burtonwood Natalie
- Burunsuzoglu Senem
- Butler Robert
- Butler Robert
- Byrne Jean
- Bøtker Hans Erik
- Capel Robert
- Cappelen Helle
- Carruthers Gayle
- Carstensen Steen
- Castro Rafael
- Champney Felicity
- Chant Nicholas
- Charles Thabitha
- Chester Emma
- Chong Jun
- Christensen Erika Frischknecht
- Christiansen Evald Høj
- Christiansen Martin Kirk
- Christmas Natasha
- Chu Rebecca
- Chung Alan
- Cimas Teodorna
- Clapp Brian
- Clare Thomas
- Clarke Millie
- Clayton Tim
- Clifford Piers
- Cockayne Laura
- Colicchia Martina
- Collier Lucy
- Cooper Theresa
- Copas Andrew
- Copestick Jane
- Corps Ellie
- Corrigan Julie
- Cottam Victoria
- Cotton James
- Coward Paul
- Cox Emily
- Crause Jacolene
- Cruden Nick
- Cunliffe Denise
- Cunnington Michael
- Cuxton Josephine
- Dana Ali
- Dana Ali
- Darby Damaris
- Davies John
- Davies Justin
- Davies Nina
- de Cima Sara
- de la Hera Galarza Jesus Maria
- de la Roz Manuel
- De Mance Gianluigi
- De Sousa Phillipa
- Deen Zakhira
- del Valle Raquel
- Delaney Jane
- Denman Joanne
- Dias Priyanthi
- Dillon Angela
- Dimond Kirsty
- Din J.
- Dockerty Francesca
- Dodd Matthew
- Douglas James
- Douthwaite Rebecca
- Drew Martin
- Díaz-González Eloy
- East Clare
- Eaton Michelle
- Ellert Julia
- Elliott Rebecca
- Ellis Howard
- Elshiekh Dr Mohamed
- Elston Ruth
- Emery Lisa
- Engstrom Thomas
- Erntgaard Dennis
- Evans Richard
- Fahrai Gregor
- Farag Mohamed
- Fath-Orboubadi DR Fazin
- Fati Pene
- Fayed Hossam
- Fente Ana I.
- Fernandez Olga
- Fernández Elena
- Fernández-Carral Marcos Fernández-Carral
- Fernández-Gonzalo David
- Fernández-Mallo Francisco J.
- Finch Amanda
- Fleming Catherine
- Fofie Joyce
- Foundun Aboo
- Francis Rohin
- Francis Rohin
- Frank Emma
- Freeman Philip
- Freestone Beth
- Fuentes María D.
- Gale Joanne
- Gale Joanne
- Gallagher Ian
- Galván-Núñez Pablo
- Gamma Reto
- Garcia-Ruiz José Manuel
- García-Alonso María
- García-Castro Alfonso
- Gaughran Lisa
- Germon Rachel
- Gibson Kirsty
- Giebner Matthias
- Gill Abby
- Gill Simrat
- Giuffrida Gaia
- Given Rachel
- Glen James
- Goitia-Martín Javier
- Gomes Sara
- Gorog Diana
- Gorog Diana A
- Gowing Anne
- Gracey Jay
- Grech Ever
- Greenwood John
- Greenwood John P
- Gregory Sally
- Gregson Lisa
- Griffiths Huw
- Grosser Konrad
- Gue Ying
- Guinea Rocío
- Gunn Julian
- Guyatt Samantha
- Hall Charlotte
- Hall Ian
- Hall Lorna
- Hamid Mahmood
- Hansen Henrik Steen
- Hansen Knud Nørregård
- Hansen Poul Anders
- Hansen Troels Martin Hansen
- Harfield Scott
- Harkins Ruth
- Harland Charlotte
- Hartley Amy
- Hausenloy Derek J
- Haworth Peter
- Hayes Michelle
- Hedegaard Kim Witting
- Hedrera Segundo A.
- Helqvist Steffen
- Henderson Rob
- Hendry Cara
- Heppell Richard
- Hermosa Francisco J.
- Hernández Ernesto
- Hetherington Daniel
- Hetherington Simon
- Hildick-Smith David
- Hindle Julia
- Hjort Jakob
- Hoare Amy
- Hobson Alex
- Hodgson Adrian
- Hodierne Jeremy
- Hogrefe Kai
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- Hoole Stephen
- Hopper Oliver
- Horler Stephanie
- Horner Victoria
- Horwood Carol
- Houghton Richard F
- Housley Kay
- Howe Serena
- Hudson Karen
- Hussein Jodie
- Hyndman Samantha
- Ibanez Borja
- Iglesias-Llaca Fernando
- Ilsley Mary
- Ingoldby Fiona
- Iqbal , Javid
- Iversen Allan
- Jack Pearse
- Jackson-Lawrence Karen
- Jakobsen Lars
- Jamal Zahra
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- Jennison Alan
- Jensen Lisette Okkels
- Jensen Svend Eggert
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- Jones Sophie
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- Jørgensen Erik
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- Kaus Henning
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- Kelbæk Henning
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- Kelsall Nicci
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- Kennard Sarah
- Khan Arif
- Kharbanda Rajesh
- Kharbanda Rajesh K
- Khawaja Muhammed Zeeshan
- Knight Rosemary
- Knighton Abigail
- Kobson Barbara
- Kodoth Vivek
- Kolakaluri Laurel
- Koothoor Raiji
- Korsgaard Mette Tidemand
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- Krishnamoorthy Suresh
- Krishnamurthy Arvindra
- Kristensen Steen Dalby
- Laca Sonia I.
- Lakeman Nicki
- Langrish Jeremy
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- Lassen Jens Flensted
- Laurence Julia
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- Lee Dr Kaeng
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- Lenzi Valentina
- Leonard Gerry
- Lippert Freddy K
- Llorente-Álvarez Susana
- Lloyd Steph
- Loder Chris
- Longbottom Colin
- Longman Kristel
- Lozano Iñigo
- Lucking Andrew
- Ludman Andrew
- Lønborg Jacob T
- Maart Clint
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- Madsen Morten
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- Malik Iqbal
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- Markham-Jones Helene
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- Martins Joe
- Martínez-Bastida Ginés
- Martínez-Fernández César M.
- Martínez-Pérez Polácido J.
- Martínez-Valle Marta
- Massey Ian
- Mathur Anthony
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- Mehmedbegovic Zlatko
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- Milasinovic Dejan
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- Riedel Ella
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- Rondán Juan
- Ross David
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- Ryding Alisdair
- Ryding Alisdair D
- Saclot Louie
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- Schmidt Michael R
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- Scott Kerry
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- Spence Sharon
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- Spinthakis Nicholas
- Stables Rod
- Staines Jocasta
- Stankovic Goran
- Stimson Leah
- Storey Robert F.
- Strike Philip
- Subotic Ida
- Suttling Anne
- Suárez Alfonso
- Suárez-Coto Raquel
- Suárez-Noriega Raquel
- Sørensen Henrik Toft
- Sørensen Rikke
- Tapp Luke
- Tawiah Cecilia
- Taylor Rebecca
- Terkelsen Christian Juhl
- Thambi Sunil
- Theodorou Nana
- Thim Troels
- Thomas Isobel
- Thompson Rebecca
- Thornborough Lauren
- Thornton Emma
- Thuesen Leif
- Thygesen Kristian
- Tilsted Hans Henrik
- Tipping Aoife
- Tomlinson Lucy
- Tomlinson Sharon
- Topic Dragan
- Tresguerres Jose M.
- Turner Charlotte
- Turner Jenny
- Turney Sharon
- Upton Robert
- Uscumlic Ana
- Van Dyck Laura
- Varma Madhusudhan
- Varma Madhusudhan
- Veerapen Jessry
- Vega-Fernández José L.
- Vegas-Valle Jose M.
- Veien Karsten
- Venugopal Vinod
- Vertue Mark
- Victor Saji
- Villadsen Anton Boel
- Villanueva María J.
- Villar-Fernández Lara
- Vinagrero María S.
- Viribay Fernando M.
- Vlad Ionela
- von Weitzel-Mudersbach Paul
- Vukcevic Vladan
- Vázquez-Suárez María
- Waddington Natalia
- Wain Jill
- Waitrak Paulina
- Waldron Molly
- Wallace Lauren
- Walshe Siobhan
- Walvin Tom
- Warner Karen
- Watkins Richard
- Watkinson Oliver
- Weatherlley Louise
- Webb Ian
- Webb Ian
- Wells Nicki
- Westwood Mark
- Wheeldon Nigel
- Whitehead Helena
- Whiteside Charlene
- Wilkinson Conor
- Wilson Karen
- Wittrock Daniel
- Wolyrum Mathias
- Woods Sarah
- Wragg Christopher
- Yellon Derek M
- Publication venue
- 'Elsevier BV'
- Publication date
- 01/01/2019
- Field of study
BACKGROUND: Remote ischaemic conditioning with transient ischaemia and reperfusion applied to the arm has been shown to reduce myocardial infarct size in patients with ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PPCI). We investigated whether remote ischaemic conditioning could reduce the incidence of cardiac death and hospitalisation for heart failure at 12 months. METHODS: We did an international investigator-initiated, prospective, single-blind, randomised controlled trial (CONDI-2/ERIC-PPCI) at 33 centres across the UK, Denmark, Spain, and Serbia. Patients (age >18 years) with suspected STEMI and who were eligible for PPCI were randomly allocated (1:1, stratified by centre with a permuted block method) to receive standard treatment (including a sham simulated remote ischaemic conditioning intervention at UK sites only) or remote ischaemic conditioning treatment (intermittent ischaemia and reperfusion applied to the arm through four cycles of 5-min inflation and 5-min deflation of an automated cuff device) before PPCI. Investigators responsible for data collection and outcome assessment were masked to treatment allocation. The primary combined endpoint was cardiac death or hospitalisation for heart failure at 12 months in the intention-to-treat population. This trial is registered with ClinicalTrials.gov (NCT02342522) and is completed. FINDINGS: Between Nov 6, 2013, and March 31, 2018, 5401 patients were randomly allocated to either the control group (n=2701) or the remote ischaemic conditioning group (n=2700). After exclusion of patients upon hospital arrival or loss to follow-up, 2569 patients in the control group and 2546 in the intervention group were included in the intention-to-treat analysis. At 12 months post-PPCI, the Kaplan-Meier-estimated frequencies of cardiac death or hospitalisation for heart failure (the primary endpoint) were 220 (8·6%) patients in the control group and 239 (9·4%) in the remote ischaemic conditioning group (hazard ratio 1·10 [95% CI 0·91-1·32], p=0·32 for intervention versus control). No important unexpected adverse events or side effects of remote ischaemic conditioning were observed. INTERPRETATION: Remote ischaemic conditioning does not improve clinical outcomes (cardiac death or hospitalisation for heart failure) at 12 months in patients with STEMI undergoing PPCI. FUNDING: British Heart Foundation, University College London Hospitals/University College London Biomedical Research Centre, Danish Innovation Foundation, Novo Nordisk Foundation, TrygFonden
Thigh-length compression stockings and DVT after stroke
- Author
- Abbas M
- Abbasi S
- Abbasi S
- Abdelaziz A
- Abdelfattah M
- Abdul B
- Abdulmumeen A
- Abdulshukkoor N
- Abdusamad K
- Aboaba A
- Abouibrahim M
- Abraham M
- Abraham T
- Abrams J
- Abung A
- Acharya D
- Acharya D
- Acheson J
- Acosta A
- Acosta A
- Acton C
- Adam M
- Adams C
- Adams K
- Adamus M
- Adegoke K
- Adenwalla S
- Adeyeye E
- Adnan A
- Agbo C
- Aggarwal S
- Agwada-Akeru J
- Agyapong K Ansu
- Ah-Chuen J
- Ahmad M
- Ahmed I
- Ahmed I
- Ahmed L
- Ahmed L
- Ahmed M
- Ahmed M Cecilia
- Ahmed N
- Ahmed N
- Ahmed R
- Ahmed RA
- Ahmed S
- Ahmed S Haris
- Ail D
- Ainsley A
- Ainsworth M
- Aitken L
- Ajibode A
- Ajmi A
- Ajmi A
- Akhtar N
- Akili S
- Akindolie O
- Al Balushi A
- Al-Asadi A
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- Al-Jibury M
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- Publication venue
- 'Elsevier BV'
- Publication date
- 01/07/1994
- Field of study
Controversy exists as to whether neoadjuvant chemotherapy improves survival in patients with invasive bladder cancer, despite randomised controlled trials of more than 3000 patients. We undertook a systematic review and meta-analysis to assess the effect of such treatment on survival in patients with this disease
Mapping the human genetic architecture of COVID-19
- Author
- Abdelrazik M.
- Abdullah T.
- Abe R.
- Abe S.
- Abecasis G. R.
- Abel L.
- Abernathy C.
- Abraheem A.
- Abul-Husn N. S.
- Acosta-Herrera M.
- Acquilini D.
- Adachi T.
- Adachi Y.
- Adams C.
- Adams K.
- Adanini O.
- Adeleye O.
- Adeniji K.
- Adra D.
- Afifi N.
- Afilalo J.
- Afilalo M.
- Afolabi D.
- Afrasiabi Z.
- Afset J. E.
- Agasou A.
- Aghemo A.
- Agranoff D.
- Agrawal S.
- Aguirre L. A.
- Agwuh K.
- Ahmad H. F.
- Ahmad N.
- Ahmed A.
- Ahmed C.
- Ahmed K. A.
- Ai M.
- Ail D.
- Akeroyd L.
- Akhtar M. N.
- Akhtar S.
- Akinkugbe O.
- Aksentijevich A.
- Al Thani A.
- Al-Muftah W.
- Al-Sarraj Y.
- Alarcon C.
- Alarcon-Riquelme M. E.
- Alasdair F.
- Alaverdian D.
- Alavere H.
- Albertos R.
- Albillos A.
- Albrecht W.
- Albrich W.
- Albrich W. C.
- Aldera E. L.
- Aldridge J.
- Alegria A.
- Alex B.
- Alexander P.
- Alfonso J.
- Algera A. G.
- Ali A.
- Ali I. A. M.
- Ali S.
- Aliberti S.
- Allan A.
- Allan E.
- Allan J.
- Alldis Z.
- Allen L.
- Allen S.
- Allibone S.
- Allison K. S.
- Allos R.
- Ally S. M.
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- Publication venue
- 'Springer Science and Business Media LLC'
- Publication date
- 01/01/2021
- Field of study
The genetic make-up of an individual contributes to the susceptibility and response to viral infection. Although environmental, clinical and social factors have a role in the chance of exposure to SARS-CoV-2 and the severity of COVID-191,2, host genetics may also be important. Identifying host-specific genetic factors may reveal biological mechanisms of therapeutic relevance and clarify causal relationships of modifiable environmental risk factors for SARS-CoV-2 infection and outcomes. We formed a global network of researchers to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity. Here we describe the results of three genome-wide association meta-analyses that consist of up to 49,562 patients with COVID-19 from 46 studies across 19 countries. We report 13 genome-wide significant loci that are associated with SARS-CoV-2 infection or severe manifestations of COVID-19. Several of these loci correspond to previously documented associations to lung or autoimmune and inflammatory diseases3–7. They also represent potentially actionable mechanisms in response to infection. Mendelian randomization analyses support a causal role for smoking and body-mass index for severe COVID-19 although not for type II diabetes. The identification of novel host genetic factors associated with COVID-19 was made possible by the community of human genetics researchers coming together to prioritize the sharing of data, results, resources and analytical frameworks. This working model of international collaboration underscores what is possible for future genetic discoveries in emerging pandemics, or indeed for any complex human disease
Recommended from our members
GWAS and meta-analysis identifies 49 genetic variants underlying critical COVID-19
- Author
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- Publication venue
- Springer Nature
- Publication date
- 17/05/2023
- Field of study
Data availability: Downloadable summary data are available through the GenOMICC data site (https://genomicc.org/data). Summary statistics are available, but without the 23andMe summary statistics, except for the 10,000 most significant hits, for which full summary statistics are available. The full GWAS summary statistics for the 23andMe discovery dataset will be made available through 23andMe to qualified researchers under an agreement with 23andMe that protects the privacy of the 23andMe participants. For further information and to apply for access to the data, see the 23andMe website (https://research.23andMe.com/dataset-access/). All individual-level genotype and whole-genome sequencing data (for both academic and commercial uses) can be accessed through the UKRI/HDR UK Outbreak Data Analysis Platform (https://odap.ac.uk). A restricted dataset for a subset of GenOMICC participants is also available through the Genomics England data service. Monocyte RNA-seq data are available under the title ‘Monocyte gene expression data’ within the Oxford University Research Archives (https://doi.org/10.5287/ora-ko7q2nq66). Sequencing data will be made freely available to organizations and researchers to conduct research in accordance with the UK Policy Framework for Health and Social Care Research through a data access agreement. Sequencing data have been deposited at the European Genome–Phenome Archive (EGA), which is hosted by the EBI and the CRG, under accession number EGAS00001007111.Extended data figures and tables are available online at https://www.nature.com/articles/s41586-023-06034-3#Sec21 .Supplementary information is available online at https://www.nature.com/articles/s41586-023-06034-3#Sec22 .Code availability:
Code to calculate the imputation of P values on the basis of SNPs in linkage disequilibrium is available at GitHub (https://github.com/baillielab/GenOMICC_GWAS).Acknowledgements: We thank the members of the Banco Nacional de ADN and the GRA@CE cohort group; and the research participants and employees of 23andMe for making this work possible. A full list of contributors who have provided data that were collated in the HGI project, including previous iterations, is available online (https://www.covid19hg.org/acknowledgements).Change history: 11 July 2023: A Correction to this paper has been published at: https://doi.org/10.1038/s41586-023-06383-z. -- In the version of this article initially published, the name of Ana Margarita Baldión-Elorza, of the SCOURGE Consortium, appeared incorrectly (as Ana María Baldion) and has now been amended in the HTML and PDF versions of the article.Copyright © The Author(s) 2023, Critical illness in COVID-19 is an extreme and clinically homogeneous disease phenotype that we have previously shown1 to be highly efficient for discovery of genetic associations2. Despite the advanced stage of illness at presentation, we have shown that host genetics in patients who are critically ill with COVID-19 can identify immunomodulatory therapies with strong beneficial effects in this group3. Here we analyse 24,202 cases of COVID-19 with critical illness comprising a combination of microarray genotype and whole-genome sequencing data from cases of critical illness in the international GenOMICC (11,440 cases) study, combined with other studies recruiting hospitalized patients with a strong focus on severe and critical disease: ISARIC4C (676 cases) and the SCOURGE consortium (5,934 cases). To put these results in the context of existing work, we conduct a meta-analysis of the new GenOMICC genome-wide association study (GWAS) results with previously published data. We find 49 genome-wide significant associations, of which 16 have not been reported previously. To investigate the therapeutic implications of these findings, we infer the structural consequences of protein-coding variants, and combine our GWAS results with gene expression data using a monocyte transcriptome-wide association study (TWAS) model, as well as gene and protein expression using Mendelian randomization. We identify potentially druggable targets in multiple systems, including inflammatory signalling (JAK1), monocyte–macrophage activation and endothelial permeability (PDE4A), immunometabolism (SLC2A5 and AK5), and host factors required for viral entry and replication (TMPRSS2 and RAB2A).GenOMICC was funded by Sepsis Research (the Fiona Elizabeth Agnew Trust), the Intensive Care Society, a Wellcome Trust Senior Research Fellowship (to J.K.B., 223164/Z/21/Z), the Department of Health and Social Care (DHSC), Illumina, LifeArc, the Medical Research Council, UKRI, a BBSRC Institute Program Support Grant to the Roslin Institute (BBS/E/D/20002172, BBS/E/D/10002070 and BBS/E/D/30002275) and UKRI grants MC_PC_20004, MC_PC_19025, MC_PC_1905 and MRNO2995X/1. A.D.B. acknowledges funding from the Wellcome PhD training fellowship for clinicians (204979/Z/16/Z), the Edinburgh Clinical Academic Track (ECAT) programme. This research is supported in part by the Data and Connectivity National Core Study, led by Health Data Research UK in partnership with the Office for National Statistics and funded by UK Research and Innovation (grant MC_PC_20029). Laboratory work was funded by a Wellcome Intermediate Clinical Fellowship to B.F. (201488/Z/16/Z). We acknowledge the staff at NHS Digital, Public Health England and the Intensive Care National Audit and Research Centre who provided clinical data on the participants; and the National Institute for Healthcare Research Clinical Research Network (NIHR CRN) and the Chief Scientist’s Office (Scotland), who facilitate recruitment into research studies in NHS hospitals, and to the global ISARIC and InFACT consortia. GenOMICC genotype controls were obtained using UK Biobank Resource under project 788 funded by Roslin Institute Strategic Programme Grants from the BBSRC (BBS/E/D/10002070 and BBS/E/D/30002275) and Health Data Research UK (HDR-9004 and HDR-9003). UK Biobank data were used in the GSMR analyses presented here under project 66982. The UK Biobank was established by the Wellcome Trust medical charity, Medical Research Council, Department of Health, Scottish Government and the Northwest Regional Development Agency. It has also had funding from the Welsh Assembly Government, British Heart Foundation and Diabetes UK. The work of L.K. was supported by an RCUK Innovation Fellowship from the National Productivity Investment Fund (MR/R026408/1). J.Y. is supported by the Westlake Education Foundation. SCOURGE is funded by the Instituto de Salud Carlos III (COV20_00622 to A.C., PI20/00876 to C.F.), European Union (ERDF) ‘A way of making Europe’, Fundación Amancio Ortega, Banco de Santander (to A.C.), Cabildo Insular de Tenerife (CGIEU0000219140 ‘Apuestas científicas del ITER para colaborar en la lucha contra la COVID-19’ to C.F.) and Fundación Canaria Instituto de Investigación Sanitaria de Canarias (PIFIISC20/57 to C.F.). We also acknowledge the contribution of the Centro National de Genotipado (CEGEN) and Centro de Supercomputación de Galicia (CESGA) for funding this project by providing supercomputing infrastructures. A.D.L. is a recipient of fellowships from the National Council for Scientific and Technological Development (CNPq)-Brazil (309173/2019-1 and 201527/2020-0)
Azithromycin in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial
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- Publication venue
- 'Elsevier BV'
- Publication date
- 01/02/2021
- Field of study
Background Azithromycin has been proposed as a treatment for COVID-19 on the basis of its immunomodulatory actions. We aimed to evaluate the safety and efficacy of azithromycin in patients admitted to hospital with COVID-19. Methods In this randomised, controlled, open-label, adaptive platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), several possible treatments were compared with usual care in patients admitted to hospital with COVID-19 in the UK. The trial is underway at 176 hospitals in the UK. Eligible and consenting patients were randomly allocated to either usual standard of care alone or usual standard of care plus azithromycin 500 mg once per day by mouth or intravenously for 10 days or until discharge (or allocation to one of the other RECOVERY treatment groups). Patients were assigned via web-based simple (unstratified) randomisation with allocation concealment and were twice as likely to be randomly assigned to usual care than to any of the active treatment groups. Participants and local study staff were not masked to the allocated treatment, but all others involved in the trial were masked to the outcome data during the trial. The primary outcome was 28-day all-cause mortality, assessed in the intention-to-treat population. The trial is registered with ISRCTN, 50189673, and ClinicalTrials.gov, NCT04381936. Findings Between April 7 and Nov 27, 2020, of 16 442 patients enrolled in the RECOVERY trial, 9433 (57%) were eligible and 7763 were included in the assessment of azithromycin. The mean age of these study participants was 65·3 years (SD 15·7) and approximately a third were women (2944 [38%] of 7763). 2582 patients were randomly allocated to receive azithromycin and 5181 patients were randomly allocated to usual care alone. Overall, 561 (22%) patients allocated to azithromycin and 1162 (22%) patients allocated to usual care died within 28 days (rate ratio 0·97, 95% CI 0·87–1·07; p=0·50). No significant difference was seen in duration of hospital stay (median 10 days [IQR 5 to >28] vs 11 days [5 to >28]) or the proportion of patients discharged from hospital alive within 28 days (rate ratio 1·04, 95% CI 0·98–1·10; p=0·19). Among those not on invasive mechanical ventilation at baseline, no significant difference was seen in the proportion meeting the composite endpoint of invasive mechanical ventilation or death (risk ratio 0·95, 95% CI 0·87–1·03; p=0·24). Interpretation In patients admitted to hospital with COVID-19, azithromycin did not improve survival or other prespecified clinical outcomes. Azithromycin use in patients admitted to hospital with COVID-19 should be restricted to patients in whom there is a clear antimicrobial indication. Funding UK Research and Innovation (Medical Research Council) and National Institute of Health Research
Presentation, care and outcomes of patients with NSTEMI according to World Bank country income classification: the ACVC-EAPCI EORP NSTEMI Registry of the European Society of Cardiology.
- Author
- Abdekader R
- Abdelhameed M
- Abdelhamid M
- Abdelmottaleb W
- Abdin A
- Abdrabou M
- Abid L
- Abraham J A
- Abraheem A
- Abras M
- Adam C
- Adamyan M
- Adel M
- Adlam D
- Aerts S
- Affleck D-C
- Afsar A
- Ageev F
- Aguiar C Tavares
- Ahangari F
- Ahmad W A Wan
- Ahmad Wan Azman Wan
- Ahmed A
- Ahmed A
- Ahmed F
- Ahmed I M
- Ahmed S
- Ahmed S Waqar
- Ailoaei S
- Akgun A
- Akhmatova F
- Akhtar N
- Al Mahmeed W A R
- Al-Kinani T
- Al-Mashari S
- Al-Obaidi F
- Al-Riyami A
- Al-Riyami H
- Al-Zaidi M
- Alegre O
- Alemzadeh-Ansari M J
- Aleti S
- Algamal H Mahrous
- Alhussein F
- Ali A
- Ali H Hameed
- Ali M
- Ali M
- Ali T
- Ali Y
- Alla M Dafa
- Almeida A Rocha
- Almeida I
- Almeida S
- Almubarak E
- Almyahi M Hashim
- Alrahimi J
- Alsina M
- Altaher S
- Altinier A
- Alvarado K
- Alyavi A
- Alyavi B
- Alyavi Baxrom
- Amadi C
- Amber K
- Ambroziak M
- Amen S
- Amirov B
- Andrade L A Fajardo
- Andrei C-L
- Aneel A
- Anguita M J Fernandez
- Anselmi M
- Antonijevic J
- Antoniou A
- Antovski A
- Appelman Y
- Appelman Yolande
- Appelman Yolande
- Appelman Yolande
- Arat-Ozkan A
- Ardelean A
- Arefin M M
- Arefyev M N
- Argyropoulos K
- Ari H
- Ari S
- Ariza-Solé A
- Arizcuren A Munarriz
- Armangau P
- Arroyo-Monino D F
- Asim A
- Assaf O
- Assembekov B
- Astarcioglu M A
- Atallah B
- Atanaskovic V
- Atkinson C
- Atos J S
- Atta A Radi
- Attia N
- Augagneur M
- Avanzas P
- Averkov O V
- Avraamides P
- Ayesta A
- Aytekin V
- Aytekin Vedat
- Azam J
- Azam M G
- Azaryan K
- Azzahhafi J
- Babaeva L
- Babes E Emilia
- Babinski W
- Bacic G
- Badariene J
- Badri M
- Baglikov A
- Bahaa H
- Bahloul A
- Bahon L
- Bajramovic N Sabanovic
- Bajramovic Nirvana Sabanovic
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- Silvestrova G
- Simbelyte T
- Simon C
- Sinagra G
- Sinan U Y
- Sinanis T
- Sinanis Theodoros
- Sindelarova S
- Sinescu C-J
- Singh R
- Sinha A
- Sinha Ajay
- Sinnaeve F
- Sionis A
- Siswanto B B
- Sitar J
- Skantzis P
- Skuladottir F Bjork
- Smith J
- Smith J
- Smith S
- Snepvangers M
- Sobkowicz B
- Sobolewska J
- Sola N Basterra
- Somers V
- Somkereki C
- Sonego E
- Sorici G
- Sorrentino S
- Sosnowska-Pasiarska B
- Sotelo L Rodriguez
- Sousa C
- Spaccarotella C
- Spagnolo C
- Spica G
- Spychaj J-C
- Srinivasan M
- Ssemanda S
- Stables R
- Stachura J
- Staigyte J
- Stamatiadis N
- Stankovic M
- Stanojevic D
- Staroverov I
- Steblovnik K
- Stimjanin E
- Stirrup J
- Stolbova S
- Storey R F
- Strisciuglio T
- Strong C
- Styliadis I
- Subo A
- Subotic I
- Sugi K
- Sukhinina T
- Summerhayes A
- Summers-Wall J
- Surmeli A O
- Sus I
- Sustersic M
- Sut M
- Sutton J
- Szastok H
- Szygula J
- Szyszkowska A
- Tadevosyan M
- Taha H Salah Eldin
- Taleska B Zafirovska
- Taneja A
- Tapia V
- Tasar O
- Tasnic M
- Tavares J
- Taylor B
- Taylor T
- Tchetche D
- Teimouri-Jervekani Z
- Tello-Montoliu A
- Temple N
- Ten Berg J
- Teterina M
- Theobald T
- Thomas C
- Thomas H E
- Tibaut M
- Tierney C
- Timiras E
- Timóteo A T
- Tomoaia R
- Tomulic V
- Tonks L
- Toohie J
- Torbica A
- Torres S
- Torromeo C
- Torun A
- Totladze L
- Toulgaridis F
- Tousek F
- Trajkovic M
- Tralhão A
- Trim F
- Tripathy N
- Tsinopoulos G
- Tsognemekh B
- Tuncay B
- Tupare S
- Turnbull A
- Turner A
- Turner V
- Turney S
- Tutic M
- Twiss S
- Tycinska A
- Tyrovolas K
- Tzanis G
- Tzifos V
- Tzvetkov B
- Upegui M P Tobon
- Uscumlic A
- Usmiani T
- Utku O
- Uttley A
- Uuetoa T
- Uulu E Sultan
- Uzokov J
- Vahanian A
- Vailati L
- Van Caenegem O
- Van de Werf F
- Van Den Buijs D
- Van'T Hof A
- Vardanyan A
- Vargas C Mendez
- Varlot J
- Vavlukis M
- Vecherko V I
- Vendrametto F
- Vervaet P
- Ververeli C-L
- Vesic O
- Vidal P
- Vinod M
- Virbickiene A
- Viswanathan G
- Vizel R
- Volcescu A
- Volkova A L
- Vorobeva D
- Vucic R
- Wain J
- Wajid I
- Walker R
- Wallentin L
- Wanda I
- Ward T
- Warda H M
- Watkin R
- Weferling M
- Weidinger F
- Weidinger F
- Wells K
- Wells T
- Wester A
- Weston C
- Whyte A
- Widdows P
- Wiklo K
- Wilkinson A
- Wilkinson V
- Williams F
- Williams M
- Wilmshurst N
- Wilson A
- Wolter J-S
- Wouters S
- Wray G
- Wren L
- Wright J
- Wybraniec M
- Xuereb R G
- Xuereb Robert George
- Xuereb S
- Yadangi S
- Yagmur B
- Yanes G
- Yaseen I F
- Yashoman M
- Yildirim C
- Yildiz Ö
- Yin D Chan Pin
- Yonis A
- Young E
- Zachoval C
- Zagnoni S
- Zahran A
- Zaliunas R
- Zamorano J L
- Zapata P Sanchez
- Zaputovic L
- Zateyshchikov D
- Zeren G
- Zeymer U
- Zeymer U
- Zhanyshbekova N
- Zhukova N
- Zibounoumi N
- Zimbakov Z
- Ziubryte G
- Ziyrek M
- Zlatic N
- Zubova E
- Zventsova V
- Zvizdic F
- Publication venue
- 'Oxford University Press (OUP)'
- Publication date
- 03/02/2023
- Field of study