4 research outputs found
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Thiopurine monotherapy is effective in ulcerative colitis but significantly less so in Crohn’s disease: long-term outcomes for 11 928 patients in the UK inflammatory bowel disease bioresource
- Author
- Ahmad Tariq
- Appleby Richard
- Baburajan Bijay
- Baker-Moffat Michelle
- Banim Paul
- Barbour Jamie
- Beckly John
- Ben Warner Laura Hancock
- Bevan Roisin
- Bloom Stuart
- Bose Monica
- Brinkworth Elaine
- Brookes Matthew
- Butterworth Jeff
- Carter Martyn
- Clark Katie
- Cole Anew
- Collum Joseph
- Cooney Rachel
- Cummings Fraser
- Davies Albert
- deCaestecker John
- Dhar Anjan
- Durai Dharmaraj
- Edwards Cathryn
- Elamin Khalid
- Foley Stephen
- Gavin Daniel
- Gordon John
- Gunasekera Anton
- Hancock Laura
- Hanna Mina
- Hart Alisa
- Hobday David
- Hong You Yi
- Irving Peter
- Jarvis Mark
- Javaid Babur
- Johnson Matthew
- Keld Richard
- Kennedy Nick
- Kent Alexana
- Kok Klaartje Bel
- Koss Konrad
- Lamb Chris
- Landy Jonathan
- Lees Charlie
- Lewis Stephen
- Li Andy
- Limdi Jimmy
- Lobo Alan
- Loehry Juliette
- MacDonald Chris
- Mahmood Zahid
- Mansfield John
- Mathew Sanju
- McLaughlin John
- McLaughlin Simon
- Mear Lin
- Moran Gordon
- Muddu Ajay
- Murray Charles
- Nair Prakash
- Nwokolo Chuka
- Oglesby Arabis
- Oza Chirag
- Panter Simon
- Pappas Apostolos
- Parkes Miles
- Patel Vinod
- Penn Ruth
- Philips Anne
- Phillis Kath
- Pollok Richard
- Prescott Natalie
- Preston Cathryn
- Probert Chris
- Qian Wendi
- Rahman Monira
- Raine Tim
- Ramadas Arvind
- Ramage John
- Ramakrishnan Subramaniam
- Rees Colin
- Roberts Phil
- Satsangi Jack
- Saunders John
- Scott Glyn
- Sebastian Shaji
- Selinger Christian
- Sharpstone Dan
- Shawky Rasha
- Shenderey Richard
- Shenoy Achuth
- Shmueli Udi
- Silva Aminda de
- Simmons Alison
- Singh Salil
- Sinha Leena
- Sivagi Ganesh
- Smith Melissa
- Steed Helen
- Stournaras Evangelos
- Subramanian Sreedhar
- Theron Byron
- Tilbury Jude
- Tindall Theresa
- Tremelling Mark
- UK IBD BioResource Investigators
- UK IBD Bioresource Investigators
- Vani Deven
- Verma Ajay
- Warren Dawn
- Wesley Emma
- Wiles Alan
- Wilkins Joy
- Willia Horace
- Woods Annette
- Publication venue
- Gut
- Publication date
- 06/10/2020
- Field of study
Objective: Thiopurines are widely used as maintenance therapy in inflammatory bowel disease (IBD) but the evidence base for their use is sparse and their role increasingly questioned. Using the largest series reported to date, we assessed the long-term effectiveness of thiopurines in ulcerative colitis (UC) and Crohn’s disease (CD), including their impact on need for surgery. Design: Outcomes were assessed in 11 928 patients (4968 UC, 6960 CD) in the UK IBD BioResource initiated on thiopurine monotherapy with the intention of maintaining medically induced remission. Effectiveness was assessed retrospectively using patient-level data and a definition that required avoidance of escalation to biological therapy or surgery while on thiopurines. Analyses included overall effectiveness, time-to-event analysis for treatment escalation and comparison of surgery rates in patients tolerant or intolerant of thiopurines. Results: Using 68 132 patient-years of exposure, thiopurine monotherapy appeared effective for the duration of treatment in 2617/4968 (52.7%) patients with UC compared with 2378/6960 (34.2%) patients with CD (p<0.0001). This difference was corroborated in a multivariable analysis: after adjusting for variables including treatment era, thiopurine monotherapy was less effective in CD than UC (OR 0.47, 95% CI 0.43 to 0.51, p<0.0001). Thiopurine intolerance was associated with increased risk of surgery in UC (HR 2.44, p<0.0001); with a more modest impact on need for surgery in CD (HR=1.23, p=0.0015). Conclusion: Thiopurine monotherapy is an effective long-term treatment for UC but significantly less effective in CD
Convalescent plasma in patients admitted to hospital with COVID-19 (RECOVERY): a randomised controlled, open-label, platform trial
- Author
- Abani Obbina
- Abbas Ali
- Abbas Fatima
- Abbas Mustafa
- Abbasi Sadia
- Abbass Hakam
- Abbott Alfie
- Abdallah Nabeel
- Abdelaziz Ashraf
- Abdelfattah Mohamed
- Abdelqader Bushra
- Abdo David
- Abdul Rasheed Althaf
- Abdul Basir
- Abdul-Kadir Rezan
- Abdul-Raheem Rasheed
- Abdulakeem Ajibode
- Abdulle Amina
- Abdulmumeen Abdulfatahi
- Abdulshukkoor Niyaz
- Abdusamad Kula
- Abed El Khaleq Yazeed
- Abedalla Mai
- Abeer Ul Amna Abeer Ul Amna
- Abernethy Katrina
- Abo-Leyah Hani
- Aboaba Adebanke
- Abou-Haggar Ahmed
- Abouibrahim Mahmoud
- Abraham Miriam
- Abraham Tizzy
- Abraheem Abraheem
- Abrams Judith
- Abu Hyacinth-John
- Abu-Arafeh Ahmed
- Abubacker Syed M
- Abung Akata
- Aceampong Yaa
- Achara Amaka
- Acharya Devikumar
- Acheampong Sarah
- Acheson Janet
- Acosta Andres
- Acton Catherine
- Adabie-Ankrah Jacqueline
- Adair Sara
- Adam Fiona
- Adam Matthew
- Adamali Huzaifa
- Adams Carol
- Adams Charlotte
- Adams Kate
- Adams Lisa
- Adams Richard
- Adams Tim
- Adcock Kirsty
- Addai Jemaimah
- Adebiyi Ade
- Adegoke Ken
- Adell Vicki
- Ademokun Debo
- Adenwalla Sherna
- Adesemoye Oluwasegun A
- Adewunmi Emmanuel O
- Adeyemi Joyce
- Adhikary Rina
- Adkins Gabrielle
- Adnan Adnan
- Aeron-Thomas John
- Affleck Debbie
- Affron Dominic
- Afnan Carmel
- Afridi Muhammad
- Aftab Zainab A
- Agarwal Meenakshi
- Agbeko Rachel
- Agbo Chris
- Agent Penny
- Aggarwal Sunil
- Aghababaie Arameh
- Ahamed Sadiq Shafana
- Ahammed Nazeer Mohamed H
- Ahmad Humayun
- Ahmad Mohammad
- Ahmad Syed
- Ahmed Ali Roa
- Ahmed Asim
- Ahmed Bilal
- Ahmed Forizuddin
- Ahmed Hamze
- Ahmed Iram
- Ahmed Irshad
- Ahmed Khaled
- Ahmed Liban
- Ahmed Mahin
- Ahmed Maria C
- Ahmed Muhammad S
- Ahmed Naseer
- Ahmed Nausheen
- Ahmed Osama
- Ahmed Rajia A
- Ahmed Rizwan
- Ahmed Saif
- Ahmed Sammiya
- Ahmed Sana
- Ahmed Sara
- Ahmed Sophia
- Ahmed Syed
- Ahmed Syed Haris
- Ahmer Sana
- Ail Dhiraj
- Ainsworth Mark
- Airoldi Giulia
- Aissa Myriam
- Aitken Lindianne
- Ajay Bini
- Ajeneye Francis
- Ajibode Abdulakeem
- Ajmi Ayesha
- Akbar Tahir
- Akhtar Naim
- Akhtar Nasim
- Akhtar Nauman
- Akili Suha
- Akindolie Oludoyinsola
- Akinfenwa Yinka
- Akinkugbe Olugbenga
- Akinpelu Ibrahim
- Akinwumiju Olajide
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- Al Aaraj Ahmad
- Al Balushi Asma
- Al Dakhola Majd
- Al Swaifi Aladdin
- Al-Abadi Eslam
- Al-Asadi Abbas
- Al-Asadi Karina
- Al-Bayati Manaf
- Al-Fori Julyan
- Al-Hakim Bahij
- Al-Hity Shams
- Al-Jibury Maithem
- Al-Juboori Saba
- Al-Khalil Majid
- Al-Moasseb Hassan
- Al-Obaidi Magda
- Al-Rabahi Akram
- Al-Ramadhani Bahar
- Al-Saadi Zayneb
- Al-Shahi Salman Rustam
- Al-Shamkhani Warkaq
- Al-Sheklly Bashar
- Aladangady Narendra
- Alam Ayaz
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- Alcorn Stephen
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- Alderdice David
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- Aldridge Jonathan
- Aldridge Nicolas
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- Alexander Alison
- Alexander John
- Alexander Peter D G
- Alford Charlotte
- Alghazawi Laith
- Ali Ali
- Ali Asad
- Ali Fawzia R
- Ali Hoodo
- Ali Jawad
- Ali Mariam
- Ali Mohammad
- Ali Nayab
- Ali Oudai
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- Ali Sakina
- Ali Syed
- Alina Abid
- Aliyuda Fine
- Alizadeh Katrin
- Alkhusheh Moutaz
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- Ambrogetti Robert
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- Ameen Amir
- Amenyah Kenneth
- Amezaga Maria R
- Amin Allison
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- Amsha Khaled
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- Andrikopoulos Gregory
- Aneke Kanayochukwu
- Ang Andrew
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- Anichtchik Oleg
- Anim-Somuah Millicent
- Aniruddhan Krishnan
- Annett Jessica
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- Anstey Rebekah
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- Ashour Abd-El-Aziz
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- Azharuddin Mohammed
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- Aziz N
- Azkoul Ali
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- Bacon Gina
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- Burrage Daniel
- Burrage Sadie
- Burrows Kate
- Burston Claire
- Burton Ben
- Burton Fiona
- Burton Matthew
- Busby Angela
- Butcher Deborah
- Butler Aaron
- Butler Jessica
- Butler Joanne
- Butler Joshua
- Butler Lesley
- Butler Peter
- Butler Susan
- Butt Al-Tahoor
- Butt Mohammad M
- Butt Sophia
- Butterworth Caryl
- Butterworth-Cowin Nicola
- Buttery Robert
- Buttle Tom
- Button Heather
- Buttress Daniel
- Publication venue
- 'Elsevier BV'
- Publication date
- 13/02/2021
- Field of study
SummaryBackground Azithromycin has been proposed as a treatment for COVID-19 on the basis of its immunomodulatoryactions. 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-19Therapy [RECOVERY]), several possible treatments were compared with usual care in patients admitted to hospitalwith COVID-19 in the UK. The trial is underway at 176 hospitals in the UK. Eligible and consenting patients wererandomly allocated to either usual standard of care alone or usual standard of care plus azithromycin 500 mg once perday by mouth or intravenously for 10 days or until discharge (or allocation to one of the other RECOVERY treatmentgroups). Patients were assigned via web-based simple (unstratified) randomisation with allocation concealment andwere twice as likely to be randomly assigned to usual care than to any of the active treatment groups. Participants andlocal study staff were not masked to the allocated treatment, but all others involved in the trial were masked to theoutcome data during the trial. The primary outcome was 28-day all-cause mortality, assessed in the intention-to-treatpopulation. 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%) wereeligible and 7763 were included in the assessment of azithromycin. The mean age of these study participants was65·3 years (SD 15·7) and approximately a third were women (2944 [38%] of 7763). 2582 patients were randomlyallocated 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 (median10 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, nosignificant difference was seen in the proportion meeting the composite endpoint of invasive mechanical ventilationor 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 otherprespecified clinical outcomes. Azithromycin use in patients admitted to hospital with COVID-19 should be restrictedto patients in whom there is a clear antimicrobial indication
Stratified analyses refine association between TLR7 rare variants and severe COVID-19
- Author
- A. Gulati
- Aaron Butler
- Aayesha Kazi
- Abdelhakim Altabaibeh
- Abdul Kayani
- Abhinav Gupta
- Abigail Crew
- Abigail Knighton
- Abigail Short
- Abigail Taylor
- Abiola Harrison
- Adam Brayne
- Adam Brown
- Adam Loveridge
- Adama Fofano
- Aditya Kuravi
- Adriana Botello
- Adriana Palom
- Agilan Kaliappan
- Agilan Kaliappan
- Agnieszka Kubisz-Pudelko
- Agustín Albillos
- Ahmed Zaki
- Ailbhe Brady
- Ailsa Golightly
- Ailstair Nichol
- Ainhi Mac
- Ajay Raithatha
- Alain Vuylsteke
- Alan Maclean
- Alan Morrison
- Alan Neal
- Alasdair Bamford
- Alasdair Hay
- Alastair McGregor
- Alastair Rose
- Alastair Thomas
- Aled Morgan
- Alessandra Bandera
- Alessio Gerussi
- Alex Howlett
- Alex Lyon
- Alex McCurdy
- Alex Puxty
- Alexander Hoischen
- Alexandra Metcalfe
- Alexandra Williams
- Alexandre C. Pereira
- Alfredo Serrano-Ruiz
- Alice Harvey
- Alice Michael Mitchell
- Alice Nicholson
- Alice Poole
- Alice Thomas
- Alicia A.C. Waite
- Alicia Knight
- Alicia Price
- Alison Brown
- Alison Brown
- Alison Durie
- Alison Ghosh
- Alison Harrison
- Alison Lewis
- Alison Lye
- Alison Quinn
- Alison Turnbull
- Alison Williams
- Alison Wilson
- Alissa Kent
- Alistair Gales
- Alistair Hughes
- Alistair Meikle
- Alistair Nichol
- Alistair Roy
- Allison Daniels
- Alun Rees
- Amanda Ayers
- Amanda Cowton
- Amanda Lyle
- Amanda McGregor
- Amanda Sanderson
- Amanda Tyler
- Amanda Whileman
- Amber Cox
- Amber Ford
- Ambreen Tariq
- Amelia Daniel
- Amelia Stacey
- Ami Wilkinson
- Amie Reddy
- Amit Patel
- Amitaa Maharajh
- Amro Katary
- Amy Bowes
- Amy Clark
- Amy Collins
- Amy Cunningham
- Amy Easthope
- Amy Easthope
- Amy Easthope
- Amy Gardner
- Amy Kirkby
- Amy Pickard
- Amy Shepherd
- Ana Alvaro
- Ana Lisboa
- Ana Luisa Tomas
- Ana Vochin
- Anca Gherman
- Andre Franke
- Andrea Biondi
- Andrea Kay
- Andrea Webster
- Andres Naranjo
- Andrew Burtenshaw
- Andrew Fagan
- Andrew Gratrix
- Andrew Higham
- Andrew Higham
- Andrew Stenhouse
- Andrew Swain
- Andy Campbell
- Andy Drummond
- Andy Law
- Anelise C. Zborowski
- Aneta Bociek
- Anezka Pratley
- Angela Allan
- Angela Andrew
- Angela Lombardi
- Angharad Williams
- Angie Fawkes
- Angiy Michael
- Anil Hormis
- Anila Sukumaran
- Anisha Sukha
- Anita Agasou
- Anita Furlong
- Anna Cavazza
- Anna Joseph
- Anna Morris
- Anna Reed
- Anna Reyes
- Anna Roynon-Reed
- Annalisa Dance
- Anne Carter
- Anne Cowley
- Anne Cowley
- Anne Emma Heron
- Anne Haldeos
- Anne Hayes
- Anne Hudson
- Anne Nicholson
- Anne Nicholson
- Anne Saunderson
- Anne Todd
- Anne Zak
- Annette Hilldrith
- Annette Nilsson
- Anthony Barron
- Anthony Gordon
- Anthony Murphy
- Anthony Ng
- Anthony Rostron
- Anton Mayer
- Antonio Julià
- Aparna George
- Archana Bashyal
- Arianna Bellini
- Arianna Tucci
- Armorel Salberg
- Arnold Dela Rosa
- Arunkumar Ganesan
- Ascanio Tridente
- Ashar Ahmed
- Ashley Kinch
- Ashok Sundar
- Asifa Ali
- Atideb Mitra
- Atul Garg
- Audrey Coutts
- Austin Rattray
- Avril Donaldson
- Axel Schmidt
- Ayaa Eltayeb
- Ayesha Javaid
- Azmerelda Abraheem
- Baird Tracy
- Bally Purewal
- Balvinder Baines
- Barbara Winter-Goodwin
- Barney Scholefield
- Barry Milligan
- Beatriz Nafria
- Becky Lenagh
- Beena David
- Beena Eapen
- Belinda Roberts
- Ben Attwood
- Ben Creagh-Brown
- Ben Donne
- Ben Player
- Benedict Andrew
- Benjamin Shelley
- Benjamin Thomas
- Berina Zametica
- Bernadette Gallagher
- Bernadette King
- Bernard Hadebe
- Bethan Blackledge
- Bethan Blackledge
- Bethan Charles
- Bethan Deacon
- Bethan Deacon
- Bethan Gay
- Bethan Ogg
- Bethan Stowe
- Bethany Gumbrill
- Beverley Faulkner
- Beverley Wadams
- Bijal Patel
- Bijoy Mathew
- Borislava Borislavova
- Brendan Sloan
- Brian Digby
- Brian Johnston
- Brian Wilkinson
- Brice Djeugam
- Bridget Fuller
- Bridget Hopkins
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- Carlos Castro Delgado
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- Carmel Stuart
- Carole Hays
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- Caspar I. van der Made
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- Catherine Dennis
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- Cathrine Basikolo
- Cathy Jones
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- Ceilia Boz
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- Charmaine Shovelton
- Chenqing Zheng
- Cheryl Finch
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- Chris Thorpe
- Christine Almaden-Boyle
- Christine Eastgate-Jackson
- Christine Sicat
- Christopher Fine
- Christopher McParland
- Christopher Thompson
- Christopher Wasson
- Christopher Whitton
- Chrsitopher Woodford
- Chunda Sri-Chandana
- Ciara Collins
- Claire Cheyne
- Claire Fox
- Claire Gorman
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- Claire Jarman
- Claire Jennings
- Claire Marie Beith
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- Claire Phillips
- Claire Phillips
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- Craig Brandwood
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- Cristiana Bianco
- Dabheoc Coleman
- Dan Hawcutt
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- Daniel Martin
- Daniel Menzies
- Daniele Cristiano
- Daniele Prati
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- Danielle Walker
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- Daphene Clarke
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- Darsh Potla
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- Tracy Wood
- Trevor Paterson
- Una Poultney
- Val Irvine
- Valeria Rimoldi
- Valerie Beech
- Valerie Joan Page
- Valli Ratnam
- Vanessa Linnett
- Vanessa Rivers
- Varun Sarathy
- Veronica Wagstaff
- Veronika Pristopan
- Vicky Martinson
- Vicky Thomas
- Vicky Thwaites
- Vicky Thwaites
- Victoria Bastion
- Victoria Bridgett
- Victoria Clark
- Victoria Frost
- Victoria Lake
- Victoria Maynard
- Victoria Maynard
- Victoria Parris
- Victoria Parris
- Victoria Slater
- Victoria Tuckey
- Victoria Turner
- Victoria Waugh
- Vidya Kasipandian
- Vikki Crickmore
- Vikram Anumakonda
- Vinodh Krishnamurthy
- Vinodh Krishnamurthy
- Vishal Amin
- Wall Alanna
- Waqas Khaliq
- Waqas Khaliq
- Watkins Claire
- Wendy Goddard
- Wendy Harrison
- Wendy McCormick
- West Joe
- Wiesia Woodyatt
- Wild Laura
- William James Hurt
- Wilna Oosthuyzen
- Xavier Farré
- Xinyi Qiu
- Yasmin Choudhury
- Yasmin Death
- Yasmin Hussain
- Yolanda Baird
- Yusuf Cheema
- Yvette Thirlwall
- Yvonne Jackson
- Zahira Maqsood
- Zakaula Belagodu
- Zena Bradshaw
- Ziortza Fernandez
- Zoe Alldis
- Zoe Coton
- Zoe Daly
- Zoe Garland
- Zoe Lamond
- Zoe Prime
- Zoe Scott
- Zohra Omar
- Zohreh Farzad
- Publication venue
- Elsevier
- Publication date
- 01/10/2024
- Field of study
Summary: Despite extensive global research into genetic predisposition for severe COVID-19, knowledge on the role of rare host genetic variants and their relation to other risk factors remains limited. Here, 52 genes with prior etiological evidence were sequenced in 1,772 severe COVID-19 cases and 5,347 population-based controls from Spain/Italy. Rare deleterious TLR7 variants were present in 2.4% of young (<60 years) cases with no reported clinical risk factors (n = 378), compared to 0.24% of controls (odds ratio [OR] = 12.3, p = 1.27 × 10−10). Incorporation of the results of either functional assays or protein modeling led to a pronounced increase in effect size (ORmax = 46.5, p = 1.74 × 10−15). Association signals for the X-chromosomal gene TLR7 were also detected in the female-only subgroup, suggesting the existence of additional mechanisms beyond X-linked recessive inheritance in males. Additionally, supporting evidence was generated for a contribution to severe COVID-19 of the previously implicated genes IFNAR2, IFIH1, and TBK1. Our results refine the genetic contribution of rare TLR7 variants to severe COVID-19 and strengthen evidence for the etiological relevance of genes in the interferon signaling pathway
Whole-genome sequencing reveals host factors underlying critical COVID-19
- Author
- Abd Elghafar Mohamed S.
- Abdel-Aziz Mahmoud
- Abdelrazik Marwa
- Abdollahi Hamed
- Abdullah T.
- Abecasis Goncalo
- Abedalthagafi M.
- Abel Lynn
- Abernathy C.
- Abraheem Azmeralde
- Abul-Husn Noura S.
- Acquilini D.
- Adams C.
- Adams Emma L.
- Adams K.
- Adamsara Alireza
- Adanini Olurenke
- Adeleye O.
- Adra D.
- Afilalo J.
- Afilalo M.
- Afolabi D.
- Afrasiabi Z.
- Agasou A.
- Agrawal Shruti
- Agüero D.
- Ahmad N.
- Ahmadi Saeideh
- Ahmed A.
- Ahmed Cecilia
- Akeroyd L.
- Akhtar M.N.
- Akinkugbe O.
- Aksentijevich Alexandra
- Al-Afghani H.
- Al-Awdah L.
- Alaamery M.
- Alahmadey Z.Z.
- Alaverdian D.
- Alavere H.
- Albader A.
- Albaiceta G.M.
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- AlBardis H.
- Albeladi M.
- Albesher N.
- Albrich W.
- AlDhawi N.
- Aldridge J.
- Aleagha Afshar Etemadi
- Alexander Peter.
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- Åsvold Bjørn Olav
- Publication venue
- Publication date
- 01/01/2022
- Field of study
Altres ajuts: Department of Health and Social Care (DHSC); Illumina; LifeArc; Medical Research Council (MRC); UKRI; Sepsis Research (the Fiona Elizabeth Agnew Trust); the Intensive Care Society, Wellcome Trust Senior Research Fellowship (223164/Z/21/Z); BBSRC Institute Program Support Grant to the Roslin Institute (BBS/E/D/20002172, BBS/E/D/10002070, BBS/E/D/30002275); UKRI grants (MC_PC_20004, MC_PC_19025, MC_PC_1905, MRNO2995X/1); UK Research and Innovation (MC_PC_20029); the Wellcome PhD training fellowship for clinicians (204979/Z/16/Z); the Edinburgh Clinical Academic Track (ECAT) programme; the National Institute for Health Research, the Wellcome Trust; the MRC; Cancer Research UK; the DHSC; NHS England; the Smilow family; the National Center for Advancing Translational Sciences of the National Institutes of Health (CTSA award number UL1TR001878); the Perelman School of Medicine at the University of Pennsylvania; National Institute on Aging (NIA U01AG009740); the National Institute on Aging (RC2 AG036495, RC4 AG039029); the Common Fund of the Office of the Director of the National Institutes of Health; NCI; NHGRI; NHLBI; NIDA; NIMH; NINDS.Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care or hospitalization 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