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1. 1-year health outcomes associated with systemic corticosteroids for COVID-19: a longitudinal cohort study

Author: Olivia C. Leavy, Richard J. Russell, Ewen M. Harrison, Nazir I. Lone, Steven Kerr, Annemarie B. Docherty, Aziz Sheikh, Matthew Richardson, Omer Elneima, Neil J. Greening, Victoria Claire Harris, Linzy Houchen-Wolloff, Hamish J.C. McAuley, Ruth M. Saunders, Marco Sereno, Aarti Shikotra, Amisha Singapuri, Raminder Aul, Paul Beirne, Charlotte E. Bolton, Jeremy S. Brown, Gourab Choudhury, Nawar Diar Bakerly, Nicholas Easom, Carlos Echevarria, Jonathan Fuld, Nick Hart, John R. Hurst, Mark Jones, Dhruv Parekh, Paul Pfeffer, Najib M. Rahman, Sarah Rowland-Jones, Ajay M. Shah, Dan G. Wootton, Caroline Jolley, A.A. Roger Thompson, Trudie Chalder, Melanie J. Davies, Anthony De Soyza, John R. Geddes, William Greenhalf, Simon Heller, Luke Howard, Joseph Jacob, R. Gisli Jenkins, Janet M. Lord, Will D-C. Man, Gerry P. McCann, Stefan Neubauer, Peter J.M. Openshaw, Joanna Porter, Matthew J. Rowland, Janet T. Scott, Malcolm G. Semple, Sally J. Singh, David Thomas, Mark Toshner, Keir Lewis, Liam G. Heaney, Andrew Briggs, Bang Zheng, Mathew Thorpe, Jennifer K. Quint, James D. Chalmers, Ling-Pei Ho, Alex Horsley, Michael Marks, Krisnah Poinasamy, Betty Raman, Louise V. Wain, Christopher E. Brightling, and Rachael A. Evans
Subjects: Medicine
Abstract: Background In patients with coronavirus disease 2019 (COVID-19) requiring supplemental oxygen, dexamethasone reduces acute severity and improves survival, but longer-term effects are unknown. We hypothesised that systemic corticosteroid administration during acute COVID-19 would be associated with improved health-related quality of life (HRQoL) 1 year after discharge. Methods Adults admitted to hospital between February 2020 and March 2021 for COVID-19 and meeting current guideline recommendations for dexamethasone treatment were included using two prospective UK cohort studies (Post-hospitalisation COVID-19 and the International Severe Acute Respiratory and emerging Infection Consortium). HRQoL, assessed by the EuroQol-Five Dimensions–Five Levels utility index (EQ-5D-5L UI), pre-hospital and 1 year after discharge were compared between those receiving corticosteroids or not after propensity weighting for treatment. Secondary outcomes included patient-reported recovery, physical and mental health status, and measures of organ impairment. Sensitivity analyses were undertaken to account for survival and selection bias. Findings Of the 1888 participants included in the primary analysis, 1149 received corticosteroids. There was no between-group difference in EQ-5D-5L UI at 1 year (mean difference 0.004, 95% CI −0.026–0.034). A similar reduction in EQ-5D-5L UI was seen at 1 year between corticosteroid exposed and nonexposed groups (mean±sd change −0.12±0.22 versus −0.11±0.22). Overall, there were no differences in secondary outcome measures. After sensitivity analyses modelled using a cohort of 109 318 patients admitted to hospital with COVID-19, EQ-5D-5L UI at 1 year remained similar between the two groups. Interpretation Systemic corticosteroids for acute COVID-19 have no impact on the large reduction in HRQoL 1 year after hospital discharge. Treatments to address the persistent reduction in HRQoL are urgently needed.
Published: 2024
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2. Long-term impact of COVID-19 hospitalisation among individuals with pre-existing airway diseases in the UK: a multicentre, longitudinal cohort study – PHOSP-COVID

Author: Omer Elneima, John R. Hurst, Carlos Echevarria, Jennifer K. Quint, Samantha Walker, Salman Siddiqui, Petr Novotny, Paul E. Pfeffer, Jeremy S. Brown, Manu Shankar-Hari, Hamish J.C. McAuley, Olivia C. Leavy, Aarti Shikotra, Amisha Singapuri, Marco Sereno, Matthew Richardson, Ruth M. Saunders, Victoria C. Harris, Linzy Houchen-Wolloff, Neil J. Greening, Ewen M. Harrison, Annemarie B. Docherty, Nazir I. Lone, James D. Chalmers, Ling-Pei Ho, Alex Horsley, Michael Marks, Krisnah Poinasamy, Betty Raman, Rachael A. Evans, Louise V. Wain, Aziz Sheikh, Chris E. Brightling, Anthony De Soyza, Liam G. Heaney, J.K. Baillie, N.I. Lone, E. Pairo-Castineira, N. Avramidis, K. Rawlik, S Jones, L. Armstrong, B. Hairsine, H. Henson, C. Kurasz, A. Shaw, L. Shenton, H. Dobson, A. Dell, S. Fairbairn, N. Hawkings, J. Haworth, M. Hoare, V. Lewis, A. Lucey, G. Mallison, H. Nassa, C. Pennington, A. Price, C. Price, A. Storrie, G. Willis, S. Young, K. Poinasamy, S. Walker, I. Jarrold, A. Sanderson, K. Chong-James, C. David, W.Y. James, P. Pfeffer, O. Zongo, A. Martineau, C. Manisty, C. Armour, V. Brown, J. Busby, B. Connolly, T. Craig, S. Drain, L.G. Heaney, B. King, N. Magee, E. Major, D. McAulay, L. McGarvey, J. McGinness, T. Peto, R. Stone, A. Bolger, F. Davies, A. Haggar, J. Lewis, A. Lloyd, R. Manley, E. McIvor, D. Menzies, K. Roberts, W. Saxon, D. Southern, C. Subbe, V. Whitehead, A. Bularga, N.L. Mills, J. Dawson, H. El-Taweel, L. Robinson, L. Brear, K. Regan, D. Saralaya, K. Storton, S. Amoils, A. Bermperi, I. Cruz, K. Dempsey, A. Elmer, J. Fuld, H. Jones, S. Jose, S. Marciniak, M. Parkes, C. Ribeiro, J. Taylor, M. Toshner, L. Watson, J. Worsley, L. Broad, T. Evans, M. Haynes, L. Jones, L. Knibbs, A. McQueen, C. Oliver, K. Paradowski, R. Sabit, J. Williams, I. Jones, L. Milligan, E. Harris, C. Sampson, E. Davies, C. Evenden, A. Hancock, K. Hancock, C. Lynch, M. Rees, L. Roche, N. Stroud, T. Thomas-Woods, S. Heller, T. Chalder, K. Shah, E. Robertson, B. Young, M. Babores, M. Holland, N. Keenan, S. Shashaa, H. Wassall, L. Austin, E. Beranova, T. Cosier, J. Deery, T. Hazelton, H. Ramos, R. Solly, S. Turney, H. Weston, M. Ralser, L. Pearce, S. Pugmire, W. Stoker, A. Wilson, W. McCormick, E. Fraile, J. Ugoji, L. Aguilar Jimenez, G. Arbane, S. Betts, K. Bisnauthsing, A. Dewar, N. Hart, G. Kaltsakas, H. Kerslake, M.M. Magtoto, P. Marino, L.M. Martinez, M. Ostermann, J. Rossdale, T.S. Solano, M. Alvarez Corral, A. Arias, E. Bevan, D. Griffin, J. Martin, J. Owen, S. Payne, A. Prabhu, A. Reed, W. Storrar, N. Williams, C. Wrey Brown, T. Burdett, J. Featherstone, C. Lawson, A. Layton, C. Mills, L. Stephenson, Y. Ellis, P. Atkin, K. Brindle, M.G. Crooks, K. Drury, N. Easom, R. Flockton, L. Holdsworth, A. Richards, D.L. Sykes, S. Thackray-Nocera, C. Wright, S. Coetzee, K. Davies, R. Hughes, R. Loosley, H. McGuinness, A. Mohamed, L. O'Brien, Z. Omar, E. Perkins, J. Phipps, G. Ross, A. Taylor, H. Tench, R. Wolf-Roberts, L. Burden, E. Calvelo, B. Card, C. Carr, E.R. Chilvers, D. Copeland, P. Cullinan, P. Daly, L. Evison, T. Fayzan, H. Gordon, S. Haq, R.G. Jenkins, C. King, O. Kon, K. March, M. Mariveles, L. McLeavey, N. Mohamed, S. Moriera, U. Munawar, J. Nunag, U. Nwanguma, L. Orriss-Dib, A. Ross, M. Roy, E. Russell, K. Samuel, J. Schronce, N. Simpson, L. Tarusan, D.C. Thomas, C. Wood, N. Yasmin, D. Altmann, L.S. Howard, D. Johnston, A. Lingford-Hughes, W.D-C. Man, J. Mitchell, P.L. Molyneaux, C. Nicolaou, D.P. O'Regan, L. Price, J. Quint, D. Smith, R.S. Thwaites, J. Valabhji, S. Walsh, C.M. Efstathiou, F. Liew, A. Frankel, L. Lightstone, S. McAdoo, M. Wilkins, M. Willicombe, R. Touyz, A-M. Guerdette, M. Hewitt, R. Reddy, K. Warwick, S. White, A. McMahon, M. Malim, K. Bramham, M. Brown, K. Ismail, T. Nicholson, C. Pariante, C. Sharpe, S. Wessely, J. Whitney, O. Adeyemi, R. Adrego, H. Assefa-Kebede, J. Breeze, S. Byrne, P. Dulawan, A. Hoare, C.J. Jolley, A. Knighton, S. Patale, I. Peralta, N. Powell, A. Ramos, K. Shevket, F. Speranza, A. Te, A. Shah, A. Chiribiri, C. O'Brien, A. Hayday, A. Ashworth, P. Beirne, J. Clarke, C. Coupland, M. Dalton, C. Favager, J. Glossop, J. Greenwood, L. Hall, T. Hardy, A. Humphries, J. Murira, D. Peckham, S. Plein, J. Rangeley, G. Saalmink, A.L. Tan, E. Wade, B. Whittam, N. Window, J. Woods, G. Coakley, L. Turtle, L. Allerton, A.M. Allt, M. Beadsworth, A. Berridge, J. Brown, S. Cooper, A. Cross, S. Defres, S.L. Dobson, J. Earley, N. French, W. Greenhalf, K. Hainey, H.E. Hardwick, J. Hawkes, V. Highett, S. Kaprowska, A.L. Key, L. Lavelle-Langham, N. Lewis-Burke, G. Madzamba, F. Malein, S. Marsh, C. Mears, L. Melling, M.J. Noonan, L. Poll, J. Pratt, E. Richardson, A. Rowe, M.G. Semple, V. Shaw, K.A. Tripp, L.O. Wajero, S.A. Williams-Howard, D.G. Wootton, J. Wyles, S.N. Diwanji, S. Gurram, P. Papineni, S. Quaid, G.F. Tiongson, E. Watson, A. Briggs, M. Marks, C. Hastie, N. Rogers, N. Smith, D. Stensel, L. Bishop, K. McIvor, P. Rivera-Ortega, B. Al-Sheklly, C. Avram, J. Blaikely, M. Buch, N. Choudhury, D. Faluyi, T. Felton, T. Gorsuch, N.A. Hanley, A. Horsley, T. Hussell, Z. Kausar, N. Odell, R. Osbourne, K. Piper Hanley, K. Radhakrishnan, S. Stockdale, T. Kabir, J.T. Scott, P.J.M. Openshaw, I.D. Stewart, D. Burn, A. Ayoub, G. Burns, G. Davies, A. De Soyza, C. Echevarria, H. Fisher, C. Francis, A. Greenhalgh, P. Hogarth, J. Hughes, K. Jiwa, G. Jones, G. MacGowan, D. Price, A. Sayer, J. Simpson, H. Tedd, S. Thomas, S. West, M. Witham, S. Wright, A. Young, M.J. McMahon, P. Neill, D. Anderson, N. Basu, H. Bayes, A. Brown, A. Dougherty, K. Fallon, L. Gilmour, D. Grieve, K. Mangion, A. Morrow, R. Sykes, C. Berry, I.B. McInnes, K. Scott, F. Barrett, A. Donaldson, E.K. Sage, D. Bell, R. Hamil, K. Leitch, L. Macliver, M. Patel, J. Quigley, A. Smith, B. Welsh, G. Choudhury, S. Clohisey, A. Deans, A.B. Docherty, J. Furniss, E.M. Harrison, S. Kelly, A. Sheikh, J.D. Chalmers, D. Connell, C. Deas, A. Elliott, J. George, S. Mohammed, J. Rowland, A.R. Solstice, D. Sutherland, C.J. Tee, J. Bunker, R. Gill, R. Nathu, K. Holmes, H. Adamali, D. Arnold, S. Barratt, A. Dipper, S. Dunn, N. Maskell, A. Morley, L. Morrison, L. Stadon, S. Waterson, H. Welch, B. Jayaraman, T. Light, I. Vogiatzis, P. Almeida, C.E. Bolton, A. Hosseini, L. Matthews, R. Needham, K. Shaw, A.K. Thomas, J. Bonnington, M. Chrystal, C. Dupont, P.L. Greenhaff, A. Gupta, W. Jang, S. Linford, A. Nikolaidis, S. Prosper, A. Burns, N. Kanellakis, V.M. Ferreira, C. Nikolaidou, C. Xie, M. Ainsworth, A. Alamoudi, A. Bloss, P. Carter, M. Cassar, J. Chen, F. Conneh, T. Dong, R.I. Evans, E. Fraser, J.R. Geddes, F. Gleeson, P. Harrison, M. Havinden-Williams, L.P. Ho, P. Jezzard, I. Koychev, P. Kurupati, H. McShane, C. Megson, S. Neubauer, D. Nicoll, G. Ogg, E. Pacpaco, M. Pavlides, Y. Peng, N. Petousi, J. Pimm, N.M. Rahman, B. Raman, M.J. Rowland, K. Saunders, M. Sharpe, N. Talbot, E.M. Tunnicliffe, A. Korszun, S. Kerr, R.E. Barker, D. Cristiano, N. Dormand, P. George, M. Gummadi, S. Kon, K. Liyanage, C.M. Nolan, B. Patel, S. Patel, O. Polgar, P. Shah, S. Singh, J.A. Walsh, M. Gibbons, S. Ahmad, S. Brill, J. Hurst, H. Jarvis, L. Lim, S. Mandal, D. Matila, O. Olaosebikan, C. Singh, C. Laing, H. Baxendale, L. Garner, C. Johnson, J. Mackie, A. Michael, J. Newman, J. Pack, K. Paques, H. Parfrey, J. Parmar, A. Reddy, M. Halling-Brown, P. Dark, N. Diar-Bakerly, D. Evans, E. Hardy, A. Harvey, D. Holgate, S. Knight, N. Mairs, N. Majeed, L. McMorrow, J. Oxton, J. Pendlebury, C. Summersgill, R. Ugwuoke, S. Whittaker, W. Matimba-Mupaya, S. Strong-Sheldrake, P. Chowienczyk, J. Bagshaw, M. Begum, K. Birchall, R. Butcher, H. Carborn, F. Chan, K. Chapman, Y. Cheng, L. Chetham, C. Clark, Z. Coburn, J. Cole, M. Dixon, A. Fairman, J. Finnigan, H. Foot, D. Foote, A. Ford, R. Gregory, K. Harrington, L. Haslam, L. Hesselden, J. Hockridge, A. Holbourn, B. Holroyd-Hind, L. Holt, A. Howell, E. Hurditch, F. Ilyas, C. Jarman, A. Lawrie, J-H. Lee, E. Lee, R. Lenagh, A. Lye, I. Macharia, M. Marshall, A. Mbuyisa, J. McNeill, S. Megson, J. Meiring, L. Milner, S. Misra, H. Newell, T. Newman, C. Norman, L. Nwafor, D. Pattenadk, M. Plowright, J. Porter, P. Ravencroft, C. Roddis, J. Rodger, S.L. Rowland-Jones, P. Saunders, J. Sidebottom, J. Smith, L. Smith, N. Steele, G. Stephens, R. Stimpson, B. Thamu, A.A.R. Thompson, N. Tinker, K. Turner, H. Turton, P. Wade, J. Watson, I. Wilson, A. Zawia, L. Allsop, K. Bennett, P. Buckley, M. Flynn, M. Gill, C. Goodwin, M. Greatorex, H. Gregory, C. Heeley, L. Holloway, M. Holmes, J. Hutchinson, J. Kirk, W. Lovegrove, T.A. Sewell, S. Shelton, D. Sissons, K. Slack, S. Smith, D. Sowter, S. Turner, V. Whitworth, I. Wynter, J. Tomlinson, L. Warburton, S. Painter, S. Palmer, D. Redwood, J. Tilley, C. Vickers, T. Wainwright, G. Breen, M. Hotopf, R. Aul, D. Forton, M. Ali, A. Dunleavy, M. Mencias, N. Msimanga, T. Samakomva, S. Siddique, V. Tavoukjian, J. Teixeira, R. Ahmed, R. Francis, L. Connor, A. Cook, G.A. Davies, T. Rees, F. Thaivalappil, C. Thomas, M. McNarry, K.E. Lewis, M. Coulding, S. Kilroy, J. McCormick, J. McIntosh, V. Turner, J. Vere, A. Butt, H. Savill, S.S. Kon, G. Landers, H. Lota, S. Portukhay, M. Nasseri, A. Daniels, A. Hormis, J. Ingham, L. Zeidan, M. Chablani, L. Osborne, S. Aslani, A. Banerjee, R. Batterham, G. Baxter, R. Bell, A. David, E. Denneny, A.D. Hughes, W. Lilaonitkul, P. Mehta, A. Pakzad, B. Rangelov, B. Williams, J. Willoughby, M. Xu, N. Ahwireng, D. Bang, D. Basire, J.S. Brown, R.C. Chambers, A. Checkley, R. Evans, M. Heightman, T. Hillman, J. Jacob, R. Jastrub, M. Lipman, S. Logan, D. Lomas, M. Merida Morillas, H. Plant, J.C. Porter, K. Roy, E. Wall, T. Treibel, N. Ahmad Haider, C. Atkin, R. Baggott, M. Bates, A. Botkai, A. Casey, B. Cooper, J. Dasgin, C. Dawson, K. Draxlbauer, N. Gautam, J. Hazeldine, T. Hiwot, S. Holden, K. Isaacs, T. Jackson, V. Kamwa, D. Lewis, J.M. Lord, S. Madathil, C. McGhee, K. McGee, A. Neal, A. Newton-Cox, J. Nyaboko, D. Parekh, Z. Peterkin, H. Qureshi, L. Ratcliffe, E. Sapey, J. Short, T. Soulsby, J. Stockley, Z. Suleiman, T. Thompson, M. Ventura, S. Walder, C. Welch, D. Wilson, S. Yasmin, K.P. Yip, N. Chaudhuri, C. Childs, R. Djukanovic, S. Fletcher, M. Harvey, M.G. Jones, E. Marouzet, B. Marshall, R. Samuel, T. Sass, T. Wallis, H. Wheeler, R. Steeds, P. Beckett, C. Dickens, U. Nanda, M. Aljaroof, N. Armstrong, H. Arnold, H. Aung, M. Bakali, M. Bakau, E. Baldry, M. Baldwin, C. Bourne, M. Bourne, C.E. Brightling, N. Brunskill, P. Cairns, L. Carr, A. Charalambou, C. Christie, M.J. Davies, E. Daynes, S. Diver, R. Dowling, S. Edwards, C. Edwardson, O. Elneima, H. Evans, R.A. Evans, J. Finch, S. Finney, S. Glover, N. Goodman, B. Gooptu, N.J. Greening, K. Hadley, P. Haldar, B. Hargadon, V.C. Harris, L. Houchen-Wolloff, W. Ibrahim, L. Ingram, K. Khunti, A. Lea, D. Lee, H.J.C. McAuley, G.P. McCann, P. McCourt, T. McNally, G. Mills, W. Monteiro, M. Pareek, S. Parker, A. Prickett, I.N. Qureshi, A. Rowland, R. Russell, M. Sereno, A. Shikotra, S. Siddiqui, A. Singapuri, S.J. Singh, J. Skeemer, M. Soares, E. Stringer, S. Terry, T. Thornton, M. Tobin, T.J.C. Ward, F. Woodhead, T. Yates, A.J. Yousuf, B. Guillen Guiio, O.C. Leavy, L.V. Wain, M. Broome, P. McArdle, D. Thickett, R. Upthegrove, D. Wilkinson, P. Moss, D. Wraith, J. Evans, E. Bullmore, J.L. Heeney, C. Langenberg, W. Schwaeble, C. Summers, J. Weir McCall, D. Adeloye, D.E. Newby, R. Pius, I. Rudan, M. Shankar-Hari, C.L. Sudlow, M. Thorpe, S. Walmsley, B. Zheng, L. Allan, C. Ballard, A. McGovern, J. Dennis, J. Cavanagh, S. MacDonald, K. O'Donnell, J. Petrie, N. Sattar, M. Spears, E. Guthrie, M. Henderson, R.J. Allen, M. Bingham, T. Brugha, R. Free, D. Jones, L. Gardiner, A.J. Moss, E. Mukaetova-Ladinska, P. Novotny, C. Overton, J.E. Pearl, T. Plekhanova, M. Richardson, N. Samani, J. Sargent, M. Sharma, M. Steiner, C. Taylor, C. Tong, E. Turner, J. Wormleighton, B. Zhao, K. Ntotsis, R.M. Saunders, D. Lozano-Rojas, D. Cuthbertson, G. Kemp, A. McArdle, B. Michael, W. Reynolds, L.G. Spencer, B. Vinson, M. Ashworth, K. Abel, H. Chinoy, B. Deakin, M. Harvie, C.A. Miller, S. Stanel, P. Barran, D. Trivedi, H. McAllister-Williams, S. Paddick, A. Rostron, J.P. Taylor, D. Baguley, C. Coleman, E. Cox, L. Fabbri, S. Francis, I. Hall, E. Hufton, S. Johnson, F. Khan, P. Kitterick, R. Morriss, N. Selby, L. Wright, C. Antoniades, A. Bates, M. Beggs, K. Bhui, K. Breeze, K.M. Channon, D. Clark, X. Fu, M. Husain, X. Li, E. Lukaschuk, C. McCracken, K. McGlynn, R. Menke, K. Motohashi, T.E. Nichols, G. Ogbole, S. Piechnik, I. Propescu, J. Propescu, A.A. Samat, Z.B. Sanders, L. Sigfrid, M. Webster, L. Kingham, P. Klenerman, H. Lamlum, G. Carson, M. Taquet, L. Finnigan, L.C. Saunders, J.M. Wild, P.C. Calder, N. Huneke, G. Simons, D. Baldwin, S. Bain, L. Daines, E. Bright, P. Crisp, R. Dharmagunawardena, M. Stern, L. Bailey, A. Reddington, A. Wight, A. Ashish, J. Cooper, E. Robinson, A. Broadley, L. Barman, C. Brookes, K. Elliott, L. Griffiths, Z. Guy, K. Howard, D. Ionita, H. Redfearn, C. Sarginson, and A. Turnbull
Subjects: Medicine
Abstract: Background The long-term outcomes of COVID-19 hospitalisation in individuals with pre-existing airway diseases are unknown. Methods Adult participants hospitalised for confirmed or clinically suspected COVID-19 and discharged between 5 March 2020 and 31 March 2021 were recruited to the Post-hospitalisation COVID-19 (PHOSP-COVID) study. Participants attended research visits at 5 months and 1 year post discharge. Clinical characteristics, perceived recovery, burden of symptoms and health-related quality of life (HRQoL) of individuals with pre-existing airway disease (i.e., asthma, COPD or bronchiectasis) were compared to the non-airways group. Results A total of 615 out of 2697 (22.8%) participants had a history of pre-existing airway diseases (72.0% diagnosed with asthma, 22.9% COPD and 5.1% bronchiectasis). At 1 year, the airways group participants were less likely to feel fully recovered (20.4% versus 33.2%, p
Published: 2024
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3. Accelerated immune ageing is associated with COVID-19 disease severity

Author: Janet M. Lord, Tonny Veenith, Jack Sullivan, Archana Sharma-Oates, Alex G. Richter, Neil J. Greening, Hamish J. C. McAuley, Rachael A. Evans, Paul Moss, Shona C. Moore, Lance Turtle, Nandan Gautam, Ahmed Gilani, Manan Bajaj, Louise V. Wain, Christopher Brightling, Betty Raman, Michael Marks, Amisha Singapuri, Omer Elneima, Peter J. M. Openshaw, Niharika A. Duggal, on behalf of the PHOSP-COVID Study collaborative group, and ISARIC4C investigators
Subjects: Immunologic diseases. Allergy, RC581-607, Geriatrics, RC952-954.6
Abstract: Abstract Background The striking increase in COVID-19 severity in older adults provides a clear example of immunesenescence, the age-related remodelling of the immune system. To better characterise the association between convalescent immunesenescence and acute disease severity, we determined the immune phenotype of COVID-19 survivors and non-infected controls. Results We performed detailed immune phenotyping of peripheral blood mononuclear cells isolated from 103 COVID-19 survivors 3–5 months post recovery who were classified as having had severe (n = 56; age 53.12 ± 11.30 years), moderate (n = 32; age 52.28 ± 11.43 years) or mild (n = 15; age 49.67 ± 7.30 years) disease and compared with age and sex-matched healthy adults (n = 59; age 50.49 ± 10.68 years). We assessed a broad range of immune cell phenotypes to generate a composite score, IMM-AGE, to determine the degree of immune senescence. We found increased immunesenescence features in severe COVID-19 survivors compared to controls including: a reduced frequency and number of naïve CD4 and CD8 T cells (p
Published: 2024
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4. Genome-wide association study of thyroid-stimulating hormone highlights new genes, pathways and associations with thyroid disease

Author: Alexander T. Williams, Jing Chen, Kayesha Coley, Chiara Batini, Abril Izquierdo, Richard Packer, Erik Abner, Stavroula Kanoni, David J. Shepherd, Robert C. Free, Edward J. Hollox, Nigel J. Brunskill, Ioanna Ntalla, Nicola Reeve, Christopher E. Brightling, Laura Venn, Emma Adams, Catherine Bee, Susan E. Wallace, Manish Pareek, Anna L. Hansell, Tõnu Esko, Estonian Biobank Research Team, Daniel Stow, Benjamin M. Jacobs, David A. van Heel, Genes & Health Research Team, William Hennah, Balasubramanya S. Rao, Frank Dudbridge, Louise V. Wain, Nick Shrine, Martin D. Tobin, and Catherine John
Subjects: Science
Abstract: Abstract Thyroid hormones play a critical role in regulation of multiple physiological functions and thyroid dysfunction is associated with substantial morbidity. Here, we use electronic health records to undertake a genome-wide association study of thyroid-stimulating hormone (TSH) levels, with a total sample size of 247,107. We identify 158 novel genetic associations, more than doubling the number of known associations with TSH, and implicate 112 putative causal genes, of which 76 are not previously implicated. A polygenic score for TSH is associated with TSH levels in African, South Asian, East Asian, Middle Eastern and admixed American ancestries, and associated with hypothyroidism and other thyroid disease in South Asians. In Europeans, the TSH polygenic score is associated with thyroid disease, including thyroid cancer and age-of-onset of hypothyroidism and hyperthyroidism. We develop pathway-specific genetic risk scores for TSH levels and use these in phenome-wide association studies to identify potential consequences of pathway perturbation. Together, these findings demonstrate the potential utility of genetic associations to inform future therapeutics and risk prediction for thyroid diseases.
Published: 2023
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5. Association study of human leukocyte antigen variants and idiopathic pulmonary fibrosis

Author: Beatriz Guillen-Guio, Megan L. Paynton, Richard J. Allen, Daniel P.W. Chin, Lauren J. Donoghue, Amy Stockwell, Olivia C. Leavy, Tamara Hernandez-Beeftink, Carl Reynolds, Paul Cullinan, Fernando Martinez, Helen L. Booth, William A. Fahy, Ian P. Hall, Simon P. Hart, Mike R. Hill, Nik Hirani, Richard B. Hubbard, Robin J. McAnulty, Ann B. Millar, Vidya Navaratnam, Eunice Oballa, Helen Parfrey, Gauri Saini, Ian Sayers, Martin D. Tobin, Moira K.B. Whyte, Ayodeji Adegunsoye, Naftali Kaminski, Shwu-Fan Ma, Mary E. Strek, Yingze Zhang, Tasha E. Fingerlin, Maria Molina-Molina, Margaret Neighbors, X. Rebecca Sheng, Justin M. Oldham, Toby M. Maher, Philip L. Molyneaux, Carlos Flores, Imre Noth, David A. Schwartz, Brian L. Yaspan, R. Gisli Jenkins, Louise V. Wain, and Edward J. Hollox
Subjects: Medicine
Abstract: Introduction Idiopathic pulmonary fibrosis (IPF) is a chronic interstitial pneumonia marked by progressive lung fibrosis and a poor prognosis. Recent studies have highlighted the potential role of infection in the pathogenesis of IPF, and a prior association of the HLA-DQB1 gene with idiopathic fibrotic interstitial pneumonia (including IPF) has been reported. Owing to the important role that the human leukocyte antigen (HLA) region plays in the immune response, here we evaluated if HLA genetic variation was associated specifically with IPF risk. Methods We performed a meta-analysis of associations of the HLA region with IPF risk in individuals of European ancestry from seven independent case–control studies of IPF (comprising 5159 cases and 27 459 controls, including a prior study of fibrotic interstitial pneumonia). Single nucleotide polymorphisms, classical HLA alleles and amino acids were analysed and signals meeting a region-wide association threshold of p90% were considered significant. We sought to replicate the previously reported HLA-DQB1 association in the subset of studies independent of the original report. Results The meta-analysis of all seven studies identified four significant independent single nucleotide polymorphisms associated with IPF risk. However, none met the posterior probability for replication criterion. The HLA-DQB1 association was not replicated in the independent IPF studies. Conclusion Variation in the HLA region was not consistently associated with risk in studies of IPF. However, this does not preclude the possibility that other genomic regions linked to the immune response may be involved in the aetiology of IPF.
Published: 2024
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6. A comparison of software for analysis of rare and common short tandem repeat (STR) variation using human genome sequences from clinical and population-based samples

Author: John W. Oketch, Louise V. Wain, and Edward J. Hollox
Subjects: Medicine, Science
Published: 2024

7. Genome-wide association study of susceptibility to hospitalised respiratory infections [version 2; peer review: 1 approved, 2 approved with reservations]

Author: Sina A. Gharib, Louise V. Wain, Tõnu Esko, Gail P. Jarvik, Scott Hebbring, Eric B. Larson, Sarah H. Landis, Ruth J.F. Loos, Jiangyuan Liu, Caroline Hayward, Arden Moscati, Yuan Luo, Bahram Namjou, Hana Mullerova, Marjo-Riitta Järvelin, Jennifer K. Quint, Eeva Sliz, Marylyn D. Ritchie, Laurent Thomas, Ian B. Stanaway, Kristian Hveem, David Michalovich, Ian P. Hall, James F. Wilson, Jing Chen, Alexander T. Williams, Martin D. Tobin, Joanna C. Betts, Hardeep Naghra-van Gijzel, Richard Packer, Edith M. Hessel, Astrid J. Yeo, Nicola F. Reeve, Bjørn Olav Åsvold, Erik Abner, Archie Campbell, Traci M. Bartz, Juha Auvinen, Catherine John, Ben Brumpton, Yuki Bradford, Su Chu, David J. Porteous, Nick Shrine, Michael H. Cho, QiPing Feng, and David R. Crosslin
Subjects: Respiratory infections, GWAS, UK Biobank, electronic medical records, eng, Medicine, Science
Abstract: Background: Globally, respiratory infections contribute to significant morbidity and mortality. However, genetic determinants of respiratory infections are understudied and remain poorly understood. Methods: We conducted a genome-wide association study in 19,459 hospitalised respiratory infection cases and 101,438 controls from UK Biobank (Stage 1). We followed-up well-imputed top signals from our Stage 1 analysis in 50,912 respiratory infection cases and 150,442 controls from 11 cohorts (Stage 2). We aggregated effect estimates across studies using inverse variance-weighted meta-analyses. Additionally, we investigated the function of the top signals in order to gain understanding of the underlying biological mechanisms. Results: From our Stage 1 analysis, we report 56 signals at P
Published: 2023
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8. Shared genetic risk factors: implications for treatment of idiopathic pulmonary fibrosis and systemic hypertension

Author: Gina Parcesepe, Richard J. Allen, Beatriz Guillen-Guio, Samuel Moss, R. Gisli Jenkins, and Louise V. Wain
Subjects: Medicine
Published: 2023
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9. The effect of COVID rehabilitation for ongoing symptoms Post HOSPitalisation with COVID-19 (PHOSP-R): protocol for a randomised parallel group controlled trial on behalf of the PHOSP consortium

Author: Enya Daynes, Molly Baldwin, Neil J. Greening, Thomas Yates, Nicolette C. Bishop, George Mills, Matthew Roberts, Malik Hamrouni, Tatiana Plekhanova, Ioannis Vogiatzis, Carlos Echevarria, Rashmita Nathu, Hamish J. C. McAuley, Lorna Latimer, Jennifer Glennie, Francesca Chambers, Ruth Penfold, Emily Hume, Dimitrios Magaritis, Charikleia Alexiou, Sebastian Potthoff, Mitchell James Hogg, Catherine Haighton, Bethany Nichol, Olivia C. Leavy, Matthew Richardson, Omer Elneima, Amisha Singapuri, Marco Sereno, Ruth M. Saunders, Victoria C. Harris, Claire M. Nolan, Charlotte Bolton, Linzy Houchen-Wolloff, Ewen M. Harrison, Nazir Lone, Jennifer Quint, James D. Chalmers, Ling-Pei Ho, Alex Horsley, Michael Marks, Krisnah Poinasamy, Betty Ramen, Louise V. Wain, Christopher Brightling, William D.-C. Man, Rachael Evans, and Sally J. Singh
Subjects: COVID-19, Rehabilitation, Digital, Randomised controlled trial, Medicine (General), R5-920
Abstract: Abstract Introduction Many adults hospitalised with COVID-19 have persistent symptoms such as fatigue, breathlessness and brain fog that limit day-to-day activities. These symptoms can last over 2 years. Whilst there is limited controlled studies on interventions that can support those with ongoing symptoms, there has been some promise in rehabilitation interventions in improving function and symptoms either using face-to-face or digital methods, but evidence remains limited and these studies often lack a control group. Methods and analysis This is a nested single-blind, parallel group, randomised control trial with embedded qualitative evaluation comparing rehabilitation (face-to-face or digital) to usual care and conducted within the PHOSP-COVID study. The aim of this study is to determine the effectiveness of rehabilitation interventions on exercise capacity, quality of life and symptoms such as breathlessness and fatigue. The primary outcome is the Incremental Shuttle Walking Test following the eight week intervention phase. Secondary outcomes include measures of function, strength and subjective assessment of symptoms. Blood inflammatory markers and muscle biopsies are an exploratory outcome. The interventions last eight weeks and combine symptom-titrated exercise therapy, symptom management and education delivered either in a face-to-face setting or through a digital platform ( www.yourcovidrecovery.nhs.uk ). The proposed sample size is 159 participants, and data will be intention-to-treat analyses comparing rehabilitation (face-to-face or digital) to usual care. Ethics and dissemination Ethical approval was gained as part of the PHOSP-COVID study by Yorkshire and the Humber Leeds West Research NHS Ethics Committee, and the study was prospectively registered on the ISRCTN trial registry (ISRCTN13293865). Results will be disseminated to stakeholders, including patients and members of the public, and published in appropriate journals. Article summary Strengths and limitations of this study • This protocol utilises two interventions to support those with ongoing symptoms of COVID-19 • This is a two-centre parallel-group randomised controlled trial • The protocol has been supported by patient and public involvement groups who identified treatments of symptoms and activity limitation as a top priority
Published: 2023
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10. A genome-wide association study of survival in patients with sepsis

Author: Tamara Hernandez-Beeftink, Beatriz Guillen-Guio, Jose M. Lorenzo-Salazar, Almudena Corrales, Eva Suarez-Pajes, Rui Feng, Luis A. Rubio-Rodríguez, Megan L. Paynton, Raquel Cruz, M. Isabel García-Laorden, Miryam Prieto-González, Aurelio Rodríguez-Pérez, Demetrio Carriedo, Jesús Blanco, Alfonso Ambrós, Elena González-Higueras, Elena Espinosa, Arturo Muriel, Eduardo Tamayo, María M. Martin, Leonardo Lorente, David Domínguez, Abelardo García de Lorenzo, Heather M. Giannini, John P. Reilly, Tiffanie K. Jones, José M. Añón, Marina Soro, Ángel Carracedo, Louise V. Wain, Nuala J. Meyer, Jesús Villar, Carlos Flores, and the Genetics of Sepsis (GEN-SEP) Network
Subjects: Sepsis, Genome-wide association study, Genomics, 28 days, Outcome, Medical emergencies. Critical care. Intensive care. First aid, RC86-88.9
Abstract: Abstract Background Sepsis is a severe systemic inflammatory response to infections that is accompanied by organ dysfunction and has a high mortality rate in adult intensive care units. Most genetic studies have identified gene variants associated with development and outcomes of sepsis focusing on biological candidates. We conducted the first genome-wide association study (GWAS) of 28-day survival in adult patients with sepsis. Methods This study was conducted in two stages. The first stage was performed on 687 European sepsis patients from the GEN-SEP network and 7.5 million imputed variants. Association testing was conducted with Cox regression models, adjusting by sex, age, and the main principal components of genetic variation. A second stage focusing on the prioritized genetic variants was performed on 2,063 ICU sepsis patients (1362 European Americans and 701 African-Americans) from the MESSI study. A meta-analysis of results from the two stages was conducted and significance was established at p
Published: 2022
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11. Identification and characterisation of a rare MTTP variant underlying hereditary non-alcoholic fatty liver disease

Author: Jane I. Grove, Peggy C.K. Lo, Nick Shrine, Julian Barwell, Louise V. Wain, Martin D. Tobin, Andrew M. Salter, Aditi N. Borkar, Sara Cuevas-Ocaña, Neil Bennett, Catherine John, Ioanna Ntalla, Gabriela E. Jones, Christopher P. Neal, Mervyn G. Thomas, Helen Kuht, Pankaj Gupta, Vishwaraj M. Vemala, Allister Grant, Adeolu B. Adewoye, Kotacherry T. Shenoy, Leena K. Balakumaran, Edward J. Hollox, Nicholas R.F. Hannan, and Guruprasad P. Aithal
Subjects: Microsomal triglyceride transfer protein, Abetalipoproteinaemia, hiPSC-derived hepatocytes, Lipoprotein ApoB, Diseases of the digestive system. Gastroenterology, RC799-869
Abstract: Background & Aims: Non-alcoholic fatty liver disease (NAFLD) is a complex trait with an estimated prevalence of 25% globally. We aimed to identify the genetic variant underlying a four-generation family with progressive NAFLD leading to cirrhosis, decompensation, and development of hepatocellular carcinoma in the absence of common risk factors such as obesity and type 2 diabetes. Methods: Exome sequencing and genome comparisons were used to identify the likely causal variant. We extensively characterised the clinical phenotype and post-prandial metabolic responses of family members with the identified novel variant in comparison with healthy non-carriers and wild-type patients with NAFLD. Variant-expressing hepatocyte-like cells (HLCs) were derived from human-induced pluripotent stem cells generated from homozygous donor skin fibroblasts and restored to wild-type using CRISPR-Cas9. The phenotype was assessed using imaging, targeted RNA analysis, and molecular expression arrays. Results: We identified a rare causal variant c.1691T>C p.I564T (rs745447480) in MTTP, encoding microsomal triglyceride transfer protein (MTP), associated with progressive NAFLD, unrelated to metabolic syndrome and without characteristic features of abetalipoproteinaemia. HLCs derived from a homozygote donor had significantly lower MTP activity and lower lipoprotein ApoB secretion than wild-type cells, while having similar levels of MTP mRNA and protein. Cytoplasmic triglyceride accumulation in HLCs triggered endoplasmic reticulum stress, secretion of pro-inflammatory mediators, and production of reactive oxygen species. Conclusions: We have identified and characterised a rare causal variant in MTTP, and homozygosity for MTTP p.I564T is associated with progressive NAFLD without any other manifestations of abetalipoproteinaemia. Our findings provide insights into mechanisms driving progressive NAFLD. Impact and Implications: A rare genetic variant in the gene MTTP has been identified as responsible for the development of severe non-alcoholic fatty liver disease in a four-generation family with no typical disease risk factors. A cell line culture created harbouring this variant gene was characterised to understand how this genetic variation leads to a defect in liver cells, which results in accumulation of fat and processes that promote disease. This is now a useful model for studying the disease pathways and to discover new ways to treat common types of fatty liver disease.
Published: 2023
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12. Device-assessed sleep and physical activity in individuals recovering from a hospital admission for COVID-19: a multicentre study

Author: Tatiana Plekhanova, Alex V. Rowlands, Rachael A. Evans, Charlotte L. Edwardson, Nicolette C. Bishop, Charlotte E. Bolton, James D. Chalmers, Melanie J. Davies, Enya Daynes, Paddy C. Dempsey, Annemarie B. Docherty, Omer Elneima, Neil J. Greening, Sharlene A. Greenwood, Andrew P. Hall, Victoria C. Harris, Ewen M. Harrison, Joseph Henson, Ling-Pei Ho, Alex Horsley, Linzy Houchen-Wolloff, Kamlesh Khunti, Olivia C. Leavy, Nazir I. Lone, Michael Marks, Ben Maylor, Hamish J. C. McAuley, Claire M. Nolan, Krisnah Poinasamy, Jennifer K. Quint, Betty Raman, Matthew Richardson, Jack A. Sargeant, Ruth M. Saunders, Marco Sereno, Aarti Shikotra, Amisha Singapuri, Michael Steiner, David J. Stensel, Louise V. Wain, Julie Whitney, Dan G. Wootton, Christopher E. Brightling, William D-C. Man, Sally J. Singh, Tom Yates, and Writing group (on behalf of the PHOSP-COVID Collaborative Group)
Subjects: Accelerometer, Long COVID, MVPA, Sleep timing, PHOSP-COVID, Nutritional diseases. Deficiency diseases, RC620-627, Public aspects of medicine, RA1-1270
Abstract: Abstract Background The number of individuals recovering from severe COVID-19 is increasing rapidly. However, little is known about physical behaviours that make up the 24-h cycle within these individuals. This study aimed to describe physical behaviours following hospital admission for COVID-19 at eight months post-discharge including associations with acute illness severity and ongoing symptoms. Methods One thousand seventy-seven patients with COVID-19 discharged from hospital between March and November 2020 were recruited. Using a 14-day wear protocol, wrist-worn accelerometers were sent to participants after a five-month follow-up assessment. Acute illness severity was assessed by the WHO clinical progression scale, and the severity of ongoing symptoms was assessed using four previously reported data-driven clinical recovery clusters. Two existing control populations of office workers and individuals with type 2 diabetes were comparators. Results Valid accelerometer data from 253 women and 462 men were included. Women engaged in a mean ± SD of 14.9 ± 14.7 min/day of moderate-to-vigorous physical activity (MVPA), with 12.1 ± 1.7 h/day spent inactive and 7.2 ± 1.1 h/day asleep. The values for men were 21.0 ± 22.3 and 12.6 ± 1.7 h /day and 6.9 ± 1.1 h/day, respectively. Over 60% of women and men did not have any days containing a 30-min bout of MVPA. Variability in sleep timing was approximately 2 h in men and women. More severe acute illness was associated with lower total activity and MVPA in recovery. The very severe recovery cluster was associated with fewer days/week containing continuous bouts of MVPA, longer total sleep time, and higher variability in sleep timing. Patients post-hospitalisation with COVID-19 had lower levels of physical activity, greater sleep variability, and lower sleep efficiency than a similarly aged cohort of office workers or those with type 2 diabetes. Conclusions Those recovering from a hospital admission for COVID-19 have low levels of physical activity and disrupted patterns of sleep several months after discharge. Our comparative cohorts indicate that the long-term impact of COVID-19 on physical behaviours is significant.
Published: 2022
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13. Prevalence of physical frailty, including risk factors, up to 1 year after hospitalisation for COVID-19 in the UK: a multicentre, longitudinal cohort studyResearch in context

Author: Hamish J.C. McAuley, Rachael A. Evans, Charlotte E. Bolton, Christopher E. Brightling, James D. Chalmers, Annemarie B. Docherty, Omer Elneima, Paul L. Greenhaff, Ayushman Gupta, Victoria C. Harris, Ewen M. Harrison, Ling-Pei Ho, Alex Horsley, Linzy Houchen-Wolloff, Caroline J. Jolley, Olivia C. Leavy, Nazir I. Lone, William D-C Man, Michael Marks, Dhruv Parekh, Krisnah Poinasamy, Jennifer K. Quint, Betty Raman, Matthew Richardson, Ruth M. Saunders, Marco Sereno, Aarti Shikotra, Amisha Singapuri, Sally J. Singh, Michael Steiner, Ai Lyn Tan, Louise V. Wain, Carly Welch, Julie Whitney, Miles D. Witham, Janet Lord, Neil J. Greening, K. Abel, H. Adamali, D. Adeloye, O. Adeyemi, R. Adrego, L.A. Aguilar Jimenez, S. Ahmad, N. Ahmad Haider, R. Ahmed, N. Ahwireng, M. Ainsworth, B. Al-Sheklly, A. Alamoudi, M. Ali, M. Aljaroof, A.M. All, L. Allan, R.J. Allen, L. Allerton, L. Allsop, P. Almeida, D. Altmann, M. Alvarez Corral, S. Amoils, D. Anderson, C. Antoniades, G. Arbane, A. Arias, C. Armour, L. Armstrong, N. Armstrong, D. Arnold, H. Arnold, A. Ashish, A. Ashworth, M. Ashworth, S. Aslani, H. Assefa-Kebede, C. Atkin, P. Atkin, R. Aul, H. Aung, L. Austin, C. Avram, A. Ayoub, M. Babores, R. Baggott, J. Bagshaw, D. Baguley, L. Bailey, J.K. Baillie, S. Bain, M. Bakali, M. Bakau, E. Baldry, D. Baldwin, M. Baldwin, C. Ballard, A. Banerjee, B. Bang, R.E. Barker, L. Barman, S. Barratt, F. Barrett, D. Basire, N. Basu, M. Bates, A. Bates, R. Batterham, H. Baxendale, H. Bayes, M. Beadsworth, P. Beckett, M. Beggs, M. Begum, P. Beirne, D. Bell, R. Bell, K. Bennett, E. Beranova, A. Bermperi, A. Berridge, C. Berry, S. Betts, E. Bevan, K. Bhui, M. Bingham, K. Birchall, L. Bishop, K. Bisnauthsing, J. Blaikely, A. Bloss, A. Bolger, C.E. Bolton, J. Bonnington, A. Botkai, C. Bourne, M. Bourne, K. Bramham, L. Brear, G. Breen, J. Breeze, A. Briggs, E. Bright, C.E. Brightling, S. Brill, K. Brindle, L. Broad, A. Broadley, C. Brookes, M. Broome, A. Brown, J. Brown, J.S. Brown, M. Brown, V. Brown, T. Brugha, N. Brunskill, M. Buch, P. Buckley, A. Bularga, E. Bullmore, L. Burden, T. Burdett, D. Burn, G. Burns, A. Burns, J. Busby, R. Butcher, A. Butt, S. Byrne, P. Cairns, P.C. Calder, E. Calvelo, H. Carborn, B. Card, C. Carr, L. Carr, G. Carson, P. Carter, A. Casey, M. Cassar, J. Cavanagh, M. Chablani, T. Chalder, J.D. Chalmers, R.C. Chambers, F. Chan, K.M. Channon, K. Chapman, A. Charalambou, N. Chaudhuri, A. Checkley, J. Chen, Y. Cheng, L. Chetham, C. Childs, E.R. Chilvers, H. Chinoy, A. Chiribiri, K. Chong-James, G. Choudhury, N. Choudhury, P. Chowienczyk, C. Christie, M. Chrystal, D. Clark, C. Clark, J. Clarke, S. Clohisey, G. Coakley, Z. Coburn, S. Coetzee, J. Cole, C. Coleman, F. Conneh, D. Connell, B. Connolly, L. Connor, A. Cook, B. Cooper, J. Cooper, S. Cooper, D. Copeland, T. Cosier, M. Coulding, C. Coupland, E. Cox, T. Craig, P. Crisp, D. Cristiano, M.G. Crooks, A. Cross, I. Cruz, P. Cullinan, D. Cuthbertson, L. Daines, M. Dalton, P. Daly, A. Daniels, P. Dark, J. Dasgin, A. David, C. David, E. Davies, F. Davies, G. Davies, G.A. Davies, K. Davies, M.J. Davies, J. Dawson, E. Daynes, A. De Soyza, B. Deakin, A. Deans, C. Deas, J. Deery, S. Defres, A. Dell, K. Dempsey, E. Denneny, J. Dennis, A. Dewar, R. Dharmagunawardena, N. Diar-Bakerly, C. Dickens, A. Dipper, S. Diver, S.N. Diwanji, M. Dixon, R. Djukanovic, H. Dobson, S.L. Dobson, A.B. Docherty, A. Donaldson, T. Dong, N. Dormand, A. Dougherty, R. Dowling, S. Drain, K. Draxlbauer, K. Drury, H.J.C. Drury, P. Dulawan, A. Dunleavy, S. Dunn, C. Dupont, J. Earley, N. Easom, C. Echevarria, S. Edwards, C. Edwardson, H. El-Taweel, A. Elliott, K. Elliott, Y. Ellis, A. Elmer, O. Elneima, D. Evans, H. Evans, J. Evans, R. Evans, R.A. Evans, R.I. Evans, T. Evans, C. Evenden, L. Evison, L. Fabbri, S. Fairbairn, A. Fairman, K. Fallon, D. Faluyi, C. Favager, T. Fayzan, J. Featherstone, T. Felton, J. Finch, S. Finney, J. Finnigan, L. Finnigan, H. Fisher, S. Fletcher, R. Flockton, M. Flynn, H. Foot, D. Foote, A. Ford, D. Forton, E. Fraile, C. Francis, R. Francis, S. Francis, A. Frankel, E. Fraser, R. Free, N. French, X. Fu, J. Fuld, J. Furniss, L. Garner, N. Gautam, J.R. Geddes, J. George, P. George, M. Gibbons, M. Gill, L. Gilmour, F. Gleeson, J. Glossop, S. Glover, N. Goodman, C. Goodwin, B. Gooptu, H. Gordon, T. Gorsuch, M. Greatorex, P.L. Greenhaff, W. Greenhalf, A. Greenhalgh, N.J. Greening, J. Greenwood, H. Gregory, R. Gregory, D. Grieve, D. Griffin, L. Griffiths, A.-M. Guerdette, B. Guillen Guio, M. Gummadi, A. Gupta, S. Gurram, E. Guthrie, Z. Guy, H.H. Henson, K. Hadley, A. Haggar, K. Hainey, B. Hairsine, P. Haldar, I. Hall, L. Hall, M. Halling-Brown, R. Hamil, A. Hancock, K. Hancock, N.A. Hanley, S. Haq, H.E. Hardwick, E. Hardy, T. Hardy, B. Hargadon, K. Harrington, E. Harris, V.C. Harris, E.M. Harrison, P. Harrison, N. Hart, A. Harvey, M. Harvey, M. Harvie, L. Haslam, M. Havinden-Williams, J. Hawkes, N. Hawkings, J. Haworth, A. Hayday, M. Haynes, J. Hazeldine, T. Hazelton, L.G. Heaney, C. Heeley, J.L. Heeney, M. Heightman, S. Heller, M. Henderson, L. Hesselden, M. Hewitt, V. Highett, T. Hillman, T. Hiwot, L.P. Ho, A. Hoare, M. Hoare, J. Hockridge, P. Hogarth, A. Holbourn, S. Holden, L. Holdsworth, D. Holgate, M. Holland, L. Holloway, K. Holmes, M. Holmes, B. Holroyd-Hind, L. Holt, A. Hormis, A. Horsley, A. Hosseini, M. Hotopf, L. Houchen-Wolloff, K. Howard, L.S. Howard, A. Howell, E. Hufton, A.D. Hughes, J. Hughes, R. Hughes, A. Humphries, N. Huneke, E. Hurditch, J. Hurst, M. Husain, T. Hussell, J. Hutchinson, W. Ibrahim, F. Ilyas, J. Ingham, L. Ingram, D. Ionita, K. Isaacs, K. Ismail, T. Jackson, J. Jacob, W.Y. James, W. Jang, C. Jarman, I. Jarrold, H. Jarvis, R. Jastrub, B. Jayaraman, R.G. Jenkins, P. Jezzard, K. Jiwa, C. Johnson, S. Johnson, D. Johnston, C.J. Jolley, D. Jones, G. Jones, H. Jones, I. Jones, L. Jones, M.G. Jones, S. Jones, S. Jose, T. Kabir, G. Kaltsakas, V. Kamwa, N. Kanellakis, S. Kaprowska, Z. Kausar, N. Keenan, S. Kelly, G. Kemp, S. Kerr, H. Kerslake, A.L. Key, F. Khan, K. Khunti, S. Kilroy, B. King, C. King, L. Kingham, J. Kirk, P. Kitterick, P. Klenerman, L. Knibbs, S. Knight, A. Knighton, O. Kon, S. Kon, S.S. Kon, S. Koprowska, A. Korszun, I. Koychev, C. Kurasz, P. Kurupati, C. Laing, H. Lamlum, G. Landers, C. Langenberg, D. Lasserson, L. Lavelle-Langham, A. Lawrie, C. Lawson, A. Layton, A. Lea, O.C. Leavy, D. Lee, J.-H. Lee, E. Lee, K. Leitch, R. Lenagh, D. Lewis, J. Lewis, K.E. Lewis, V. Lewis, N. Lewis-Burke, X. Li, T. Light, L. Lightstone, W. Lilaonitkul, L. Lim, S. Linford, A. Lingford-Hughes, M. Lipman, K. Liyanage, A. Lloyd, S. Logan, D. Lomas, N.I. Lone, R. Loosley, J.M. Lord, H. Lota, W. Lovegrove, A. Lucey, E. Lukaschuk, A. Lye, C. Lynch, S. MacDonald, G. MacGowan, I. Macharia, J. Mackie, L. Macliver, S. Madathil, G. Madzamba, N. Magee, M.M. Magtoto, N. Mairs, N. Majeed, E. Major, F. Malein, M. Malim, G. Mallison, W. D-C Man, S. Mandal, K. Mangion, C. Manisty, R. Manley, K. March, S. Marciniak, P. Marino, M. Mariveles, M. Marks, E. Marouzet, S. Marsh, B. Marshall, M. Marshall, J. Martin, A. Martineau, L.M. Martinez, N. Maskell, D. Matila, W. Matimba-Mupaya, L. Matthews, A. Mbuyisa, S. McAdoo, H. McAllister-Williams, A. McArdle, P. McArdle, D. McAulay, G.P. McCann, J. McCormick, W. McCormick, P. McCourt, L. McGarvey, C. McGee, K. Mcgee, J. McGinness, K. McGlynn, A. McGovern, H. McGuinness, I.B. McInnes, J. McIntosh, E. McIvor, K. McIvor, L. McLeavey, A. McMahon, M.J. McMahon, L. McMorrow, T. Mcnally, M. McNarry, J. McNeill, A. McQueen, H. McShane, C. Mears, C. Megson, S. Megson, P. Mehta, J. Meiring, L. Melling, M. Mencias, D. Menzies, M. Merida Morillas, A. Michael, C. Miller, L. Milligan, C. Mills, G. Mills, N.L. Mills, L. Milner, S. Misra, J. Mitchell, A. Mohamed, N. Mohamed, S. Mohammed, P.L. Molyneaux, W. Monteiro, S. Moriera, A. Morley, L. Morrison, R. Morriss, A. Morrow, A.J. Moss, P. Moss, K. Motohashi, N. Msimanga, E. Mukaetova-Ladinska, U. Munawar, J. Murira, U. Nanda, H. Nassa, M. Nasseri, A. Neal, R. Needham, P. Neill, S. Neubauer, D.E. Newby, H. Newell, T. Newman, J. Newman, A. Newton-Cox, T. Nicholson, D. Nicoll, A. Nikolaidis, C.M. Nolan, M.J. Noonan, C. Norman, P. Novotny, J. Nunag, L. Nwafor, U. Nwanguma, J. Nyaboko, C. O'Brien, K. O'Donnell, D. O'Regan, L. O’Brien, N. Odell, G. Ogg, O. Olaosebikan, C. Oliver, Z. Omar, P.J.M. Openshaw, L. Orriss-Dib, L. Osborne, R. Osbourne, M. Ostermann, C. Overton, J. Owen, J. Oxton, J. Pack, E. Pacpaco, S. Paddick, S. Painter, A. Pakzad, S. Palmer, P. Papineni, K. Paques, K. Paradowski, M. Pareek, D. Parekh, H. Parfrey, C. Pariante, S. Parker, M. Parkes, J. Parmar, S. Patale, B. Patel, M. Patel, S. Patel, D. Pattenadk, M. Pavlides, S. Payne, L. Pearce, J.E. Pearl, D. Peckham, J. Pendlebury, Y. Peng, C. Pennington, I. Peralta, E. Perkins, Z. Peterkin, T. Peto, N. Petousi, J. Petrie, P. Pfeffer, J. Phipps, J. Pimm, K. Piper Hanley, R. Pius, H. Plant, S. Plein, T. Plekhanova, M. Plowright, K. Poinasamy, O. Polgar, L. Poll, J.C. Porter, J. Porter, S. Portukhay, N. Powell, A. Prabhu, J. Pratt, A. Price, C. Price, D. Price, L. Price, A. Prickett, J. Propescu, S. Prosper, S. Pugmire, S. Quaid, J. Quigley, J. Quint, H. Qureshi, I.N. Qureshi, K. Radhakrishnan, N.M. Rahman, M. Ralser, B. Raman, A. Ramos, H. Ramos, J. Rangeley, B. Rangelov, L. Ratcliffe, P. Ravencroft, A. Reddington, R. Reddy, A. Reddy, H. Redfearn, D. Redwood, A. Reed, M. Rees, T. Rees, K. Regan, W. Reynolds, C. Ribeiro, A. Richards, E. Richardson, M. Richardson, P. Rivera-Ortega, K. Roberts, E. Robertson, E. Robinson, L. Robinson, L. Roche, C. Roddis, J. Rodger, A. Ross, G. Ross, J. Rossdale, A. Rostron, A. Rowe, A. Rowland, J. Rowland, M.J. Rowland, S.L. Rowland-Jones, K. Roy, M. Roy, I. Rudan, R. Russell, E. Russell, G. Saalmink, R. Sabit, E.K. Sage, T. Samakomva, N. Samani, C. Sampson, K. Samuel, R. Samuel, A. Sanderson, E. Sapey, D. Saralaya, J. Sargant, C. Sarginson, T. Sass, N. Sattar, K. Saunders, R.M. Saunders, P. Saunders, L.C. Saunders, H. Savill, W. Saxon, A. Sayer, J. Schronce, W. Schwaeble, J.T. Scott, K. Scott, N. Selby, M.G. Semple, M. Sereno, T.A. Sewell, A. Shah, K. Shah, P. Shah, M. Shankar-Hari, M. Sharma, C. Sharpe, M. Sharpe, S. Shashaa, A. Shaw, K. Shaw, V. Shaw, A. Sheikh, S. Shelton, L. Shenton, K. Shevket, A. Shikotra, J. Short, S. Siddique, S. Siddiqui, J. Sidebottom, L. Sigfrid, G. Simons, J. Simpson, N. Simpson, A. Singapuri, C. Singh, S. Singh, S.J. Singh, D. Sissons, J. Skeemer, K. Slack, A. Smith, D. Smith, S. Smith, J. Smith, L. Smith, M. Soares, T.S. Solano, R. Solly, A.R. Solstice, T. Soulsby, D. Southern, D. Sowter, M. Spears, L.G. Spencer, F. Speranza, L. Stadon, S. Stanel, N. Steele, M. Steiner, D. Stensel, G. Stephens, L. Stephenson, M. Stern, I. Stewart, R. Stimpson, S. Stockdale, J. Stockley, W. Stoker, R. Stone, W. Storrar, A. Storrie, K. Storton, E. Stringer, S. Strong-Sheldrake, N. Stroud, C. Subbe, C.L. Sudlow, Z. Suleiman, C. Summers, C. Summersgill, D. Sutherland, D.L. Sykes, R. Sykes, N. Talbot, A.L. Tan, L. Tarusan, V. Tavoukjian, A. Taylor, C. Taylor, J. Taylor, A. Te, H. Tedd, C.J. Tee, J. Teixeira, H. Tench, S. Terry, S. Thackray-Nocera, F. Thaivalappil, B. Thamu, D. Thickett, C. Thomas, D.C. Thomas, S. Thomas, A.K. Thomas, T. Thomas-Woods, T. Thompson, A.A.R. Thompson, T. Thornton, M. Thorpe, R.S. Thwaites, J. Tilley, N. Tinker, G.F. Tiongson, M. Tobin, J. Tomlinson, C. Tong, M. Toshner, R. Touyz, K.A. Tripp, E. Tunnicliffe, A. Turnbull, E. Turner, S. Turner, V. Turner, K. Turner, S. Turney, L. Turtle, H. Turton, J. Ugoji, R. Ugwuoke, R. Upthegrove, J. Valabhji, M. Ventura, J. Vere, C. Vickers, B. Vinson, E. Wade, P. Wade, L.V. Wain, T. Wainwright, L.O. Wajero, S. Walder, S. Walker, E. Wall, T. Wallis, S. Walmsley, J.A. Walsh, S. Walsh, L. Warburton, T.J.C. Ward, K. Warwick, H. Wassall, S. Waterson, E. Watson, L. Watson, J. Watson, J. Weir McCall, C. Welch, H. Welch, B. Welsh, S. Wessely, S. West, H. Weston, H. Wheeler, S. White, V. Whitehead, J. Whitney, S. Whittaker, B. Whittam, V. Whitworth, A. Wight, J. Wild, M. Wilkins, D. Wilkinson, B. Williams, N. Williams, J. Williams, S.A. Williams-Howard, M. Willicombe, G. Willis, J. Willoughby, A. Wilson, D. Wilson, I. Wilson, N. Window, M. Witham, R. Wolf-Roberts, C. Wood, F. Woodhead, J. Woods, D.G. Wootton, J. Wormleighton, J. Worsley, D. Wraith, C. Wrey Brown, C. Wright, L. Wright, S. Wright, J. Wyles, I. Wynter, M. Xu, N. Yasmin, S. Yasmin, T. Yates, K.P. Yip, B. Young, S. Young, A. Young, A.J. Yousuf, A. Zawia, L. Zeidan, B. Zhao, B. Zheng, and O. Zongo
Subjects: COVID-19, Physical frailty, Long-COVID, Fried's frailty phenotype, Hospitalisation, Medicine (General), R5-920
Abstract: Summary: Background: The scale of COVID-19 and its well documented long-term sequelae support a need to understand long-term outcomes including frailty. Methods: This prospective cohort study recruited adults who had survived hospitalisation with clinically diagnosed COVID-19 across 35 sites in the UK (PHOSP-COVID). The burden of frailty was objectively measured using Fried's Frailty Phenotype (FFP). The primary outcome was the prevalence of each FFP group—robust (no FFP criteria), pre-frail (one or two FFP criteria) and frail (three or more FFP criteria)—at 5 months and 1 year after discharge from hospital. For inclusion in the primary analysis, participants required complete outcome data for three of the five FFP criteria. Longitudinal changes across frailty domains are reported at 5 months and 1 year post-hospitalisation, along with risk factors for frailty status. Patient-perceived recovery and health-related quality of life (HRQoL) were retrospectively rated for pre-COVID-19 and prospectively rated at the 5 month and 1 year visits. This study is registered with ISRCTN, number ISRCTN10980107. Findings: Between March 5, 2020, and March 31, 2021, 2419 participants were enrolled with FFP data. Mean age was 57.9 (SD 12.6) years, 933 (38.6%) were female, and 429 (17.7%) had received invasive mechanical ventilation. 1785 had measures at both timepoints, of which 240 (13.4%), 1138 (63.8%) and 407 (22.8%) were frail, pre-frail and robust, respectively, at 5 months compared with 123 (6.9%), 1046 (58.6%) and 616 (34.5%) at 1 year. Factors associated with pre-frailty or frailty were invasive mechanical ventilation, older age, female sex, and greater social deprivation. Frail participants had a larger reduction in HRQoL compared with before their COVID-19 illness and were less likely to describe themselves as recovered. Interpretation: Physical frailty and pre-frailty are common following hospitalisation with COVID-19. Improvement in frailty was seen between 5 and 12 months although two-thirds of the population remained pre-frail or frail. This suggests comprehensive assessment and interventions targeting pre-frailty and frailty beyond the initial illness are required. Funding: UK Research and Innovation and National Institute for Health Research.
Published: 2023
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14. Exome-wide analysis of copy number variation shows association of the human leukocyte antigen region with asthma in UK Biobank

Author: Katherine A. Fawcett, German Demidov, Nick Shrine, Megan L. Paynton, Stephan Ossowski, Ian Sayers, Louise V. Wain, and Edward J. Hollox
Subjects: Copy number variants, Exome sequencing, UK Biobank, Asthma, Genetic association, Fine-mapping, Internal medicine, RC31-1245, Genetics, QH426-470
Abstract: Abstract Background The role of copy number variants (CNVs) in susceptibility to asthma is not well understood. This is, in part, due to the difficulty of accurately measuring CNVs in large enough sample sizes to detect associations. The recent availability of whole-exome sequencing (WES) in large biobank studies provides an unprecedented opportunity to study the role of CNVs in asthma. Methods We called common CNVs in 49,953 individuals in the first release of UK Biobank WES using ClinCNV software. CNVs were tested for association with asthma in a stage 1 analysis comprising 7098 asthma cases and 36,578 controls from the first release of sequencing data. Nominally-associated CNVs were then meta-analysed in stage 2 with an additional 17,280 asthma cases and 115,562 controls from the second release of UK Biobank exome sequencing, followed by validation and fine-mapping. Results Five of 189 CNVs were associated with asthma in stage 2, including a deletion overlapping the HLA-DQA1 and HLA-DQB1 genes, a duplication of CHROMR/PRKRA, deletions within MUC22 and TAP2, and a duplication in FBRSL1. The HLA-DQA1, HLA-DQB1, MUC22 and TAP2 genes all reside within the human leukocyte antigen (HLA) region on chromosome 6. In silico analyses demonstrated that the deletion overlapping HLA-DQA1 and HLA-DQB1 is likely to be an artefact arising from under-mapping of reads from non-reference HLA haplotypes, and that the CHROMR/PRKRA and FBRSL1 duplications represent presence/absence of pseudogenes within the HLA region. Bayesian fine-mapping of the HLA region suggested that there are two independent asthma association signals. The variants with the largest posterior inclusion probability in the two credible sets were an amino acid change in HLA-DQB1 (glutamine to histidine at residue 253) and a multi-allelic amino acid change in HLA-DRB1 (presence/absence of serine, glycine or leucine at residue 11). Conclusions At least two independent loci characterised by amino acid changes in the HLA-DQA1, HLA-DQB1 and HLA-DRB1 genes are likely to account for association of SNPs and CNVs in this region with asthma. The high divergence of haplotypes in the HLA can give rise to spurious CNVs, providing an important, cautionary tale for future large-scale analyses of sequencing data.
Published: 2022
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15. Characteristics and risk factors for post-COVID-19 breathlessness after hospitalisation for COVID-19

Author: Luke Daines, Bang Zheng, Omer Elneima, Ewen Harrison, Nazir I. Lone, John R. Hurst, Jeremy S. Brown, Elizabeth Sapey, James D. Chalmers, Jennifer K. Quint, Paul Pfeffer, Salman Siddiqui, Samantha Walker, Krisnah Poinasamy, Hamish McAuley, Marco Sereno, Aarti Shikotra, Amisha Singapuri, Annemarie B. Docherty, Michael Marks, Mark Toshner, Luke S. Howard, Alex Horsley, Gisli Jenkins, Joanna C. Porter, Ling-Pei Ho, Betty Raman, Louise V. Wain, Christopher E. Brightling, Rachael A. Evans, Liam G. Heaney, Anthony De Soyza, and Aziz Sheikh
Subjects: Medicine
Abstract: Background Persistence of respiratory symptoms, particularly breathlessness, after acute coronavirus disease 2019 (COVID-19) infection has emerged as a significant clinical problem. We aimed to characterise and identify risk factors for patients with persistent breathlessness following COVID-19 hospitalisation. Methods PHOSP-COVID is a multicentre prospective cohort study of UK adults hospitalised for COVID-19. Clinical data were collected during hospitalisation and at a follow-up visit. Breathlessness was measured by a numeric rating scale of 0–10. We defined post-COVID-19 breathlessness as an increase in score of ≥1 compared to the pre-COVID-19 level. Multivariable logistic regression was used to identify risk factors and to develop a prediction model for post-COVID-19 breathlessness. Results We included 1226 participants (37% female, median age 59 years, 22% mechanically ventilated). At a median 5 months after discharge, 50% reported post-COVID-19 breathlessness. Risk factors for post-COVID-19 breathlessness were socioeconomic deprivation (adjusted OR 1.67, 95% CI 1.14–2.44), pre-existing depression/anxiety (adjusted OR 1.58, 95% CI 1.06–2.35), female sex (adjusted OR 1.56, 95% CI 1.21–2.00) and admission duration (adjusted OR 1.01, 95% CI 1.00–1.02). Black ethnicity (adjusted OR 0.56, 95% CI 0.35–0.89) and older age groups (adjusted OR 0.31, 95% CI 0.14–0.66) were less likely to report post-COVID-19 breathlessness. Post-COVID-19 breathlessness was associated with worse performance on the shuttle walk test and forced vital capacity, but not with obstructive airflow limitation. The prediction model had fair discrimination (concordance statistic 0.66, 95% CI 0.63–0.69) and good calibration (calibration slope 1.00, 95% CI 0.80–1.21). Conclusions Post-COVID-19 breathlessness was commonly reported in this national cohort of patients hospitalised for COVID-19 and is likely to be a multifactorial problem with physical and emotional components.
Published: 2023
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16. Mapping brain endophenotypes associated with idiopathic pulmonary fibrosis genetic riskResearch in context

Author: Ali-Reza Mohammadi-Nejad, Richard J. Allen, Luke M. Kraven, Olivia C. Leavy, R. Gisli Jenkins, Louise V. Wain, Dorothee P. Auer, and Stamatios N. Sotiropoulos
Subjects: Idiopathic pulmonary fibrosis (IPF), Magnetic resonance imaging (MRI), Neuroimaging, Genetics, Lungs, Medicine, Medicine (General), R5-920
Abstract: Summary: Background: Idiopathic pulmonary fibrosis (IPF) is a serious disease of the lung parenchyma. It has a known polygenetic risk, with at least seventeen regions of the genome implicated to date. Growing evidence suggests linked multimorbidity of IPF with neurodegenerative or affective disorders. However, no study so far has explicitly explored links between IPF, associated genetic risk profiles, and specific brain features. Methods: We exploited imaging and genetic data from more than 32,000 participants available through the UK Biobank population-level resource to explore links between IPF genetic risk and imaging-derived brain endophenotypes. We performed a brain-wide imaging-genetics association study between the presence of 17 known IPF risk variants and 1248 multi-modal imaging-derived features, which characterise brain structure and function. Findings: We identified strong associations between cortical morphological features, white matter microstructure and IPF risk loci in chromosomes 17 (17q21.31) and 8 (DEPTOR). Through co-localisation analysis, we confirmed that cortical thickness in the anterior cingulate and more widespread white matter microstructure changes share a single causal variant with IPF at the chromosome 8 locus. Post-hoc preliminary analysis suggested that forced vital capacity may partially mediate the association between the DEPTOR variant and white matter microstructure, but not between the DEPTOR risk variant and cortical thickness. Interpretation: Our results reveal the associations between IPF genetic risk and differences in brain structure, for both cortex and white matter. Differences in tissue-specific imaging signatures suggest distinct underlying mechanisms with focal cortical thinning in regions with known high DEPTOR expression, unrelated to lung function, and more widespread microstructural white matter changes consistent with hypoxia or neuroinflammation with potential mediation by lung function. Funding: This study was supported by the NIHR Nottingham Biomedical Research Centre and the UK Medical Research Council.
Published: 2022
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17. Prevalence, risk factors and treatments for post-COVID-19 breathlessness: a systematic review and meta-analysis

Author: Bang Zheng, Luke Daines, Qing Han, John R. Hurst, Paul Pfeffer, Manu Shankar-Hari, Omer Elneima, Samantha Walker, Jeremy S. Brown, Salman Siddiqui, Jennifer K. Quint, Christopher E. Brightling, Rachael A. Evans, Louise V. Wain, Liam G. Heaney, and Aziz Sheikh
Subjects: Diseases of the respiratory system, RC705-779
Abstract: Persistent breathlessness >28 days after acute COVID-19 infection has been identified as a highly debilitating post-COVID symptom. However, the prevalence, risk factors, mechanisms and treatments for post-COVID breathlessness remain poorly understood. We systematically searched PubMed and Embase for relevant studies published from 1 January 2020 to 1 November 2021 (PROSPERO registration number: CRD42021285733) and included 119 eligible papers. Random-effects meta-analysis of 42 872 patients with COVID-19 reported in 102 papers found an overall prevalence of post-COVID breathlessness of 26% (95% CI 23–29) when measuring the presence/absence of the symptom, and 41% (95% CI 34–48) when using Medical Research Council (MRC)/modified MRC dyspnoea scale. The pooled prevalence decreased significantly from 1–6 months to 7–12 months post-infection. Post-COVID breathlessness was more common in those with severe/critical acute infection, those who were hospitalised and females, and was less likely to be reported by patients in Asia than those in Europe or North America. Multiple pathophysiological mechanisms have been proposed (including deconditioning, restrictive/obstructive airflow limitation, systemic inflammation, impaired mental health), but the body of evidence remains inconclusive. Seven cohort studies and one randomised controlled trial suggested rehabilitation exercises may reduce post-COVID breathlessness. There is an urgent need for mechanistic research and development of interventions for the prevention and treatment of post-COVID breathlessness.
Published: 2022
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18. Genetic correlation and causal relationships between cardio-metabolic traits and lung function impairment

Author: Matthias Wielscher, Andre F. S. Amaral, Diana van der Plaat, Louise V. Wain, Sylvain Sebert, David Mosen-Ansorena, Juha Auvinen, Karl-Heinz Herzig, Abbas Dehghan, Debbie L. Jarvis, and Marjo-Riitta Jarvelin
Subjects: Mendelian randomisation, Metabolic syndrome, Obesity, Chronic obstructive pulmonary disease, UK Biobank, Medicine, Genetics, QH426-470
Abstract: Abstract Background Associations of low lung function with features of poor cardio-metabolic health have been reported. It is, however, unclear whether these co-morbidities reflect causal associations, shared genetic heritability or are confounded by environmental factors. Methods We performed three analyses: (1) cardio-metabolic health to lung function association tests in Northern Finland Birth cohort 1966, (2) cross-trait linkage disequilibrium score regression (LDSC) to compare genetic backgrounds and (3) Mendelian randomisation (MR) analysis to assess the causal effect of cardio-metabolic traits and disease on lung function, and vice versa (bidirectional MR). Genetic associations were obtained from the UK Biobank data or published large-scale genome-wide association studies (N > 82,000). Results We observed a negative genetic correlation between lung function and cardio-metabolic traits and diseases. In Mendelian Randomisation analysis (MR), we found associations between type 2 diabetes (T2D) instruments and forced vital capacity (FVC) as well as FEV1/FVC. Body mass index (BMI) instruments were associated to all lung function traits and C-reactive protein (CRP) instruments to FVC. These genetic associations provide evidence for a causal effect of cardio-metabolic traits on lung function. Multivariable MR suggested independence of these causal effects from other tested cardio-metabolic traits and diseases. Analysis of lung function specific SNPs revealed a potential causal effect of FEV1/FVC on blood pressure. Conclusions The present study overcomes many limitations of observational studies by using Mendelian Randomisation. We provide evidence for an independent causal effect of T2D, CRP and BMI on lung function with some of the T2D effect on lung function being attributed to inflammatory mechanisms. Furthermore, this analysis suggests a potential causal effect of FEV1/FVC on blood pressure. Our detailed analysis of the interplay between cardio-metabolic traits and impaired lung function provides the opportunity to improve the quality of existing intervention strategies.
Published: 2021
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19. Correction: The effect of COVID rehabilitation for ongoing symptoms Post HOSPitalisation with COVID-19 (PHOSP-R): protocol for a randomised parallel group controlled trial on behalf of the PHOSP consortium

Author: Enya Daynes, Molly Baldwin, Neil J. Greening, Thomas Yates, Nicolette C. Bishop, George Mills, Matthew Roberts, Malik Hamrouni, Tatiana Plekhanova, Ioannis Vogiatzis, Carlos Echevarria, Rashmita Nathu, Hamish J. C. McAuley, Lorna Latimer, Jennifer Glennie, Francesca Chambers, Ruth Penfold, Emily Hume, Dimitrios Megaritis, Charikleia Alexiou, Sebastian Potthof, Mitchell James Hogg, Catherine Haighton, Bethany Nichol, Olivia C. Leavy, Matthew Richardson, Omer Elneima, Amisha Singapuri, Marco Sereno, Ruth M. Saunders, Victoria C. Harris, Claire M. Nolan, Charlotte Bolton, Linzy Houchen-Wolloff, Ewen M. Harrison, Nazir Lone, Jennifer Quint, James D. Chalmers, Ling-Pei Ho, Alex Horsley, Michael Marks, Krisnah Poinasamy, Betty Ramen, Louise V. Wain, Christopher Brightling, William D.-C. Man, Rachael Evans, and Sally J. Singh
Subjects: Medicine (General), R5-920
Published: 2023
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20. Identification of a missense variant in SPDL1 associated with idiopathic pulmonary fibrosis

Author: Ryan S. Dhindsa, Johan Mattsson, Abhishek Nag, Quanli Wang, Louise V. Wain, Richard Allen, Eleanor M. Wigmore, Kristina Ibanez, Dimitrios Vitsios, Sri V. V. Deevi, Sebastian Wasilewski, Maria Karlsson, Glenda Lassi, Henric Olsson, Daniel Muthas, Susan Monkley, Alex Mackay, Lynne Murray, Simon Young, Carolina Haefliger, FinnGen Consortium, Toby M. Maher, Maria G. Belvisi, Gisli Jenkins, Philip L. Molyneaux, Adam Platt, and Slavé Petrovski
Subjects: Biology (General), QH301-705.5
Abstract: Ryan Dhindsa et al. conducted an exome-wide association study to identify a rare variant in SPDL1 as a risk factor for idiopathic pulmonary fibrosis (IPF). Their findings implicate mitotic checkpoint signalling as a new mechanism underlying IPF.
Published: 2021
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21. Whole genome sequence analysis of pulmonary function and COPD in 19,996 multi-ethnic participants

Author: Xutong Zhao, Dandi Qiao, Chaojie Yang, Silva Kasela, Wonji Kim, Yanlin Ma, Nick Shrine, Chiara Batini, Tamar Sofer, Sarah A. Gagliano Taliun, Phuwanat Sakornsakolpat, Pallavi P. Balte, Dmitry Prokopenko, Bing Yu, Leslie A. Lange, Josée Dupuis, Brian E. Cade, Jiwon Lee, Sina A. Gharib, Michelle Daya, Cecelia A. Laurie, Ingo Ruczinski, L. Adrienne Cupples, Laura R. Loehr, Traci M. Bartz, Alanna C. Morrison, Bruce M. Psaty, Ramachandran S. Vasan, James G. Wilson, Kent D. Taylor, Peter Durda, W. Craig Johnson, Elaine Cornell, Xiuqing Guo, Yongmei Liu, Russell P. Tracy, Kristin G. Ardlie, François Aguet, David J. VanDenBerg, George J. Papanicolaou, Jerome I. Rotter, Kathleen C. Barnes, Deepti Jain, Deborah A. Nickerson, Donna M. Muzny, Ginger A. Metcalf, Harshavardhan Doddapaneni, Shannon Dugan-Perez, Namrata Gupta, Stacey Gabriel, Stephen S. Rich, George T. O’Connor, Susan Redline, Robert M. Reed, Cathy C. Laurie, Martha L. Daviglus, Liana K. Preudhomme, Kristin M. Burkart, Robert C. Kaplan, Louise V. Wain, Martin D. Tobin, Stephanie J. London, Tuuli Lappalainen, Elizabeth C. Oelsner, Goncalo R. Abecasis, Edwin K. Silverman, R. Graham Barr, NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, TOPMed Lung Working Group, Michael H. Cho, and Ani Manichaikul
Subjects: Science
Abstract: Chronic obstructive pulmonary disease is a leading cause of morbidity and mortality. Here, the authors analyse whole genome sequence data and find new loci associated with lung function and COPD.
Published: 2020
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22. Genome-wide gene-air pollution interaction analysis of lung function in 300,000 individuals

Author: Carl A. Melbourne, A. Mesut Erzurumluoglu, Nick Shrine, Jing Chen, Martin D. Tobin, Anna L. Hansell, and Louise V. Wain
Subjects: Gene-air pollution interactions, Air pollution, Genome-wide, Lung function, Chronic Obstructive Pulmonary Disease, UK Biobank, Environmental sciences, GE1-350
Abstract: Background: Impaired lung function is predictive of mortality and is a key component of chronic obstructive pulmonary disease. Lung function has a strong genetic component but is also affected by environmental factors such as increased exposure to air pollution, but the effect of their interactions is not well understood. Objectives: To identify interactions between genetic variants and air pollution measures which affect COPD risk and lung function. Additionally, to determine whether previously identified lung function genetic association signals showed evidence of interaction with air pollution, considering both individual effects and combined effects using a genetic risk score (GRS). Methods: We conducted a genome-wide gene-air pollution interaction analysis of spirometry measures with three measures of air pollution at home address: particulate matter (PM2.5 & PM10) and nitrogen dioxide (NO2), in approximately 300,000 unrelated European individuals from UK Biobank. We explored air pollution interactions with previously identified lung function signals and determined their combined interaction effect using a GRS. Results: We identified seven new genome-wide interaction signals (P
Published: 2022
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23. Adjustment for index event bias in genome-wide association studies of subsequent events

Author: Frank Dudbridge, Richard J. Allen, Nuala A. Sheehan, A. Floriaan Schmidt, James C. Lee, R. Gisli Jenkins, Louise V. Wain, Aroon D. Hingorani, and Riyaz S. Patel
Subjects: Science
Abstract: Different from GWAS for susceptibility to disease, GWAS for prognosis or survival may be vulnerable to selection bias. Here, Dudbridge et al present an approach to reduce index event bias in simulated and realistic situations, and apply it to GWAS of survival with idiopathic pulmonary fibrosis and Crohn’s disease prognosis.
Published: 2019
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24. Variants associated with HHIP expression have sex-differential effects on lung function [version 2; peer review: 2 approved]

Author: Katherine A. Fawcett, Ma'en Obeidat, Carl Melbourne, Nick Shrine, Anna L. Guyatt, Catherine John, Jian'an Luan, Anne Richmond, Marta R. Moksnes, Raquel Granell, Stefan Weiss, Medea Imboden, Sebastian May-Wilson, Pirro Hysi, Thibaud S. Boutin, Laura Portas, Claudia Flexeder, Sarah E. Harris, Carol A. Wang, Leo-Pekka Lyytikäinen, Teemu Palviainen, Rachel E. Foong, Dirk Keidel, Cosetta Minelli, Claudia Langenberg, Yohan Bossé, Maarten Van den Berge, Don D. Sin, Ke Hao, Archie Campbell, David Porteous, Sandosh Padmanabhan, Blair H. Smith, David M. Evans, Sue Ring, Arnulf Langhammer, Kristian Hveem, Cristen Willer, Ralf Ewert, Beate Stubbe, Nicola Pirastu, Lucija Klaric, Peter K. Joshi, Karina Patasova, Mangino Massimo, Ozren Polasek, John M. Starr, Stefan Karrasch, Konstantin Strauch, Thomas Meitinger, Igor Rudan, Taina Rantanen, Kirsi Pietiläinen, Mika Kähönen, Olli T. Raitakari, Graham L. Hall, Peter D. Sly, Craig E. Pennell, Jaakko Kaprio, Terho Lehtimäki, Veronique Vitart, Ian J. Deary, Debbie Jarvis, James F. Wilson, Tim Spector, Nicole Probst-Hensch, Nicholas J. Wareham, Henry Völzke, John Henderson, David P. Strachan, Ben M. Brumpton, Caroline Hayward, Ian P. Hall, Martin D. Tobin, and Louise V. Wain
Subjects: Medicine, Science
Abstract: Background: Lung function is highly heritable and differs between the sexes throughout life. However, little is known about sex-differential genetic effects on lung function. We aimed to conduct the first genome-wide genotype-by-sex interaction study on lung function to identify genetic effects that differ between males and females. Methods: We tested for interactions between 7,745,864 variants and sex on spirometry-based measures of lung function in UK Biobank (N=303,612), and sought replication in 75,696 independent individuals from the SpiroMeta consortium. Results: Five independent single-nucleotide polymorphisms (SNPs) showed genome-wide significant (P
Published: 2021
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25. Pleiotropic associations of heterozygosity for the SERPINA1 Z allele in the UK Biobank

Author: Katherine A. Fawcett, Kijoung Song, Guoqing Qian, Aliki-Eleni Farmaki, Richard Packer, Catherine John, Nick Shrine, Raquel Granell, Sue Ring, Nicholas J. Timpson, Laura M. Yerges-Armstrong, Richard Eastell, Louise V. Wain, Robert A. Scott, Martin D. Tobin, and Ian P. Hall
Subjects: Medicine
Abstract: Homozygosity for the SERPINA1 Z allele causes α1-antitrypsin deficiency, a rare condition that can cause lung and liver disease. However, the effects of Z allele heterozygosity on nonrespiratory phenotypes, and on lung function in the general population, remain unclear. We conducted a large, population-based study to determine Z allele effects on >2400 phenotypes in the UK Biobank (N=303 353). Z allele heterozygosity was strongly associated with increased height (β=1.02 cm, p=3.91×10−68), and with other nonrespiratory phenotypes including increased risk of gall bladder disease, reduced risk of heart disease and lower blood pressure, reduced risk of osteoarthritis and reduced bone mineral density, increased risk of headache and enlarged prostate, as well as with blood biomarkers of liver function. Heterozygosity was associated with higher height-adjusted forced expiratory volume in 1 s (FEV1) (β=19.36 mL, p=9.21×10−4) and FEV1/forced vital capacity (β=0.0031, p=1.22×10−5) in nonsmokers, whereas in smokers, this protective effect was abolished. Furthermore, we show for the first time that sex modifies the association of the Z allele on lung function. We conclude that Z allele heterozygosity and homozygosity exhibit opposing effects on lung function in the UK population, and that these associations are modified by smoking and sex. In exploratory analyses, heterozygosity for the Z allele also showed pleiotropic associations with nonrespiratory health-related traits and disease risk.
Published: 2021
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26. Shared genetic etiology between idiopathic pulmonary fibrosis and COVID-19 severity

Author: João Fadista, Luke M. Kraven, Juha Karjalainen, Shea J. Andrews, Frank Geller, J Kenneth Baillie, Louise V. Wain, R.Gisli Jenkins, and Bjarke Feenstra
Subjects: Mendelian randomization, Covid-19, Idiopathic pulmonary fibrosis, MUC5B, Mucin, Medicine, Medicine (General), R5-920
Abstract: Background: Idiopathic pulmonary fibrosis (IPF) is a complex lung disease, characterized by progressive lung scarring. Severe COVID-19 is associated with substantial pneumonitis and has a number of shared major risk factors with IPF. This study aimed to determine the genetic correlation between IPF and severe COVID-19 and assess a potential causal role of genetically increased risk of IPF on COVID-19 severity. Methods: The genetic correlation between IPF and COVID-19 severity was estimated with linkage disequilibrium (LD) score regression. We performed a Mendelian randomization (MR) study for IPF causality in COVID-19. Genetic variants associated with IPF susceptibility (P
Published: 2021
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27. Variants associated with HHIP expression have sex-differential effects on lung function [version 1; peer review: 2 approved]

Author: Katherine A. Fawcett, Ma'en Obeidat, Carl Melbourne, Nick Shrine, Anna L. Guyatt, Catherine John, Jian'an Luan, Anne Richmond, Marta R. Moksnes, Raquel Granell, Stefan Weiss, Medea Imboden, Sebastian May-Wilson, Pirro Hysi, Thibaud S. Boutin, Laura Portas, Claudia Flexeder, Sarah E. Harris, Carol A. Wang, Leo-Pekka Lyytikäinen, Teemu Palviainen, Rachel E. Foong, Dirk Keidel, Cosetta Minelli, Claudia Langenberg, Yohan Bossé, Maarten Van den Berge, Don D. Sin, Ke Hao, Archie Campbell, David Porteous, Sandosh Padmanabhan, Blair H. Smith, David M. Evans, Sue Ring, Arnulf Langhammer, Kristian Hveem, Cristen Willer, Ralf Ewert, Beate Stubbe, Nicola Pirastu, Lucija Klaric, Peter K. Joshi, Karina Patasova, Mangino Massimo, Ozren Polasek, John M. Starr, Stefan Karrasch, Konstantin Strauch, Thomas Meitinger, Igor Rudan, Taina Rantanen, Kirsi Pietiläinen, Mika Kähönen, Olli T. Raitakari, Graham L. Hall, Peter D. Sly, Craig E. Pennell, Jaakko Kaprio, Terho Lehtimäki, Veronique Vitart, Ian J. Deary, Debbie Jarvis, James F. Wilson, Tim Spector, Nicole Probst-Hensch, Nicholas J. Wareham, Henry Völzke, John Henderson, David P. Strachan, Ben M. Brumpton, Caroline Hayward, Ian P. Hall, Martin D. Tobin, and Louise V. Wain
Subjects: Medicine, Science
Abstract: Background: Lung function is highly heritable and differs between the sexes throughout life. However, little is known about sex-differential genetic effects on lung function. We aimed to conduct the first genome-wide genotype-by-sex interaction study on lung function to identify genetic effects that differ between males and females. Methods: We tested for interactions between 7,745,864 variants and sex on spirometry-based measures of lung function in UK Biobank (N=303,612), and sought replication in 75,696 independent individuals from the SpiroMeta consortium. Results: Five independent single-nucleotide polymorphisms (SNPs) showed genome-wide significant (P
Published: 2020
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28. Identification of susceptibility pathways for the role of chromosome 15q25.1 in modifying lung cancer risk

Author: Xuemei Ji, Yohan Bossé, Maria Teresa Landi, Jiang Gui, Xiangjun Xiao, David Qian, Philippe Joubert, Maxime Lamontagne, Yafang Li, Ivan Gorlov, Mariella de Biasi, Younghun Han, Olga Gorlova, Rayjean J. Hung, Xifeng Wu, James McKay, Xuchen Zong, Robert Carreras-Torres, David C. Christiani, Neil Caporaso, Mattias Johansson, Geoffrey Liu, Stig E. Bojesen, Loic Le Marchand, Demetrios Albanes, Heike Bickeböller, Melinda C. Aldrich, William S. Bush, Adonina Tardon, Gad Rennert, Chu Chen, M. Dawn Teare, John K. Field, Lambertus A. Kiemeney, Philip Lazarus, Aage Haugen, Stephen Lam, Matthew B. Schabath, Angeline S. Andrew, Hongbing Shen, Yun-Chul Hong, Jian-Min Yuan, Pier A. Bertazzi, Angela C. Pesatori, Yuanqing Ye, Nancy Diao, Li Su, Ruyang Zhang, Yonathan Brhane, Natasha Leighl, Jakob S. Johansen, Anders Mellemgaard, Walid Saliba, Christopher Haiman, Lynne Wilkens, Ana Fernandez-Somoano, Guillermo Fernandez-Tardon, Erik H. F. M. van der Heijden, Jin Hee Kim, Juncheng Dai, Zhibin Hu, Michael P. A. Davies, Michael W. Marcus, Hans Brunnström, Jonas Manjer, Olle Melander, David C. Muller, Kim Overvad, Antonia Trichopoulou, Rosario Tumino, Jennifer Doherty, Gary E. Goodman, Angela Cox, Fiona Taylor, Penella Woll, Irene Brüske, Judith Manz, Thomas Muley, Angela Risch, Albert Rosenberger, Kjell Grankvist, Mikael Johansson, Frances Shepherd, Ming-Sound Tsao, Susanne M. Arnold, Eric B. Haura, Ciprian Bolca, Ivana Holcatova, Vladimir Janout, Milica Kontic, Jolanta Lissowska, Anush Mukeria, Simona Ognjanovic, Tadeusz M. Orlowski, Ghislaine Scelo, Beata Swiatkowska, David Zaridze, Per Bakke, Vidar Skaug, Shanbeh Zienolddiny, Eric J. Duell, Lesley M. Butler, Woon-Puay Koh, Yu-Tang Gao, Richard Houlston, John McLaughlin, Victoria Stevens, David C. Nickle, Ma’en Obeidat, Wim Timens, Bin Zhu, Lei Song, María Soler Artigas, Martin D. Tobin, Louise V. Wain, Fangyi Gu, Jinyoung Byun, Ahsan Kamal, Dakai Zhu, Rachel F. Tyndale, Wei-Qi Wei, Stephen Chanock, Paul Brennan, and Christopher I. Amos
Subjects: Science
Abstract: The chromosome 15q25.1 locus is a leading susceptibility region for lung cancer. Here, the authors interrogate three GWAS cohorts with 42,901 individuals to investigate potential pathological pathways such as gated channel activity and neuroactive ligand receptor interaction in lung cancer etiology.
Published: 2018
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29. Formalising recall by genotype as an efficient approach to detailed phenotyping and causal inference

Author: Laura J. Corbin, Vanessa Y. Tan, David A. Hughes, Kaitlin H. Wade, Dirk S. Paul, Katherine E. Tansey, Frances Butcher, Frank Dudbridge, Joanna M. Howson, Momodou W. Jallow, Catherine John, Nathalie Kingston, Cecilia M. Lindgren, Michael O’Donavan, Stephen O’Rahilly, Michael J. Owen, Colin N. A. Palmer, Ewan R. Pearson, Robert A. Scott, David A. van Heel, John Whittaker, Tim Frayling, Martin D. Tobin, Louise V. Wain, George Davey Smith, David M. Evans, Fredrik Karpe, Mark I. McCarthy, John Danesh, Paul W. Franks, and Nicholas J. Timpson
Subjects: Science
Abstract: Recall-by-Genotype (RbG) is an approach to recall participants from genetic studies based on their specific genotype for further, more extensive phenotyping. Here, the authors discuss examples of RbG as well as practical and ethical considerations and provide an online tool to aid in designing RbG studies.
Published: 2018
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30. CNV-association meta-analysis in 191,161 European adults reveals new loci associated with anthropometric traits

Author: Aurélien Macé, Marcus A. Tuke, Patrick Deelen, Kati Kristiansson, Hannele Mattsson, Margit Nõukas, Yadav Sapkota, Ursula Schick, Eleonora Porcu, Sina Rüeger, Aaron F. McDaid, David Porteous, Thomas W. Winkler, Erika Salvi, Nick Shrine, Xueping Liu, Wei Q. Ang, Weihua Zhang, Mary F. Feitosa, Cristina Venturini, Peter J. van der Most, Anders Rosengren, Andrew R. Wood, Robin N. Beaumont, Samuel E. Jones, Katherine S. Ruth, Hanieh Yaghootkar, Jessica Tyrrell, Aki S. Havulinna, Harmen Boers, Reedik Mägi, Jennifer Kriebel, Martina Müller-Nurasyid, Markus Perola, Markku Nieminen, Marja-Liisa Lokki, Mika Kähönen, Jorma S. Viikari, Frank Geller, Jari Lahti, Aarno Palotie, Päivikki Koponen, Annamari Lundqvist, Harri Rissanen, Erwin P. Bottinger, Saima Afaq, Mary K. Wojczynski, Petra Lenzini, Ilja M. Nolte, Thomas Sparsø, Nicole Schupf, Kaare Christensen, Thomas T. Perls, Anne B. Newman, Thomas Werge, Harold Snieder, Timothy D. Spector, John C. Chambers, Seppo Koskinen, Mads Melbye, Olli T. Raitakari, Terho Lehtimäki, Martin D. Tobin, Louise V. Wain, Juha Sinisalo, Annette Peters, Thomas Meitinger, Nicholas G. Martin, Naomi R. Wray, Grant W. Montgomery, Sarah E. Medland, Morris A. Swertz, Erkki Vartiainen, Katja Borodulin, Satu Männistö, Anna Murray, Murielle Bochud, Sébastien Jacquemont, Fernando Rivadeneira, Thomas F. Hansen, Albertine J. Oldehinkel, Massimo Mangino, Michael A. Province, Panos Deloukas, Jaspal S. Kooner, Rachel M. Freathy, Craig Pennell, Bjarke Feenstra, David P. Strachan, Guillaume Lettre, Joel Hirschhorn, Daniele Cusi, Iris M. Heid, Caroline Hayward, Katrin Männik, Jacques S. Beckmann, Ruth J. F. Loos, Dale R. Nyholt, Andres Metspalu, Johan G. Eriksson, Michael N. Weedon, Veikko Salomaa, Lude Franke, Alexandre Reymond, Timothy M. Frayling, and Zoltán Kutalik
Subjects: Science
Abstract: Individual SNPs have small effects on anthropometric traits, yet the impact of CNVs has remained largely unknown. Here, Kutalik and co-workers perform a large-scale genome-wide meta-analysis of structural variation and find rare CNVs associated with height, weight and BMI with large effect sizes.
Published: 2017
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31. Large-scale GWAS identifies multiple loci for hand grip strength providing biological insights into muscular fitness

Author: Sara M. Willems, Daniel J. Wright, Felix R. Day, Katerina Trajanoska, Peter K. Joshi, John A. Morris, Amy M. Matteini, Fleur C. Garton, Niels Grarup, Nikolay Oskolkov, Anbupalam Thalamuthu, Massimo Mangino, Jun Liu, Ayse Demirkan, Monkol Lek, Liwen Xu, Guan Wang, Christopher Oldmeadow, Kyle J. Gaulton, Luca A. Lotta, Eri Miyamoto-Mikami, Manuel A. Rivas, Tom White, Po-Ru Loh, Mette Aadahl, Najaf Amin, John R. Attia, Krista Austin, Beben Benyamin, Søren Brage, Yu-Ching Cheng, Paweł Cięszczyk, Wim Derave, Karl-Fredrik Eriksson, Nir Eynon, Allan Linneberg, Alejandro Lucia, Myosotis Massidda, Braxton D. Mitchell, Motohiko Miyachi, Haruka Murakami, Sandosh Padmanabhan, Ashutosh Pandey, Ioannis Papadimitriou, Deepak K. Rajpal, Craig Sale, Theresia M. Schnurr, Francesco Sessa, Nick Shrine, Martin D. Tobin, Ian Varley, Louise V. Wain, Naomi R. Wray, Cecilia M. Lindgren, Daniel G. MacArthur, Dawn M. Waterworth, Mark I. McCarthy, Oluf Pedersen, Kay-Tee Khaw, Douglas P. Kiel, GEFOS Any-Type of Fracture Consortium, Yannis Pitsiladis, Noriyuki Fuku, Paul W. Franks, Kathryn N. North, Cornelia M. van Duijn, Karen A. Mather, Torben Hansen, Ola Hansson, Tim Spector, Joanne M. Murabito, J. Brent Richards, Fernando Rivadeneira, Claudia Langenberg, John R. B. Perry, Nick J. Wareham, and Robert A. Scott
Subjects: Science
Abstract: Hand grip strength as a proxy of muscular fitness is a clinical predictor of mortality and morbidity. In a large-scale GWA study, the authors find 16 robustly associated genetic loci that highlight roles in muscle fibre structure and function, neuronal maintenance and nervous system signal transduction.
Published: 2017
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32. Novel idiopathic pulmonary fibrosis susceptibility variants revealed by deep sequencing

Author: Jose M. Lorenzo-Salazar, Shwu-Fan Ma, Jonathan Jou, Pei-Chi Hou, Beatriz Guillen-Guio, Richard J. Allen, R. Gisli Jenkins, Louise V. Wain, Justin M. Oldham, Imre Noth, and Carlos Flores
Subjects: Medicine
Abstract: Background Specific common and rare single nucleotide variants (SNVs) increase the likelihood of developing sporadic idiopathic pulmonary fibrosis (IPF). We performed target-enriched sequencing on three loci previously identified by a genome-wide association study to gain a deeper understanding of the full spectrum of IPF genetic risk and performed a two-stage case–control association study. Methods A total of 1.7 Mb of DNA from 181 IPF patients was deep sequenced (>100×) across 11p15.5, 14q21.3 and 17q21.31 loci. Comparisons were performed against 501 unrelated controls and replication studies were assessed in 3968 subjects. Results 36 SNVs were associated with IPF susceptibility in the discovery stage (p
Published: 2019
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33. Meta-analysis of exome array data identifies six novel genetic loci for lung function [version 3; referees: 2 approved]

Author: Victoria E. Jackson, Jeanne C. Latourelle, Louise V. Wain, Albert V. Smith, Megan L. Grove, Traci M. Bartz, Ma'en Obeidat, Michael A. Province, Wei Gao, Beenish Qaiser, David J. Porteous, Patricia A. Cassano, Tarunveer S. Ahluwalia, Niels Grarup, Jin Li, Elisabeth Altmaier, Jonathan Marten, Sarah E. Harris, Ani Manichaikul, Tess D. Pottinger, Ruifang Li-Gao, Allan Lind-Thomsen, Anubha Mahajan, Lies Lahousse, Medea Imboden, Alexander Teumer, Bram Prins, Leo-Pekka Lyytikäinen, Gudny Eiriksdottir, Nora Franceschini, Colleen M. Sitlani, Jennifer A. Brody, Yohan Bossé, Wim Timens, Aldi Kraja, Anu Loukola, Wenbo Tang, Yongmei Liu, Jette Bork-Jensen, Johanne M. Justesen, Allan Linneberg, Leslie A. Lange, Rajesh Rawal, Stefan Karrasch, Jennifer E. Huffman, Blair H. Smith, Gail Davies, Kristin M. Burkart, Josyf C. Mychaleckyj, Tobias N. Bonten, Stefan Enroth, Lars Lind, Guy G. Brusselle, Ashish Kumar, Beate Stubbe, Understanding Society Scientific Group, Mika Kähönen, Annah B. Wyss, Bruce M. Psaty, Susan R. Heckbert, Ke Hao, Taina Rantanen, Stephen B. Kritchevsky, Kurt Lohman, Tea Skaaby, Charlotta Pisinger, Torben Hansen, Holger Schulz, Ozren Polasek, Archie Campbell, John M. Starr, Stephen S. Rich, Dennis O. Mook-Kanamori, Åsa Johansson, Erik Ingelsson, André G. Uitterlinden, Stefan Weiss, Olli T. Raitakari, Vilmundur Gudnason, Kari E. North, Sina A. Gharib, Don D. Sin, Kent D. Taylor, George T. O'Connor, Jaakko Kaprio, Tamara B. Harris, Oluf Pederson, Henrik Vestergaard, James G. Wilson, Konstantin Strauch, Caroline Hayward, Shona Kerr, Ian J. Deary, R. Graham Barr, Renée de Mutsert, Ulf Gyllensten, Andrew P. Morris, M. Arfan Ikram, Nicole Probst-Hensch, Sven Gläser, Eleftheria Zeggini, Terho Lehtimäki, David P. Strachan, Josée Dupuis, Alanna C. Morrison, Ian P. Hall, Martin D. Tobin, and Stephanie J. London
Subjects: Genomics, Medicine, Science
Abstract: Background: Over 90 regions of the genome have been associated with lung function to date, many of which have also been implicated in chronic obstructive pulmonary disease. Methods: We carried out meta-analyses of exome array data and three lung function measures: forced expiratory volume in one second (FEV1), forced vital capacity (FVC) and the ratio of FEV1 to FVC (FEV1/FVC). These analyses by the SpiroMeta and CHARGE consortia included 60,749 individuals of European ancestry from 23 studies, and 7,721 individuals of African Ancestry from 5 studies in the discovery stage, with follow-up in up to 111,556 independent individuals. Results: We identified significant (P
Published: 2018
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34. Meta-analysis of exome array data identifies six novel genetic loci for lung function [version 2; referees: 2 approved]

Author: Victoria E. Jackson, Jeanne C. Latourelle, Louise V. Wain, Albert V. Smith, Megan L. Grove, Traci M. Bartz, Ma'en Obeidat, Michael A. Province, Wei Gao, Beenish Qaiser, David J. Porteous, Patricia A. Cassano, Tarunveer S. Ahluwalia, Niels Grarup, Jin Li, Elisabeth Altmaier, Jonathan Marten, Sarah E. Harris, Ani Manichaikul, Tess D. Pottinger, Ruifang Li-Gao, Allan Lind-Thomsen, Anubha Mahajan, Lies Lahousse, Medea Imboden, Alexander Teumer, Bram Prins, Leo-Pekka Lyytikäinen, Gudny Eiriksdottir, Nora Franceschini, Colleen M. Sitlani, Jennifer A. Brody, Yohan Bossé, Wim Timens, Aldi Kraja, Anu Loukola, Wenbo Tang, Yongmei Liu, Jette Bork-Jensen, Johanne M. Justesen, Allan Linneberg, Leslie A. Lange, Rajesh Rawal, Stefan Karrasch, Jennifer E. Huffman, Blair H. Smith, Gail Davies, Kristin M. Burkart, Josyf C. Mychaleckyj, Tobias N. Bonten, Stefan Enroth, Lars Lind, Guy G. Brusselle, Ashish Kumar, Beate Stubbe, Understanding Society Scientific Group, Mika Kähönen, Annah B. Wyss, Bruce M. Psaty, Susan R. Heckbert, Ke Hao, Taina Rantanen, Stephen B. Kritchevsky, Kurt Lohman, Tea Skaaby, Charlotta Pisinger, Torben Hansen, Holger Schulz, Ozren Polasek, Archie Campbell, John M. Starr, Stephen S. Rich, Dennis O. Mook-Kanamori, Åsa Johansson, Erik Ingelsson, André G. Uitterlinden, Stefan Weiss, Olli T. Raitakari, Vilmundur Gudnason, Kari E. North, Sina A. Gharib, Don D. Sin, Kent D. Taylor, George T. O'Connor, Jaakko Kaprio, Tamara B. Harris, Oluf Pederson, Henrik Vestergaard, James G. Wilson, Konstantin Strauch, Caroline Hayward, Shona Kerr, Ian J. Deary, R. Graham Barr, Renée de Mutsert, Ulf Gyllensten, Andrew P. Morris, M. Arfan Ikram, Nicole Probst-Hensch, Sven Gläser, Eleftheria Zeggini, Terho Lehtimäki, David P. Strachan, Josée Dupuis, Alanna C. Morrison, Ian P. Hall, Martin D. Tobin, and Stephanie J. London
Subjects: Genomics, Medicine, Science
Abstract: Background: Over 90 regions of the genome have been associated with lung function to date, many of which have also been implicated in chronic obstructive pulmonary disease. Methods: We carried out meta-analyses of exome array data and three lung function measures: forced expiratory volume in one second (FEV1), forced vital capacity (FVC) and the ratio of FEV1 to FVC (FEV1/FVC). These analyses by the SpiroMeta and CHARGE consortia included 60,749 individuals of European ancestry from 23 studies, and 7,721 individuals of African Ancestry from 5 studies in the discovery stage, with follow-up in up to 111,556 independent individuals. Results: We identified significant (P
Published: 2018
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35. Human CCL3L1 copy number variation, gene expression, and the role of the CCL3L1-CCR5 axis in lung function [version 2; referees: 2 approved]

Author: Adeolu B. Adewoye, Nick Shrine, Linda Odenthal-Hesse, Samantha Welsh, Anders Malarstig, Scott Jelinsky, Iain Kilty, Martin D. Tobin, Edward J. Hollox, and Louise V. Wain
Subjects: Medicine, Science
Abstract: Background: The CCL3L1-CCR5 signaling axis is important in a number of inflammatory responses, including macrophage function, and T-cell-dependent immune responses. Small molecule CCR5 antagonists exist, including the approved antiretroviral drug maraviroc, and therapeutic monoclonal antibodies are in development. Repositioning of drugs and targets into new disease areas can accelerate the availability of new therapies and substantially reduce costs. As it has been shown that drug targets with genetic evidence supporting their involvement in the disease are more likely to be successful in clinical development, using genetic association studies to identify new target repurposing opportunities could be fruitful. Here we investigate the potential of perturbation of the CCL3L1-CCR5 axis as treatment for respiratory disease. Europeans typically carry between 0 and 5 copies of CCL3L1 and this multi-allelic variation is not detected by widely used genome-wide single nucleotide polymorphism studies. Methods: We directly measured the complex structural variation of CCL3L1 using the Paralogue Ratio Test and imputed (with validation) CCR5d32 genotypes in 5,000 individuals from UK Biobank, selected from the extremes of the lung function distribution, and analysed DNA and RNAseq data for CCL3L1 from the 1000 Genomes Project. Results: We confirmed the gene dosage effect of CCL3L1 copy number on CCL3L1 mRNA expression levels. We found no evidence for association of CCL3L1 copy number or CCR5d32 genotype with lung function. Conclusions: These results suggest that repositioning CCR5 antagonists is unlikely to be successful for the treatment of airflow obstruction.
Published: 2018
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36. Human CCL3L1 copy number variation, gene expression, and the role of the CCL3L1-CCR5 axis in lung function [version 1; referees: 2 approved]

Author: Adeolu B. Adewoye, Nick Shrine, Linda Odenthal-Hesse, Samantha Welsh, Anders Malarstig, Scott Jelinsky, Iain Kilty, Martin D. Tobin, Edward J. Hollox, and Louise V. Wain
Subjects: Medicine, Science
Abstract: Background: The CCL3L1-CCR5 signaling axis is important in a number of inflammatory responses, including macrophage function, and T-cell-dependent immune responses. Small molecule CCR5 antagonists exist, including the approved antiretroviral drug maraviroc, and therapeutic monoclonal antibodies are in development. Repositioning of drugs and targets into new disease areas can accelerate the availability of new therapies and substantially reduce costs. As it has been shown that drug targets with genetic evidence supporting their involvement in the disease are more likely to be successful in clinical development, using genetic association studies to identify new target repurposing opportunities could be fruitful. Here we investigate the potential of perturbation of the CCL3L1-CCR5 axis as treatment for respiratory disease. Europeans typically carry between 0 and 5 copies of CCL3L1 and this multi-allelic variation is not detected by widely used genome-wide single nucleotide polymorphism studies. Methods: We directly measured the complex structural variation of CCL3L1 using the Paralogue Ratio Test and imputed (with validation) CCR5del32 genotypes in 5,000 individuals from UK Biobank, selected from the extremes of the lung function distribution, and analysed DNA and RNAseq data for CCL3L1 from the 1000 Genomes Project. Results: We confirmed the gene dosage effect of CCL3L1 copy number on CCL3L1 mRNA expression levels. We found no evidence for association of CCL3L1 copy number or CCR5del32 genotype with lung function. Conclusions: These results suggest that repositioning CCR5 antagonists is unlikely to be successful for the treatment of airflow obstruction.
Published: 2018
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37. Residual Lung Abnormalities after COVID-19 Hospitalization: Interim Analysis of the UKILD Post–COVID-19 Study

Author: Iain Stewart, Joseph Jacob, Peter M. George, Philip L. Molyneaux, Joanna C. Porter, Richard J. Allen, Shahab Aslani, J. Kenneth Baillie, Shaney L. Barratt, Paul Beirne, Stephen M. Bianchi, John F. Blaikley, James D. Chalmers, Rachel C. Chambers, Nazia Chadhuri, Christopher Coleman, Guilhem Collier, Emma K. Denneny, Annemarie Docherty, Omer Elneima, Rachael A. Evans, Laura Fabbri, Michael A. Gibbons, Fergus V. Gleeson, Bibek Gooptu, Neil J. Greening, Beatriz Guillen Guio, Ian P. Hall, Neil A. Hanley, Victoria Harris, Ewen M. Harrison, Melissa Heightman, Toby E. Hillman, Alex Horsley, Linzy Houchen-Wolloff, Ian Jarrold, Simon R. Johnson, Mark G. Jones, Fasihul Khan, Rod Lawson, Olivia Leavy, Nazir Lone, Michael Marks, Hamish McAuley, Puja Mehta, Dhruv Parekh, Karen Piper Hanley, Manuela Platé, John Pearl, Krisnah Poinasamy, Jennifer K. Quint, Betty Raman, Matthew Richardson, Pilar Rivera-Ortega, Laura Saunders, Ruth Saunders, Malcolm G. Semple, Marco Sereno, Aarti Shikotra, A. John Simpson, Amisha Singapuri, David J. F. Smith, Mark Spears, Lisa G. Spencer, Stefan Stanel, David R. Thickett, A. A. Roger Thompson, Mathew Thorpe, Simon L. F. Walsh, Samantha Walker, Nicholas David Weatherley, Mark E. Weeks, Jim M. Wild, Dan G. Wootton, Chris E. Brightling, Ling-Pei Ho, Louise V. Wain, and Gisli R. Jenkins
Subjects: Pulmonary and Respiratory Medicine, Critical Care and Intensive Care Medicine
Published: 2023
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38. Cohort Profile: Post-hospitalisation COVID-19 study (PHOSP-COVID)

Author: Omer Elneima, Hamish J C McAuley, Olivia C Leavy, James D Chalmers, Alex Horsley, Ling-Pei Ho, Michael Marks, Krisnah Poinasamy, Betty Raman, Aarti Shikotra, Amisha Singapuri, Marco Sereno, Victoria C Harris, Linzy Houchen-Wolloff, Ruth M Saunders, Neil J Greening, Matthew Richardson, Jennifer K Quint, Andrew Briggs, Annemarie B Docherty, Steven Kerr, Ewen M Harrison, Nazir I Lone, Mathew Thorpe, Liam G Heaney, Keir E Lewis, Raminder Aul, Paul Beirne, Charlotte E Bolton, Jeremy S Brown, Gourab Choudhury, Nawar Diar Bakerly, Nicholas Easom, Carlos Echevarria, Jonathan Fuld, Nick Hart, John R Hurst, Mark G Jones, Dhruv Parekh, Paul Pfeffer, Najib M Rahman, Sarah L Rowland-Jones, AA Roger Thompson, Caroline Jolley, Ajay M Shah, Dan G Wootton, Trudie Chalder, Melanie J Davies, Anthony De Soyza, John R Geddes, William Greenhalf, Simon Heller, Luke S Howard, Joseph Jacob, R Gisli Jenkins, Janet M Lord, William D-C Man, Gerry P McCann, Stefan Neubauer, Peter JM Openshaw, Joanna C Porter, Matthew J Rowland, Janet T Scott, Malcolm G Semple, Sally J Singh, David C Thomas, Mark Toshner, Aziz Sheikh, Christopher E Brightling, Louise V Wain, and Rachael A Evans
Abstract: PHOSP-COVID is a national UK multi-centre cohort study of patients who were hospitalised for COVID-19 and subsequently discharged.PHOSP-COVID was established to investigate the medium- and long-term sequelae of severe COVID-19 requiring hospitalisation, understand the underlying mechanisms of these sequelae, evaluate the medium- and long-term effects of COVID-19 treatments, and to serve as a platform to enable future studies, including clinical trials.Data collected covered a wide range of physical measures, biological samples, and Patient Reported Outcome Measures (PROMs).Participants could join the cohort either in Tier 1 only with remote data collection using hospital records, a PROMs app and postal saliva sample for DNA, or in Tier 2 where they were invited to attend two specific research visits for further data collection and biological research sampling. These research visits occurred at five (range 2-7) months and 12 (range 10-14) months post-discharge. Participants could also participate in specific nested studies (Tier 3) at selected sites.All participants were asked to consent to further follow-up for 25 years via linkage to their electronic healthcare records and to be re-contacted for further research.In total, 7935 participants were recruited from 83 UK sites: 5238 to Tier 1 and 2697 to Tier 2, between August 2020 and March 2022.Cohort data are held in a Trusted Research Environment and samples stored in a central biobank. Data and samples can be accessed upon request and subject to approvals.
Published: 2023
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39. DeepPheWAS : an R package for phenotype generation and association analysis for phenome-wide association studies

Author: Richard J Packer, Alex T Williams, William Hennah, Micaela T Eisenberg, Nick Shrine, Katherine A Fawcett, Willow Pearson, Anna L Guyatt, Ahmed Edris, Edward J Hollox, Mikko Marttila, Balasubramanya S Rao, John Raymond Bratty, Louise V Wain, Frank Dudbridge, Martin D Tobin, and Neuroscience Center
Subjects: Statistics and Probability, Computational Mathematics, Computational Theory and Mathematics, Loci, 1184 Genetics, developmental biology, physiology, Molecular Biology, Biochemistry, Computer Science Applications
Abstract: Summary DeepPheWAS is an R package for phenome-wide association studies that creates clinically curated composite phenotypes and integrates quantitative phenotypes from primary care data, longitudinal trajectories of quantitative measures, disease progression and drug response phenotypes. Tools are provided for efficient analysis of association with any genetic input, under any genetic model, with optional sex-stratified analysis, and for developing novel phenotypes. Availability and implementation The DeepPheWAS R package is freely available under GNU general public licence v3.0 from at https://github.com/Richard-Packer/DeepPheWAS. Supplementary information Supplementary data are available at Bioinformatics online.
Published: 2023

40. Reply to: PCSK6: The endogenous PAR-1 agonist driving pulmonary fibrosis?

Author: Justin M. Oldham, Richard J Allen, Jose M. Lorenzo-Salazar, Carlos Flores, Louise V Wain, and Imre Noth
Subjects: Pulmonary and Respiratory Medicine, Critical Care and Intensive Care Medicine
Published: 2023
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41. Effects of sleep disturbance on dyspnoea and impaired lung function following hospital admission due to COVID-19 in the UK: a prospective multicentre cohort study

Author: Callum Jackson, Iain D Stewart, Tatiana Plekhanova, Peter S Cunningham, Andrew L Hazel, Bashar Al-Sheklly, Raminder Aul, Charlotte E Bolton, Trudie Chalder, James D Chalmers, Nazia Chaudhuri, Annemarie B Docherty, Gavin Donaldson, Charlotte L Edwardson, Omer Elneima, Neil J Greening, Neil A Hanley, Victoria C Harris, Ewen M Harrison, Ling-Pei Ho, Linzy Houchen-Wolloff, Luke S Howard, Caroline J Jolley, Mark G Jones, Olivia C Leavy, Keir E Lewis, Nazir I Lone, Michael Marks, Hamish J C McAuley, Melitta A McNarry, Brijesh V Patel, Karen Piper-Hanley, Krisnah Poinasamy, Betty Raman, Matthew Richardson, Pilar Rivera-Ortega, Sarah L Rowland-Jones, Alex V Rowlands, Ruth M Saunders, Janet T Scott, Marco Sereno, Ajay M Shah, Aarti Shikotra, Amisha Singapuri, Stefan C Stanel, Mathew Thorpe, Daniel G Wootton, Thomas Yates, R Gisli Jenkins, Sally J Singh, William D-C Man, Christopher E Brightling, Louise V Wain, Joanna C Porter, A A Roger Thompson, Alex Horsley, Philip L Molyneaux, Rachael A Evans, Samuel E Jones, Martin K Rutter, John F Blaikley, C Jackson, I D Stewart, T Plekhanova, P S Cunningham, A L Hazel, B Al-Sheklly, R Aul, C E Bolton, T Chalder, J D Chalmers, N Chaudhuri, A B Docherty, G Donaldson, C L Edwardson, O Elneima, N J Greening, N A Hanley, V C Harris, E M Harrison, L-P Ho, L Houchen-Wolloff, L S Howard, C J Jolley, M G Jones, O C Leavy, K E Lewis, N I Lone, M Marks, H J C McAuley, M A McNarry, B Patel, K Piper-Hanley, K Poinasamy, B Raman, M Richardson, P Rivera-Ortega, S L Rowland-Jones, A V Rowlands, R M Saunders, J T Scott, M Sereno, A M Shah, A Shikotra, A Singapuri, S C Stanel, M Thorpe, D G Wootton, T Yates, G Jenkins, S J Singh, W D-C Man, C E Brightling, L V Wain, J C Porter, R Thompson, A Horsley, P L Molyneaux, R A Evans, S E Jones, M K Rutter, J F Blaikley, K Abel, H Adamali, D Adeloye, O Adeyemi, R Adrego, L A Aguilar Jimenez, S Ahmad, N Ahmad Haider, R Ahmed, N Ahwireng, M Ainsworth, A Alamoudi, M Ali, M Aljaroof, AM All, L Allan, R J Allen, L Allerton, L Allsop, P Almeida, D Altmann, M Alvarez Corral, S Amoils, D Anderson, C Antoniades, G Arbane, A Arias, C Armour, L Armstrong, N Armstrong, D Arnold, H Arnold, A Ashish, A Ashworth, M Ashworth, S Aslani, H Assefa-Kebede, C Atkin, P Atkin, H Aung, L Austin, C Avram, A Ayoub, M Babores, R Baggott, J Bagshaw, D Baguley, L Bailey, J K Baillie, S Bain, M Bakali, M Bakau, E Baldry, D Baldwin, M Baldwin, C Ballard, A Banerjee, B Bang, R E Barker, L Barman, S Barratt, F Barrett, D Basire, N Basu, M Bates, A Bates, R Batterham, H Baxendale, H Bayes, M Beadsworth, P Beckett, M Beggs, M Begum, P Beirne, D Bell, R Bell, K Bennett, E Beranova, A Bermperi, A Berridge, C Berry, S Betts, E Bevan, K Bhui, M Bingham, K Birchall, L Bishop, K Bisnauthsing, J Blaikely, A Bloss, A Bolger, J Bonnington, A Botkai, C Bourne, M Bourne, K Bramham, L Brear, G Breen, J Breeze, A Briggs, E Bright, S Brill, K Brindle, L Broad, A Broadley, C Brookes, M Broome, A Brown, J Brown, J S Brown, M Brown, V Brown, T Brugha, N Brunskill, M Buch, P Buckley, A Bularga, E Bullmore, L Burden, T Burdett, D Burn, G Burns, A Burns, J Busby, R Butcher, A Butt, S Byrne, P Cairns, P C Calder, E Calvelo, H Carborn, B Card, C Carr, L Carr, G Carson, P Carter, A Casey, M Cassar, J Cavanagh, M Chablani, R C Chambers, F Chan, K M Channon, K Chapman, A Charalambou, A Checkley, J Chen, Y Cheng, L Chetham, C Childs, E R Chilvers, H Chinoy, A Chiribiri, K Chong-James, G Choudhury, N Choudhury, P Chowienczyk, C Christie, M Chrystal, D Clark, C Clark, J Clarke, S Clohisey, G Coakley, Z Coburn, S Coetzee, J Cole, C Coleman, F Conneh, D Connell, B Connolly, L Connor, A Cook, B Cooper, J Cooper, S Cooper, D Copeland, T Cosier, M Coulding, C Coupland, E Cox, T Craig, P Crisp, D Cristiano, M G Crooks, A Cross, I Cruz, P Cullinan, D Cuthbertson, L Daines, M Dalton, P Daly, A Daniels, P Dark, J Dasgin, A David, C David, E Davies, F Davies, G Davies, G A Davies, K Davies, M J Davies, J Dawson, E Daynes, A De Soyza, B Deakin, A Deans, C Deas, J Deery, S Defres, A Dell, K Dempsey, E Denneny, J Dennis, A Dewar, R Dharmagunawardena, N Diar-Bakerly, C Dickens, A Dipper, S Diver, S N Diwanji, M Dixon, R Djukanovic, H Dobson, S L Dobson, A Donaldson, T Dong, N Dormand, A Dougherty, R Dowling, S Drain, K Draxlbauer, K Drury, P Dulawan, A Dunleavy, S Dunn, C Dupont, J Earley, N Easom, C Echevarria, S Edwards, C Edwardson, H El-Taweel, A Elliott, K Elliott, Y Ellis, A Elmer, D Evans, H Evans, J Evans, R Evans, R I Evans, T Evans, C Evenden, L Evison, L Fabbri, S Fairbairn, A Fairman, K Fallon, D Faluyi, C Favager, T Fayzan, J Featherstone, T Felton, J Finch, S Finney, J Finnigan, L Finnigan, H Fisher, S Fletcher, R Flockton, M Flynn, H Foot, D Foote, A Ford, D Forton, E Fraile, C Francis, R Francis, S Francis, A Frankel, E Fraser, R Free, N French, X Fu, J Fuld, J Furniss, L Garner, N Gautam, J R Geddes, J George, P M George, M Gibbons, M Gill, L Gilmour, F Gleeson, J Glossop, S Glover, N Goodman, C Goodwin, B Gooptu, H Gordon, T Gorsuch, M Greatorex, P L Greenhaff, W Greenhalf, A Greenhalgh, J Greenwood, H Gregory, R Gregory, D Grieve, D Griffin, L Griffiths, A-M Guerdette, B Guillen Guio, M Gummadi, A Gupta, S Gurram, E Guthrie, Z Guy, H Henson, K Hadley, A Haggar, K Hainey, B Hairsine, P Haldar, I Hall, L Hall, M Halling-Brown, R Hamil, A Hancock, K Hancock, S Haq, H E Hardwick, E Hardy, T Hardy, B Hargadon, K Harrington, E Harris, P Harrison, N Hart, A Harvey, M Harvey, M Harvie, L Haslam, M Havinden-Williams, J Hawkes, N Hawkings, J Haworth, A Hayday, M Haynes, J Hazeldine, T Hazelton, L G Heaney, C Heeley, J L Heeney, M Heightman, S Heller, M Henderson, L Hesselden, M Hewitt, V Highett, T Hillman, T Hiwot, A Hoare, M Hoare, J Hockridge, P Hogarth, A Holbourn, S Holden, L Holdsworth, D Holgate, M Holland, L Holloway, K Holmes, M Holmes, B Holroyd-Hind, L Holt, A Hormis, A Hosseini, M Hotopf, K Howard, A Howell, E Hufton, A D Hughes, J Hughes, R Hughes, A Humphries, N Huneke, E Hurditch, J Hurst, M Husain, T Hussell, J Hutchinson, W Ibrahim, F Ilyas, J Ingham, L Ingram, D Ionita, K Isaacs, K Ismail, T Jackson, J Jacob, W Y James, W Jang, C Jarman, I Jarrold, H Jarvis, R Jastrub, B Jayaraman, R G Jenkins, P Jezzard, K Jiwa, C Johnson, S Johnson, D Johnston, D Jones, G Jones, H Jones, I Jones, L Jones, S Jones, S Jose, T Kabir, G Kaltsakas, V Kamwa, N Kanellakis, S Kaprowska, Z Kausar, N Keenan, S Kelly, G Kemp, S Kerr, H Kerslake, A L Key, F Khan, K Khunti, S Kilroy, B King, C King, L Kingham, J Kirk, P Kitterick, P Klenerman, L Knibbs, S Knight, A Knighton, O Kon, S Kon, S S Kon, S Koprowska, A Korszun, I Koychev, C Kurasz, P Kurupati, C Laing, H Lamlum, G Landers, C Langenberg, D Lasserson, L Lavelle-Langham, A Lawrie, C Lawson, A Layton, A Lea, D Lee, J-H Lee, E Lee, K Leitch, R Lenagh, D Lewis, J Lewis, V Lewis, N Lewis-Burke, X Li, T Light, L Lightstone, W Lilaonitkul, L Lim, S Linford, A Lingford-Hughes, M Lipman, K Liyanage, A Lloyd, S Logan, D Lomas, R Loosley, J M Lord, H Lota, W Lovegrove, A Lucey, E Lukaschuk, A Lye, C Lynch, S MacDonald, G MacGowan, I Macharia, J Mackie, L Macliver, S Madathil, G Madzamba, N Magee, M M Magtoto, N Mairs, N Majeed, E Major, F Malein, M Malim, G Mallison, S Mandal, K Mangion, C Manisty, R Manley, K March, S Marciniak, P Marino, M Mariveles, E Marouzet, S Marsh, B Marshall, M Marshall, J Martin, A Martineau, L M Martinez, N Maskell, D Matila, W Matimba-Mupaya, L Matthews, A Mbuyisa, S McAdoo, H McAllister-Williams, A McArdle, P McArdle, D McAulay, G P McCann, J McCormick, W McCormick, P McCourt, L McGarvey, C McGhee, K Mcgee, J McGinness, K McGlynn, A McGovern, H McGuinness, I B McInnes, J McIntosh, E McIvor, K McIvor, L McLeavey, A McMahon, M J McMahon, L McMorrow, T Mcnally, M McNarry, J McNeill, A McQueen, H McShane, C Mears, C Megson, S Megson, P Mehta, J Meiring, L Melling, M Mencias, D Menzies, M Merida Morillas, A Michael, C Miller, L Milligan, C Mills, G Mills, N L Mills, L Milner, S Misra, J Mitchell, A Mohamed, N Mohamed, S Mohammed, W Monteiro, S Moriera, A Morley, L Morrison, R Morriss, A Morrow, A J Moss, P Moss, K Motohashi, N Msimanga, E Mukaetova-Ladinska, U Munawar, J Murira, U Nanda, H Nassa, M Nasseri, A Neal, R Needham, P Neill, S Neubauer, D E Newby, H Newell, T Newman, J Newman, A Newton-Cox, T Nicholson, D Nicoll, A Nikolaidis, C M Nolan, M J Noonan, C Norman, P Novotny, J Nunag, L Nwafor, U Nwanguma, J Nyaboko, C O'Brien, K O'Donnell, D O'Regan, L O'Brien, N Odell, G Ogg, O Olaosebikan, C Oliver, Z Omar, P J M Openshaw, L Orriss-Dib, L Osborne, R Osbourne, M Ostermann, C Overton, J Owen, J Oxton, J Pack, E Pacpaco, S Paddick, S Painter, A Pakzad, S Palmer, P Papineni, K Paques, K Paradowski, M Pareek, D Parekh, H Parfrey, C Pariante, S Parker, M Parkes, J Parmar, S Patale, M Patel, S Patel, D Pattenadk, M Pavlides, S Payne, L Pearce, J E Pearl, D Peckham, J Pendlebury, Y Peng, C Pennington, I Peralta, E Perkins, Z Peterkin, T Peto, N Petousi, J Petrie, P Pfeffer, J Phipps, J Pimm, R Pius, H Plant, S Plein, M Plowright, O Polgar, L Poll, J Porter, S Portukhay, N Powell, A Prabhu, J Pratt, A Price, C Price, D Price, L Price, A Prickett, J Propescu, S Prosper, S Pugmire, S Quaid, J Quigley, J Quint, H Qureshi, I N Qureshi, K Radhakrishnan, N M Rahman, M Ralser, A Ramos, H Ramos, J Rangeley, B Rangelov, L Ratcliffe, P Ravencroft, A Reddington, R Reddy, A Reddy, H Redfearn, D Redwood, A Reed, M Rees, T Rees, K Regan, W Reynolds, C Ribeiro, A Richards, E Richardson, K Roberts, E Robertson, E Robinson, L Robinson, L Roche, C Roddis, J Rodger, A Ross, G Ross, J Rossdale, A Rostron, A Rowe, A Rowland, J Rowland, M J Rowland, K Roy, M Roy, I Rudan, R Russell, E Russell, G Saalmink, R Sabit, E K Sage, T Samakomva, N Samani, C Sampson, K Samuel, R Samuel, A Sanderson, E Sapey, D Saralaya, J Sargent, C Sarginson, T Sass, N Sattar, K Saunders, P Saunders, L C Saunders, H Savill, W Saxon, A Sayer, J Schronce, W Schwaeble, K Scott, N Selby, M G Semple, T A Sewell, K Shah, P Shah, M Shankar-Hari, M Sharma, C Sharpe, M Sharpe, S Shashaa, A Shaw, K Shaw, V Shaw, A Sheikh, S Shelton, L Shenton, K Shevket, J Short, S Siddique, S Siddiqui, J Sidebottom, L Sigfrid, G Simons, J Simpson, N Simpson, C Singh, D Sissons, J Skeemer, K Slack, A Smith, D Smith, S Smith, J Smith, L Smith, M Soares, T S Solano, R Solly, A R Solstice, T Soulsby, D Southern, D Sowter, M Spears, L G Spencer, F Speranza, L Stadon, S Stanel, N Steele, M Steiner, D Stensel, G Stephens, L Stephenson, M Stern, R Stimpson, S Stockdale, J Stockley, W Stoker, R Stone, W Storrar, A Storrie, K Storton, E Stringer, S Strong-Sheldrake, N Stroud, C Subbe, C L Sudlow, Z Suleiman, C Summers, C Summersgill, D Sutherland, D L Sykes, R Sykes, N Talbot, A L Tan, L Tarusan, V Tavoukjian, A Taylor, C Taylor, J Taylor, A Te, H Tedd, C J Tee, J Teixeira, H Tench, S Terry, S Thackray-Nocera, F Thaivalappil, B Thamu, D Thickett, C Thomas, D C Thomas, S Thomas, A K Thomas, T Thomas-Woods, T Thompson, A A R Thompson, T Thornton, R S Thwaites, J Tilley, N Tinker, G F Tiongson, M Tobin, J Tomlinson, C Tong, M Toshner, R Touyz, K A Tripp, E Tunnicliffe, A Turnbull, E Turner, S Turner, V Turner, K Turner, S Turney, L Turtle, H Turton, J Ugoji, R Ugwuoke, R Upthegrove, J Valabhji, M Ventura, J Vere, C Vickers, B Vinson, E Wade, P Wade, T Wainwright, L O Wajero, S Walder, S Walker, E Wall, T Wallis, S Walmsley, J A Walsh, S Walsh, L Warburton, T J C Ward, K Warwick, H Wassall, S Waterson, E Watson, L Watson, J Watson, J Weir McCall, C Welch, H Welch, B Welsh, S Wessely, S West, H Weston, H Wheeler, S White, V Whitehead, J Whitney, S Whittaker, B Whittam, V Whitworth, A Wight, J M Wild, M Wilkins, D Wilkinson, B Williams, N Williams, J Williams, S A Williams-Howard, M Willicombe, G Willis, J Willoughby, A Wilson, D Wilson, I Wilson, N Window, M Witham, R Wolf-Roberts, C Wood, F Woodhead, J Woods, J Wormleighton, J Worsley, D Wraith, C Wrey Brown, C Wright, L Wright, S Wright, J Wyles, I Wynter, M Xu, N Yasmin, S Yasmin, K P Yip, B Young, S Young, A Young, A J Yousuf, A Zawia, L Zeidan, B Zhao, B Zheng, O Zongo, Apollo - University of Cambridge Repository, PHOSP-COVID Study Collaborative Group, and Group, PHOSP-COVID Study Collaborative
Subjects: Pulmonary and Respiratory Medicine, PHOSP-COVID Study Collaborative Group
Abstract: Data sharing: The PHOSP-COVID study protocol, consent form, definition, and derivation of clinical characteristics and outcomes, training materials, regulatory documents, information about requests for data access, and other relevant study materials are available online. UK Biobank information can be released once necessary approvals have been obtained. Other data (eg, the R code and protocol) will be made available on reasonable request to the corresponding author. Copyright © 2023 The Author(s). Background: Sleep disturbance is common following hospital admission both for COVID-19 and other causes. The clinical associations of this for recovery after hospital admission are poorly understood despite sleep disturbance contributing to morbidity in other scenarios. We aimed to investigate the prevalence and nature of sleep disturbance after discharge following hospital admission for COVID-19 and to assess whether this was associated with dyspnoea. Methods: CircCOVID was a prospective multicentre cohort substudy designed to investigate the effects of circadian disruption and sleep disturbance on recovery after COVID-19 in a cohort of participants aged 18 years or older, admitted to hospital for COVID-19 in the UK, and discharged between March, 2020, and October, 2021. Participants were recruited from the Post-hospitalisation COVID-19 study (PHOSP-COVID). Follow-up data were collected at two timepoints: an early time point 2–7 months after hospital discharge and a later time point 10–14 months after hospital discharge. Sleep quality was assessed subjectively using the Pittsburgh Sleep Quality Index questionnaire and a numerical rating scale. Sleep quality was also assessed with an accelerometer worn on the wrist (actigraphy) for 14 days. Participants were also clinically phenotyped, including assessment of symptoms (ie, anxiety [Generalised Anxiety Disorder 7-item scale questionnaire], muscle function [SARC-F questionnaire], dyspnoea [Dyspnoea-12 questionnaire] and measurement of lung function), at the early timepoint after discharge. Actigraphy results were also compared to a matched UK Biobank cohort (non-hospitalised individuals and recently hospitalised individuals). Multivariable linear regression was used to define associations of sleep disturbance with the primary outcome of breathlessness and the other clinical symptoms. PHOSP-COVID is registered on the ISRCTN Registry (ISRCTN10980107). Findings: 2320 of 2468 participants in the PHOSP-COVID study attended an early timepoint research visit a median of 5 months (IQR 4–6) following discharge from 83 hospitals in the UK. Data for sleep quality were assessed by subjective measures (the Pittsburgh Sleep Quality Index questionnaire and the numerical rating scale) for 638 participants at the early time point. Sleep quality was also assessed using device-based measures (actigraphy) a median of 7 months (IQR 5–8 months) after discharge from hospital for 729 participants. After discharge from hospital, the majority (396 [62%] of 638) of participants who had been admitted to hospital for COVID-19 reported poor sleep quality in response to the Pittsburgh Sleep Quality Index questionnaire. A comparable proportion (338 [53%] of 638) of participants felt their sleep quality had deteriorated following discharge after COVID-19 admission, as assessed by the numerical rating scale. Device-based measurements were compared to an age-matched, sex-matched, BMI-matched, and time from discharge-matched UK Biobank cohort who had recently been admitted to hospital. Compared to the recently hospitalised matched UK Biobank cohort, participants in our study slept on average 65 min (95% CI 59 to 71) longer, had a lower sleep regularity index (–19%; 95% CI –20 to –16), and a lower sleep efficiency (3·83 percentage points; 95% CI 3·40 to 4·26). Similar results were obtained when comparisons were made with the non-hospitalised UK Biobank cohort. Overall sleep quality (unadjusted effect estimate 3·94; 95% CI 2·78 to 5·10), deterioration in sleep quality following hospital admission (3·00; 1·82 to 4·28), and sleep regularity (4·38; 2·10 to 6·65) were associated with higher dyspnoea scores. Poor sleep quality, deterioration in sleep quality, and sleep regularity were also associated with impaired lung function, as assessed by forced vital capacity. Depending on the sleep metric, anxiety mediated 18–39% of the effect of sleep disturbance on dyspnoea, while muscle weakness mediated 27–41% of this effect. Interpretation: Sleep disturbance following hospital admission for COVID-19 is associated with dyspnoea, anxiety, and muscle weakness. Due to the association with multiple symptoms, targeting sleep disturbance might be beneficial in treating the post-COVID-19 condition. Funding: UK Research and Innovation, National Institute for Health Research, and Engineering and Physical Sciences Research Council. UK Research and Innovation, National Institute for Health Research, and Engineering and Physical Sciences Research Council.
Published: 2023
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42. Cluster analysis of transcriptomic datasets to identify endotypes of idiopathic pulmonary fibrosis

Author: Luke M Kraven, Adam R Taylor, Philip L Molyneaux, Toby M Maher, John E McDonough, Marco Mura, Ivana V Yang, David A Schwartz, Yong Huang, Imre Noth, Shwu Fan Ma, Astrid J Yeo, William A Fahy, R Gisli Jenkins, and Louise V Wain
Subjects: Pulmonary and Respiratory Medicine, respiratory system, Article, respiratory tract diseases
Abstract: BackgroundConsiderable clinical heterogeneity in idiopathic pulmonary fibrosis (IPF) suggests the existence of multiple disease endotypes. Identifying these endotypes would improve our understanding of the pathogenesis of IPF and could allow for a biomarker-driven personalised medicine approach. We aimed to identify clinically distinct groups of patients with IPF that could represent distinct disease endotypes.MethodsWe co-normalised, pooled and clustered three publicly available blood transcriptomic datasets (total 220 IPF cases). We compared clinical traits across clusters and used gene enrichment analysis to identify biological pathways and processes that were over-represented among the genes that were differentially expressed across clusters. A gene-based classifier was developed and validated using three additional independent datasets (total 194 IPF cases).FindingsWe identified three clusters of patients with IPF with statistically significant differences in lung function (p=0.009) and mortality (p=0.009) between groups. Gene enrichment analysis implicated mitochondrial homeostasis, apoptosis, cell cycle and innate and adaptive immunity in the pathogenesis underlying these groups. We developed and validated a 13-gene cluster classifier that predicted mortality in IPF (high-risk clusters vs low-risk cluster: HR 4.25, 95% CI 2.14 to 8.46, p=3.7×10−5).InterpretationWe have identified blood gene expression signatures capable of discerning groups of patients with IPF with significant differences in survival. These clusters could be representative of distinct pathophysiological states, which would support the theory of multiple endotypes of IPF. Although more work must be done to confirm the existence of these endotypes, our classifier could be a useful tool in patient stratification and outcome prediction in IPF.
Published: 2022
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43. PCSK6 and survival in idiopathic pulmonary fibrosis

Author: Justin M. Oldham, Richard J Allen, Jose M. Lorenzo-Salazar, Philip L Molyneaux, Shwu-Fan Ma, Chitra Joseph, John S. Kim, Beatriz Guillen-Guio, Tamara Hernández-Beeftink, Jonathan A Kropski, Yong Huang, Cathryn T. Lee, Ayodeji Adegunsoye, Janelle Vu Pugashetti, Angela L Linderholm, Vivian Vo, Mary E. Strek, Jonathan Jou, Adrian Muñoz-Barrera, Luis A. Rubio-Rodriguez, Richard Hubbard, Nik Hirani, Moira K. B. Whyte, Simon Hart, Andrew G Nicholson, Lisa Lancaster, Helen Parfrey, Doris Rassl, William Wallace, Eleanor Valenzi, Yingze Zhang, Josyf Mychaleckyj, Amy Stockwell, Naftali Kaminski, Paul J Wolters, Maria Molina-Molina, Nicholas E Banovich, William A Fahy, Fernando J. Martinez, Ian P. Hall, Martin D Tobin, Toby M. Maher, Timothy S Blackwell, Brian L Yaspan, R Gisli Jenkins, Carlos Flores, Louise V Wain, and Imre Noth
Subjects: Pulmonary and Respiratory Medicine, Critical Care and Intensive Care Medicine
Abstract: RATIONALE: Idiopathic pulmonary fibrosis (IPF) is a devastating disease characterized by limited treatment options and high mortality. A better understanding of the molecular drivers of IPF progression is needed. OBJECTIVE: To identify and validate molecular determinants of IPF survival. METHODS: A staged genome-wide association study (GWAS) was performed using paired genomic and survival data. Stage I cases were drawn from centers across the US and Europe and stage II cases from Vanderbilt University. Cox proportional hazards regression was used to identify gene variants associated with differential transplant-free survival (TFS). Stage I variants with nominal significance (p
Published: 2023

44. SARS-CoV-2-specific nasal IgA wanes 9 months after hospitalisation with COVID-19 and is not induced by subsequent vaccination

Author: Felicity Liew, Shubha Talwar, Andy Cross, Brian J. Willett, Sam Scott, Nicola Logan, Matthew K. Siggins, Dawid Swieboda, Jasmin K. Sidhu, Claudia Efstathiou, Shona C. Moore, Chris Davis, Noura Mohamed, Jose Nunag, Clara King, A.A. Roger Thompson, Sarah L. Rowland-Jones, Annemarie B. Docherty, James D. Chalmers, Ling-Pei Ho, Alexander Horsley, Betty Raman, Krisnah Poinasamy, Michael Marks, Onn Min Kon, Luke Howard, Daniel G. Wootton, Susanna Dunachie, Jennifer K. Quint, Rachael A. Evans, Louise V. Wain, Sara Fontanella, Thushan I. de Silva, Antonia Ho, Ewen Harrison, J. Kenneth Baillie, Malcolm G. Semple, Christopher Brightling, Ryan S. Thwaites, Lance Turtle, Peter J.M. Openshaw, Beatrice Alex, Petros Andrikopoulos, Benjamin Bach, Wendy S. Barclay, Debby Bogaert, Meera Chand, Kanta Chechi, Graham S. Cooke, Ana da Silva Filipe, Thushan de Silva, Gonçalo dos Santos Correia, Marc-Emmanuel Dumas, Jake Dunning, Tom Fletcher, Christopher A. Green, William Greenhalf, Julian Griffin, Rishi K. Gupta, Ewen M. Harrison, Antonia Y.W. Ho, Karl Holden, Peter W. Horby, Samreen Ijaz, Say Khoo, Paul Klenerman, Andrew Law, Matthew Lewis, Sonia Liggi, Wei Shen Lim, Lynn Maslen, Alexander J. Mentzer, Laura Merson, Alison M Meynert, Mahdad Noursadeghi, Michael Olanipekun, Anthonia Osagie, Massimo Palmarini, Carlo Palmieri, William A. Paxton, Georgios Pollakis, Nicholas Price, Andrew Rambaut, David L Robertson, Clark D. Russell, Vanessa Sancho-Shimizu, Caroline Sands, Janet T. Scott, Louise Sigfrid, Tom Solomon, Shiranee Sriskandan, David Stuart, Charlotte Summers, Olivia V. Swann, Zoltan Takats, Panteleimon Takis, Richard S. Tedder, Emma C. Thomson, Lance C.W. Turtle, Maria Zambon, Thomas M. Drake, Cameron J. Fairfield, Stephen R. Knight, Kenneth A. Mclean, Derek Murphy, Lisa Norman, Riinu Pius, Catherine A. Shaw, Marie Connor, Jo Dalton, Carrol Gamble, Michelle Girvan, Sophie Halpin, Janet Harrison, Clare Jackson, James Lee, Laura Marsh, Daniel Plotkin, Stephanie Roberts, Egle Saviciute, Sara Clohisey, Ross Hendry, Susan Knight, Eva Lahnsteiner, Gary Leeming, Lucy Norris, James Scott-Brown, Sarah Tait, Murray Wham, Richard Clark, Audrey Coutts, Lorna Donelly, Angie Fawkes, Tammy Gilchrist, Katarzyna Hafezi, Louise MacGillivray, Alan Maclean, Sarah McCafferty, Kirstie Morrice, Lee Murphy, Nicola Wrobel, Gail Carson, Kayode Adeniji, Daniel Agranoff, Ken Agwuh, Dhiraj Ail, Erin L. Aldera, Ana Alegria, Sam Allen, Brian Angus, Abdul Ashish, Dougal Atkinson, Shahedal Bari, Gavin Barlow, Stella Barnass, Nicholas Barrett, Christopher Bassford, Sneha Basude, David Baxter, Michael Beadsworth, Jolanta Bernatoniene, John Berridge, Colin Berry, Nicola Best, Pieter Bothma, Robin Brittain-Long, Naomi Bulteel, Tom Burden, Andrew Burtenshaw, Vikki Caruth, David Chadwick, Duncan Chambler, Nigel Chee, Jenny Child, Srikanth Chukkambotla, Tom Clark, Paul Collini, Catherine Cosgrove, Jason Cupitt, Maria-Teresa Cutino-Moguel, Paul Dark, Chris Dawson, Samir Dervisevic, Phil Donnison, Sam Douthwaite, Andrew Drummond, Ingrid DuRand, Ahilanadan Dushianthan, Tristan Dyer, Cariad Evans, Chi Eziefula, Chrisopher Fegan, Adam Finn, Duncan Fullerton, Sanjeev Garg, Atul Garg, Effrossyni Gkrania-Klotsas, Jo Godden, Arthur Goldsmith, Clive Graham, Tassos Grammatikopoulos, Elaine Hardy, Stuart Hartshorn, Daniel Harvey, Peter Havalda, Daniel B. Hawcutt, Maria Hobrok, Luke Hodgson, Anil Hormis, Joanne Howard, Michael Jacobs, Susan Jain, Paul Jennings, Agilan Kaliappan, Vidya Kasipandian, Stephen Kegg, Michael Kelsey, Jason Kendall, Caroline Kerrison, Ian Kerslake, Oliver Koch, Gouri Koduri, George Koshy, Shondipon Laha, Steven Laird, Susan Larkin, Tamas Leiner, Patrick Lillie, James Limb, Vanessa Linnett, Jeff Little, Mark Lyttle, Michael MacMahon, Emily MacNaughton, Ravish Mankregod, Huw Masson, Elijah Matovu, Katherine McCullough, Ruth McEwen, Manjula Meda, Gary Mills, Jane Minton, Kavya Mohandas, Quen Mok, James Moon, Elinoor Moore, Patrick Morgan, Craig Morris, Katherine Mortimore, Samuel Moses, Mbiye Mpenge, Rohinton Mulla, Michael Murphy, Thapas Nagarajan, Megan Nagel, Mark Nelson, Lillian Norris, Matthew K. O'Shea, Marlies Ostermann, Igor Otahal, Mark Pais, Selva Panchatsharam, Danai Papakonstantinou, Padmasayee Papineni, Hassan Paraiso, Brij Patel, Natalie Pattison, Justin Pepperell, Mark Peters, Mandeep Phull, Stefania Pintus, Tim Planche, Frank Post, David Price, Rachel Prout, Nikolas Rae, Henrik Reschreiter, Tim Reynolds, Neil Richardson, Mark Roberts, Devender Roberts, Alistair Rose, Guy Rousseau, Bobby Ruge, Brendan Ryan, Taranprit Saluja, Sarah Sarah, Matthias Schmid, Aarti Shah, Manu Shankar-Hari, Prad Shanmuga, Anil Sharma, Anna Shawcross, Jagtur Singh Pooni, Jeremy Sizer, Richard Smith, Catherine Snelson, Nick Spittle, Nikki Staines, Tom Stambach, Richard Stewart, Pradeep Subudhi, Tamas Szakmany, Kate Tatham, Jo Thomas, Chris Thompson, Robert Thompson, Ascanio Tridente, Darell Tupper-Carey, Mary Twagira, Nick Vallotton, Rama Vancheeswaran, Rachel Vincent, Lisa Vincent-Smith, Shico Visuvanathan, Alan Vuylsteke, Sam Waddy, Rachel Wake, Andrew Walden, Ingeborg Welters, Tony Whitehouse, Paul Whittaker, Ashley Whittington, Meme Wijesinghe, Martin Williams, Lawrence Wilson, Stephen Winchester, Martin Wiselka, Adam Wolverson, Daniel G Wootton, Andrew Workman, Bryan Yates, Peter Young, Sarah E. McDonald, Victoria Shaw, Katie A. Ahmed, Jane A. Armstrong, Milton Ashworth, Innocent G. Asiimwe, Siddharth Bakshi, Samantha L Barlow, Laura Booth, Benjamin Brennan, Katie Bullock, Nicola Carlucci, Emily Cass, Benjamin W.A. Catterall, Jordan J. Clark, Emily A. Clarke, Sarah Cole, Louise Cooper, Helen Cox, Christopher Davis, Oslem Dincarslan, Alejandra Doce Carracedo, Chris Dunn, Philip Dyer, Angela Elliott, Anthony Evans, Lorna Finch, Lewis W.S. Fisher, Lisa Flaherty, Terry Foster, Isabel Garcia-Dorival, Philip Gunning, Catherine Hartley, Anthony Holmes, Rebecca L. Jensen, Christopher B. Jones, Trevor R. Jones, Shadia Khandaker, Katharine King, Robyn T. Kiy, Chrysa Koukorava, Annette Lake, Suzannah Lant, Diane Latawiec, Lara Lavelle-Langham, Daniella Lefteri, Lauren Lett, Lucia A Livoti, Maria Mancini, Hannah Massey, Nicole Maziere, Sarah McDonald, Laurence McEvoy, John McLauchlan, Soeren Metelmann, Nahida S. Miah, Joanna Middleton, Joyce Mitchell, Ellen G Murphy, Rebekah Penrice-Randal, Jack Pilgrim, Tessa Prince, Will Reynolds, P. Matthew Ridley, Debby Sales, Victoria E. Shaw, Rebecca K. Shears, Benjamin Small, Krishanthi S. Subramaniam, Agnieska Szemiel, Aislynn Taggart, Jolanta Tanianis-Hughes, Jordan Thomas, Erwan Trochu, Libby van Tonder, Eve Wilcock, J. Eunice Zhang, Seán Keating, Cara Donegan, Rebecca G. Spencer, Chloe Donohue, Fiona Griffiths, Hayley Hardwick, Wilna Oosthuyzen, K. Abel, H. Adamali, D. Adeloye, O. Adeyemi, R. Adrego, L.A. Aguilar Jimenez, S. Ahmad, N. Ahmad Haider, R. Ahmed, N. Ahwireng, M. Ainsworth, B. Al-Sheklly, A. Alamoudi, M. Ali, M. Aljaroof, A.M. All, L. Allan, R.J. Allen, L. Allerton, L. Allsop, P. Almeida, D. Altmann, M. Alvarez Corral, S. Amoils, D. Anderson, C. Antoniades, G. Arbane, A. Arias, C. Armour, L. Armstrong, N. Armstrong, D. Arnold, H. Arnold, A. Ashish, A. Ashworth, M. Ashworth, S. Aslani, H. Assefa-Kebede, C. Atkin, P. Atkin, R. Aul, H. Aung, L. Austin, C. Avram, A. Ayoub, M. Babores, R. Baggott, J. Bagshaw, D. Baguley, L. Bailey, J.K. Baillie, S. Bain, M. Bakali, M. Bakau, E. Baldry, D. Baldwin, M. Baldwin, C. Ballard, A. Banerjee, B. Bang, R.E. Barker, L. Barman, S. Barratt, F. Barrett, D. Basire, N. Basu, M. Bates, A. Bates, R. Batterham, H. Baxendale, H. Bayes, M. Beadsworth, P. Beckett, M. Beggs, M. Begum, P. Beirne, D. Bell, R. Bell, K. Bennett, E. Beranova, A. Bermperi, A. Berridge, C. Berry, S. Betts, E. Bevan, K. Bhui, M. Bingham, K. Birchall, L. Bishop, K. Bisnauthsing, J. Blaikely, A. Bloss, A. Bolger, C.E. Bolton, J. Bonnington, A. Botkai, C. Bourne, M. Bourne, K. Bramham, L. Brear, G. Breen, J. Breeze, A. Briggs, E. Bright, C.E. Brightling, S. Brill, K. Brindle, L. Broad, A. Broadley, C. Brookes, M. Broome, A. Brown, J. Brown, J.S. Brown, M. Brown, V. Brown, T. Brugha, N. Brunskill, M. Buch, P. Buckley, A. Bularga, E. Bullmore, L. Burden, T. Burdett, D. Burn, G. Burns, A. Burns, J. Busby, R. Butcher, A. Butt, S. Byrne, P. Cairns, P.C. Calder, E. Calvelo, H. Carborn, B. Card, C. Carr, L. Carr, G. Carson, P. Carter, A. Casey, M. Cassar, J. Cavanagh, M. Chablani, T. Chalder, J.D. Chalmers, R.C. Chambers, F. Chan, K.M. Channon, K. Chapman, A. Charalambou, N. Chaudhuri, A. Checkley, J. Chen, Y. Cheng, L. Chetham, C. Childs, E.R. Chilvers, H. Chinoy, A. Chiribiri, K. Chong-James, G. Choudhury, N. Choudhury, P. Chowienczyk, C. Christie, M. Chrystal, D. Clark, C. Clark, J. Clarke, S. Clohisey, G. Coakley, Z. Coburn, S. Coetzee, J. Cole, C. Coleman, F. Conneh, D. Connell, B. Connolly, L. Connor, A. Cook, B. Cooper, J. Cooper, S. Cooper, D. Copeland, T. Cosier, M. Coulding, C. Coupland, E. Cox, T. Craig, P. Crisp, D. Cristiano, M.G. Crooks, A. Cross, I. Cruz, P. Cullinan, D. Cuthbertson, L. Daines, M. Dalton, P. Daly, A. Daniels, P. Dark, J. Dasgin, A. David, C. David, E. Davies, F. Davies, G. Davies, G.A. Davies, K. Davies, M.J. Davies, J. Dawson, E. Daynes, A. De Soyza, B. Deakin, A. 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Geddes, J. George, P. George, M. Gibbons, M. Gill, L. Gilmour, F. Gleeson, J. Glossop, S. Glover, N. Goodman, C. Goodwin, B. Gooptu, H. Gordon, T. Gorsuch, M. Greatorex, P.L. Greenhaff, W. Greenhalf, A. Greenhalgh, N.J. Greening, J. Greenwood, H. Gregory, R. Gregory, D. Grieve, D. Griffin, L. Griffiths, A-M. Guerdette, B. Guillen Guio, M. Gummadi, A. Gupta, S. Gurram, E. Guthrie, Z. Guy, H. H Henson, K. Hadley, A. Haggar, K. Hainey, B. Hairsine, P. Haldar, I. Hall, L. Hall, M. Halling-Brown, R. Hamil, A. Hancock, K. Hancock, N.A. Hanley, S. Haq, H.E. Hardwick, E. Hardy, T. Hardy, B. Hargadon, K. Harrington, E. Harris, V.C. Harris, E.M. Harrison, P. Harrison, N. Hart, A. Harvey, M. Harvey, M. Harvie, L. Haslam, M. Havinden-Williams, J. Hawkes, N. Hawkings, J. Haworth, A. Hayday, M. Haynes, J. Hazeldine, T. Hazelton, L.G. Heaney, C. Heeley, J.L. Heeney, M. Heightman, S. Heller, M. Henderson, L. Hesselden, M. Hewitt, V. Highett, T. Hillman, T. Hiwot, L.P. Ho, A. Hoare, M. Hoare, J. 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Kon, S. Kon, S.S. Kon, S. Koprowska, A. Korszun, I. Koychev, C. Kurasz, P. Kurupati, C. Laing, H. Lamlum, G. Landers, C. Langenberg, D. Lasserson, L. Lavelle-Langham, A. Lawrie, C. Lawson, A. Layton, A. Lea, O.C. Leavy, D. Lee, J-H. Lee, E. Lee, K. Leitch, R. Lenagh, D. Lewis, J. Lewis, K.E. Lewis, V. Lewis, N. Lewis-Burke, X. Li, T. Light, L. Lightstone, W. Lilaonitkul, L. Lim, S. Linford, A. Lingford-Hughes, M. Lipman, K. Liyanage, A. Lloyd, S. Logan, D. Lomas, N.I. Lone, R. Loosley, J.M. Lord, H. Lota, W. Lovegrove, A. Lucey, E. Lukaschuk, A. Lye, C. Lynch, S. MacDonald, G. MacGowan, I. Macharia, J. Mackie, L. Macliver, S. Madathil, G. Madzamba, N. Magee, M.M. Magtoto, N. Mairs, N. Majeed, E. Major, F. Malein, M. Malim, G. Mallison, W.D.-C. Man, S. Mandal, K. Mangion, C. Manisty, R. Manley, K. March, S. Marciniak, P. Marino, M. Mariveles, M. Marks, E. Marouzet, S. Marsh, B. Marshall, M. Marshall, J. Martin, A. Martineau, L.M. Martinez, N. Maskell, D. Matila, W. Matimba-Mupaya, L. Matthews, A. Mbuyisa, S. McAdoo, H. McAllister-Williams, A. McArdle, P. McArdle, D. McAulay, G.P. McCann, H.J.C. drury, J. McCormick, W. McCormick, P. McCourt, L. McGarvey, C. McGee, K. Mcgee, J. McGinness, K. McGlynn, A. McGovern, H. McGuinness, I.B. McInnes, J. McIntosh, E. McIvor, K. McIvor, L. McLeavey, A. McMahon, M.J. McMahon, L. McMorrow, T. Mcnally, M. McNarry, J. McNeill, A. McQueen, H. McShane, C. Mears, C. Megson, S. Megson, P. Mehta, J. Meiring, L. Melling, M. Mencias, D. Menzies, M. Merida Morillas, A. Michael, C. Miller, L. Milligan, C. Mills, N.L. Mills, L. Milner, S. Misra, J. Mitchell, A. Mohamed, N. Mohamed, S. Mohammed, P.L. Molyneaux, W. Monteiro, S. Moriera, A. Morley, L. Morrison, R. Morriss, A. Morrow, A.J. Moss, P. Moss, K. Motohashi, N. Msimanga, E. Mukaetova-Ladinska, U. Munawar, J. Murira, U. Nanda, H. Nassa, M. Nasseri, A. Neal, R. Needham, P. Neill, S. Neubauer, D.E. Newby, H. Newell, T. Newman, A. Newton-Cox, T. Nicholson, D. Nicoll, A. Nikolaidis, C.M. 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Pugmire, S. Quaid, J. Quigley, J. Quint, H. Qureshi, I.N. Qureshi, K. Radhakrishnan, N.M. Rahman, M. Ralser, B. Raman, A. Ramos, H. Ramos, J. Rangeley, B. Rangelov, L. Ratcliffe, P. Ravencroft, A. Reddington, R. Reddy, H. Redfearn, D. Redwood, A. Reed, M. Rees, T. Rees, K. Regan, W. Reynolds, C. Ribeiro, A. Richards, E. Richardson, M. Richardson, P. Rivera-Ortega, K. Roberts, E. Robertson, E. Robinson, L. Robinson, L. Roche, C. Roddis, J. Rodger, A. Ross, G. Ross, J. Rossdale, A. Rostron, A. Rowe, A. Rowland, J. Rowland, M.J. Rowland, S.L. Rowland-Jones, K. Roy, M. Roy, I. Rudan, R. Russell, E. Russell, G. Saalmink, R. Sabit, E.K. Sage, T. Samakomva, N. Samani, C. Sampson, K. Samuel, R. Samuel, A. Sanderson, E. Sapey, D. Saralaya, J. Sargant, C. Sarginson, T. Sass, N. Sattar, K. Saunders, R.M. Saunders, P. Saunders, L.C. Saunders, H. Savill, W. Saxon, A. Sayer, J. Schronce, W. Schwaeble, J.T. Scott, K. Scott, N. Selby, M.G. Semple, M. Sereno, T.A. Sewell, A. Shah, K. Shah, P. Shah, M. Shankar-Hari, M. Sharma, C. Sharpe, M. Sharpe, S. Shashaa, A. Shaw, K. Shaw, V. Shaw, A. Sheikh, S. Shelton, L. Shenton, K. Shevket, A. Shikotra, J. Short, S. Siddique, S. Siddiqui, J. Sidebottom, L. Sigfrid, G. Simons, J. Simpson, N. Simpson, A. Singapuri, C. Singh, S. Singh, S.J. Singh, D. Sissons, J. Skeemer, K. Slack, A. Smith, D. Smith, S. Smith, J. Smith, L. Smith, M. Soares, T.S. Solano, R. Solly, A.R. Solstice, T. Soulsby, D. Southern, D. Sowter, M. Spears, L.G. Spencer, F. Speranza, L. Stadon, S. Stanel, N. Steele, M. Steiner, D. Stensel, G. Stephens, L. Stephenson, M. Stern, I. Stewart, R. Stimpson, S. Stockdale, J. Stockley, W. Stoker, R. Stone, W. Storrar, A. Storrie, K. Storton, E. Stringer, S. Strong-Sheldrake, N. Stroud, C. Subbe, C.L. Sudlow, Z. Suleiman, C. Summers, C. Summersgill, D. Sutherland, D.L. Sykes, R. Sykes, N. Talbot, A.L. Tan, L. Tarusan, V. Tavoukjian, A. Taylor, C. Taylor, J. Taylor, A. Te, H. Tedd, C.J. Tee, J. Teixeira, H. Tench, S. Terry, S. Thackray-Nocera, F. Thaivalappil, B. Thamu, D. Thickett, C. Thomas, D.C. Thomas, S. Thomas, A.K. Thomas, T. Thomas-Woods, T. Thompson, A.A.R. Thompson, T. Thornton, M. Thorpe, R.S. Thwaites, J. Tilley, N. Tinker, G.F. Tiongson, M. Tobin, J. Tomlinson, C. Tong, M. Toshner, R. Touyz, K.A. Tripp, E. Tunnicliffe, A. Turnbull, E. Turner, S. Turner, V. Turner, K. Turner, S. Turney, L. Turtle, H. Turton, J. Ugoji, R. Ugwuoke, R. Upthegrove, J. Valabhji, M. Ventura, J. Vere, C. Vickers, B. Vinson, E. Wade, P. Wade, L.V. Wain, T. Wainwright, L.O. Wajero, S. Walder, S. Walker, E. Wall, T. Wallis, S. Walmsley, J.A. Walsh, S. Walsh, L. Warburton, T.J.C. Ward, K. Warwick, H. Wassall, S. Waterson, E. Watson, L. Watson, J. Watson, J. Weir McCall, C. Welch, H. Welch, B. Welsh, S. Wessely, S. West, H. Weston, H. Wheeler, S. White, V. Whitehead, J. Whitney, S. Whittaker, B. Whittam, V. Whitworth, A. Wight, J. Wild, M. Wilkins, D. Wilkinson, B. Williams, N. Williams, J. Williams, S.A. Williams-Howard, M. Willicombe, G. Willis, J. Willoughby, A. Wilson, D. Wilson, I. Wilson, N. Window, M. Witham, R. Wolf-Roberts, C. Wood, F. Woodhead, J. Woods, D.G. Wootton, J. Wormleighton, J. Worsley, D. Wraith, C. Wrey Brown, C. Wright, L. Wright, S. Wright, J. Wyles, I. Wynter, M. Xu, N. Yasmin, S. Yasmin, T. Yates, K.P. Yip, B. Young, S. Young, A. Young, A.J. Yousuf, A. Zawia, L. Zeidan, B. Zhao, B. Zheng, O. Zongo, Investigators, ISARIC4C, group, PHOSP-COVID collaborative, Sigfrid, L, ISARIC4C Investigators, and PHOSP-COVID collaborative group
Subjects: SARS-CoV-2 variants, Mucosal immunity, Nasal antibody, SDG 3 - Good Health and Well-being, Biochemistry, Genetics and Molecular Biology(all), SARS-CoV-2 immunity, Vaccination, COVID-19, General Medicine, Convalescent, General Biochemistry, Genetics and Molecular Biology
Abstract: Data sharing statement This is an Open Access article under the CC BY 4.0 license The ISARIC4C protocol, data sharing and publication policy are available at https://isaric4c.net. ISARIC4C's Independent Data and Material Access Committee welcomes applications for access to data and materials (https://isaric4c.net). The PHOSP-COVID protocol, consent form, definition and derivation of clinical characteristics and outcomes, training materials, regulatory documents, information about requests for data access, and other relevant study materials are available online: https://phosp.org/resource/. Access to these materials can be granted by contacting phosp@leicester.ac.uk and Phospcontracts@leicester.ac.uk. All data used in this study is available within ODAP and accessible under reasonable request. Data access criteria and information about how to request access is available online: https://phosp.org/resource/. If criteria are met and a request is made, access can be gained by signing the eDRIS user agreement. Supplementary data are available online at https://www.thelancet.com/journals/ebiom/article/PIIS2352-3964(22)00584-9/fulltext#supplementaryMaterial . Copyright © 2022 The Author(s). Background: Most studies of immunity to SARS-CoV-2 focus on circulating antibody, giving limited insights into mucosal defences that prevent viral replication and onward transmission. We studied nasal and plasma antibody responses one year after hospitalisation for COVID-19, including a period when SARS-CoV-2 vaccination was introduced. Methods: In this follow up study, plasma and nasosorption samples were prospectively collected from 446 adults hospitalised for COVID-19 between February 2020 and March 2021 via the ISARIC4C and PHOSP-COVID consortia. IgA and IgG responses to NP and S of ancestral SARS-CoV-2, Delta and Omicron (BA.1) variants were measured by electrochemiluminescence and compared with plasma neutralisation data. Findings: Strong and consistent nasal anti-NP and anti-S IgA responses were demonstrated, which remained elevated for nine months (p < 0.0001). Nasal and plasma anti-S IgG remained elevated for at least 12 months (p < 0.0001) with plasma neutralising titres that were raised against all variants compared to controls (p < 0.0001). Of 323 with complete data, 307 were vaccinated between 6 and 12 months; coinciding with rises in nasal and plasma IgA and IgG anti-S titres for all SARS-CoV-2 variants, although the change in nasal IgA was minimal (1.46-fold change after 10 months, p = 0.011) and the median remained below the positive threshold determined by pre-pandemic controls. Samples 12 months after admission showed no association between nasal IgA and plasma IgG anti-S responses (R = 0.05, p = 0.18), indicating that nasal IgA responses are distinct from those in plasma and minimally boosted by vaccination. Interpretation: The decline in nasal IgA responses 9 months after infection and minimal impact of subsequent vaccination may explain the lack of long-lasting nasal defence against reinfection and the limited effects of vaccination on transmission. These findings highlight the need to develop vaccines that enhance nasal immunity. Funding: This study has been supported by ISARIC4C and PHOSP-COVID consortia. ISARIC4C is supported by grants from the National Institute for Health and Care Research and the Medical Research Council. Liverpool Experimental Cancer Medicine Centre provided infrastructure support for this research. The PHOSP-COVD study is jointly funded by UK Research and Innovation and National Institute of Health and Care Research. The funders were not involved in the study design, interpretation of data or the writing of this manuscript. This work is supported by the following grants: The PHOSP-COVD study is jointly funded by UK Research and Innovation and National Institute for Health and Care Research (grant references: MR/V027859/1 and COV0319). ISARIC4C is supported by grants from the National Institute for Health and Care Research (award CO-CIN-01) and the Medical Research Council (grant MC_PC_19059) Liverpool Experimental Cancer Medicine Centre provided infrastructure support for this research (grant reference: C18616/A25153). Other grants which have supported this work include: the UK Coronavirus Immunology Consortium [funder reference:1257927], the Imperial Biomedical Research Centre (NIHR Imperial BRC, grant IS-BRC-1215-20013), the Health Protection Research Unit (HPRU) in Respiratory Infections at Imperial College London and NIHR HPRU in Emerging and Zoonotic Infections at University of Liverpool, both in partnership with Public Health England, [NIHR award 200907], Wellcome Trust and Department for International Development [215091/Z/18/Z], Health Data Research UK (HDR UK) [grant code: 2021.0155], Medical Research Council [grant code: MC_UU_12014/12], and NIHR Clinical Research Network for providing infrastructure support for this research. FL is supported by an MRC clinical training fellowship [award MR/W000970/1]. LPH is supported by Oxford NIHR Biomedical Research Centre. AART is supported by a BHF Intermediate Clinical Fellowship (FS/18/13/33281). SLRJ receives support from UKRI, GCRF, Rosetrees Trust, BHIVA, EDCTP, Globvac. JDC has grants from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Gilead Sciences, Grifols, Novartis and Insmed. RAE holds a NIHR Clinician Scientist Fellowship (CS-2016-16-020). AH is currently supported by UK Research and Innovation. NIHR and NIHR Manchester BRC. BR receives support from BHF Oxford Centre of Research Excellence, NIHR Oxford BRC and MRC. SJD is funded by an NIHR Global Research Professorship [NIHR300791]. DW is supported by an NIHR Advanced Fellowship. AH has received support from MRC and the Coronavirus Immunology Consortium (MR/V028448/1). LVW has received support from UKRI, GSK/Asthma + Lung UK and NIHR for this study. MGS has received support from NIHR UK, MRC UK and Health Protection Research Unit in Emerging & Zoonotic Infections, University of Liverpool. JKB is supported by the Wellcome Trust (223164/Z/21/Z) and UKRI (MC_PC_20004, MC_PC_19025, MC_PC_1905, MRNO2995X/1, and MC_PC_20029). PJMO is supported by a NIHR Senior Investigator Award [award 201385]. LT is supported by the Wellcome Trust [clinical career development fellowship grant number 205228/Z/16/Z], the Centre of Excellence in Infectious Diseases Research (CEIDR) and the Alder Hey Charity.
Published: 2022
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45. Residual Lung Abnormalities Following COVID-19 Hospitalization:Interim Analysis of the UKILD Post-COVID Study

Author: Iain, Stewart, Joseph, Jacob, Peter M, George, Philip L, Molyneaux, Joanna C, Porter, Richard J, Allen, Shahab, Aslani, J Kenneth, Baillie, Shaney L, Barratt, Paul, Beirne, Stephen M, Bianchi, John F, Blaikley, James D, Chalmers, Rachel C, Chambers, Nazia, Chaudhuri, Christopher, Coleman, Guilhem, Collier, Emma K, Denneny, Annemarie, Docherty, Omer, Elneima, Rachel A, Evans, Laura, Fabbri, Michael A, Gibbons, Fergus V, Gleeson, Bibek, Gooptu, Neil J, Greening, Beatriz, Guillen Guio, Ian P, Hall, Neil A, Hanley, Victoria, Harris, Ewen M, Harrison, Melissa, Heightman, Toby E, Hillman, Alex, Horsley, Linzy, Houchen-Wolloff, Ian, Jarrold, Simon R, Johnson, Mark G, Jones, Fasihul, Khan, Rod, Lawson, Olivia, Leavy, Nazir, Lone, Michael, Marks, Hamish, McAuley, Puja, Mehta, Dhruv, Parekh, Karen, Piper Hanley, Manuela, Platé, John, Pearl, Krisnah, Poinasamy, Jennifer K, Quint, Betty, Raman, Matthew, Richardson, Pilar, Rivera-Ortega, Laura, Saunders, Ruth, Saunders, Malcolm G, Semple, Marco, Sereno, Aarti, Shikotra, A John, Simpson, Amisha, Singapuri, David Jf, Smith, Mark, Spears, Lisa G, Spencer, Stefan, Stanel, David, Thickett, A A Roger, Thompson, Mathew, Thorpe, Simon Lf, Walsh, Samantha, Walker, Nicholas David, Weatherley, Mark, Weeks, Jim M, Wild, Dan G, Wootton, Chris E, Brightling, Ling-Pei, Ho, Louise V, Wain, and R Gisli, Jenkins
Abstract: RATIONALE: Shared symptoms and genetic architecture between COVID-19 and lung fibrosis suggests SARS-CoV-2 infection may lead to progressive lung damage.OBJECTIVES: The UKILD Post-COVID study interim analysis was planned to estimate the prevalence of residual lung abnormalities in people hospitalized with COVID-19 based on risk strata.METHODS: The Post-HOSPitalisation COVID Study (PHOSP-COVID) was used for capture of routine and research follow-up within 240 days from discharge. Thoracic CTs linked by PHOSP-COVID identifiers were scored for percentage of residual lung abnormalities (ground glass opacities and reticulations). Risk factors in linked CT were estimated with Bayesian binomial regression and risk strata were generated. Numbers within strata were used to estimate post-hospitalization prevalence using Bayesian binomial distributions. Sensitivity analysis was restricted to participants with protocol driven research follow-up.MEASUREMENTS AND MAIN RESULTS: The interim cohort comprised 3700 people. Of 209 subjects with linked CTs (median 119 days, interquartile range 83-155), 166 people (79.4%) had >10% involvement of residual lung abnormalities. Risk factors included abnormal chest X-ray (RR 1·21 95%CrI 1·05; 1·40), percent predicted DLcoCONCLUSIONS: Residual lung abnormalities were estimated in up to 11% of people discharged following COVID-19 related hospitalization. Health services should monitor at-risk individuals to elucidate long-term functional implications. This article is open access and distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).
Published: 2022
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46. Plasma steroid concentrations reflect disease severity during acute illness but not recovery after hospitalisation with COVID-19

Author: Kerri Devine, Brian R Walker, Natalie ZM Homer, Peter JM Openshaw, Baillie J. Kenneth, Ruth Andrew, Louise V Wain, Malcolm G Semple, and Rebecca M Reynolds
Published: 2022
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47. Rheumatoid arthritis and idiopathic pulmonary fibrosis: a bidirectional Mendelian randomisation study

Author: Olivia C Leavy, Leticia Kawano-Dourado, Iain D Stewart, Jennifer K Quint, Joshua J Solomon, Raphael Borie, Bruno Crestani, Louise V Wain, R Gisli Jenkins, Philippe Dieudé, and Cosetta Minelli
Abstract: IntroductionA usual interstitial pneumonia (UIP) pattern of lung injury is a key feature of idiopathic pulmonary fibrosis (IPF) and is also observed in up to 40% of individuals with rheumatoid arthritis (RA) related Interstitial Lung Disease (RA-ILD). The RA-UIP phenotype could result from either a causal relationship of RA on UIP or vice versa, or from a simple co-occurrence of RA and IPF due to shared demographic, genetic or environmental risk factors.MethodsWe used two-sample bidirectional Mendelian Randomisation (MR) to investigate the causal effects of RA on UIP and of UIP on RA, using variants from genome-wide association studies of RA (separately for seropositive and seronegative RA) and of IPF as genetic instruments. We conducted inverse-variance-weighted fixed-effect MR as a primary analysis and undertook sensitivity analyses to assess potential violations of the key MR assumption of no (horizontal) pleiotropy.ResultsSeropositive RA showed a significant protective effect on IPF (Odds Ratio, OR = 0.93; 95% Confidence Interval, CI: 0.87-0.99; P=0.032), while the MR in the other direction showed a strongly significant causal effect of IPF on seropositive RA (OR = 1.06, 95% CI: 1.04-1.08, P=1.22×10−11).ConclusionOur findings support the hypothesis that RA-UIP may be due to a cause-effect relationship between IPF and RA, rather than due to a coincidental occurrence of IPF in patients with RA. The causal effect of IPF on seropositive RA suggests that patho-mechanisms involved in the development of UIP may promote RA and would suggest that screening for UIP in asymptomatic RA patients may be warranted and may influence therapy management of patients with RA-UIP.
Published: 2022
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48. The causal relationship between gastro-esophageal reflux disease and idiopathic pulmonary fibrosis: A bidirectional two-sample Mendelian randomization study

Author: Carl J Reynolds, Fabiola Del Greco M, Richard J Allen, Carlos Flores, R Gisli Jenkins, Toby M Maher, Philip L Molyneaux, Imre Noth, Justin M Oldham, Louise V Wain, Jiyuan An, Jue-Sheng Ong, Stuart MacGregor, Tom A. Yates, Paul Cullinan, and Cosetta Minelli
Abstract: BackgroundGastro-esophageal reflux disease (GERD) is associated with idiopathic pulmonary fibrosis (IPF) in observational studies. It is not known if this association arises because GERD causes IPF, or IPF causes GERD, or because of confounding by factors, such as smoking, associated with both GERD and IPF. We used bidirectional Mendelian randomisation (MR), where genetic variants are used as instrumental variables to address issues of confounding and reverse causation, to examine how, if at all, GERD and IPF are causally related.Methods and resultsA bidirectional two-sample MR was performed to estimate the causal effect of GERD on IPF risk, and of IPF on GERD risk, using genetic data from the largest GERD (78,707 cases and 288,734 controls) and IPF (4,125 cases and 20,464 controls) genome-wide association meta-analyses currently available. GERD increased the risk of IPF, with an odds ratio (OR) of 1.6 (95% Confidence Interval, CI: 1.04-2.49; p=0.032). There was no evidence of a causal effect of IPF on the risk of GERD, with an OR of 0.99 (95%CI: 0.97-1.02; p=0.615).ConclusionWe found that GERD increases the risk of IPF, but found no evidence that IPF increases the risk of GERD. GERD should be considered in future studies of IPF risk, and interest in it as a potential therapeutic target should be renewed. The mechanisms underlying the effect of GERD on IPF should also be investigated.
Published: 2022
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49. A systematic analysis of protein-altering exonic variants in chronic obstructive pulmonary disease

Author: Josée Dupuis, Victoria E. Jackson, Hanfei Xu, Brian D. Hobbs, Edwin K. Silverman, Michael H. Cho, Megan L. Grove, Jennifer N. Nguyen, Jiangyuan Liu, George T. O'Connor, Natalie Terzikhan, Ani Manichaikul, Patricia A. Cassano, Colleen M. Sitlani, Buhm Han, Ian P. Hall, Bing Yu, Sina A. Gharib, Lies Lahousse, Louise V. Wain, Traci M. Bartz, Christopher J. Benway, R. Graham Barr, Phuwanat Sakornsakolpat, Guy Brusselle, Stephanie J. London, Kun Hee Kim, Martin D. Tobin, Matthew Moll, Jinkyeong Park, Woo Jin Kim, Bonnie K Patchen, Stephen S. Rich, and Epidemiology
Subjects: 0301 basic medicine, Nonsynonymous substitution, Pulmonary and Respiratory Medicine, EXPRESSION, Genetic Markers, Physiology, Genome-wide association study, Biology, Polymorphism, Single Nucleotide, chronic obstructive pulmonary disease, GENETIC ASSOCIATION, 03 medical and health sciences, Pulmonary Disease, Chronic Obstructive, 0302 clinical medicine, DESIGN, Meta-Analysis as Topic, Physiology (medical), Medicine and Health Sciences, genomics, COPD, Humans, Exome, Genetic Predisposition to Disease, exon, Allele, GENOME-WIDE ASSOCIATION, Genotyping, Genetic association, Genetics, ZINC-FINGER PROTEIN, Odds ratio, Cell Biology, GENOTYPE, Minor allele frequency, LUNG-FUNCTION, functional, 030104 developmental biology, 030228 respiratory system, ATHEROSCLEROSIS, Gene Expression Regulation, SMOKING, exome, Genome-Wide Association Study, Research Article
Abstract: Genome-wide association studies (GWASs) have identified regions associated with chronic obstructive pulmonary disease (COPD). GWASs of other diseases have shown an approximately 10-fold overrepresentation of nonsynonymous variants, despite limited exonic coverage on genotyping arrays. We hypothesized that a large-scale analysis of coding variants could discover novel genetic associations with COPD, including rare variants with large effect sizes. We performed a meta-analysis of exome arrays from 218,399 controls and 33,851 moderate-to-severe COPD cases. All exome-wide significant associations were present in regions previously identified by GWAS. We did not identify any novel rare coding variants with large effect sizes. Within GWAS regions on chromosomes 5q, 6p, and 15q, four coding variants were conditionally significant ( P < 0.00015) when adjusting for lead GWAS single-nucleotide polymorphisms A common gasdermin B ( GSDMB) splice variant (rs11078928) previously associated with a decreased risk for asthma was nominally associated with a decreased risk for COPD [minor allele frequency (MAF) = 0.46, P = 1.8e-4]. Two stop variants in coiled-coil α-helical rod protein 1 ( CCHCR1), a gene involved in regulating cell proliferation, were associated with COPD (both P < 0.0001). The SERPINA1 Z allele was associated with a random-effects odds ratio of 1.43 for COPD (95% confidence interval = 1.17–1.74), though with marked heterogeneity across studies. Overall, COPD-associated exonic variants were identified in genes involved in DNA methylation, cell-matrix interactions, cell proliferation, and cell death. In conclusion, we performed the largest exome array meta-analysis of COPD to date and identified potential functional coding variants. Future studies are needed to identify rarer variants and further define the role of coding variants in COPD pathogenesis.
Published: 2021
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50. The use of genetic information to define idiopathic pulmonary fibrosis in UK biobank

Author: Olivia C. Leavy, Richard J. Allen, Luke M. Kraven, Ann D. Morgan, Martin D. Tobin, Jennifer K. Quint, R. Gisli Jenkins, and Louise V. Wain
Subjects: Pulmonary and Respiratory Medicine, Cardiology and Cardiovascular Medicine, Critical Care and Intensive Care Medicine
Published: 2022

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