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1. Misexpression of inactive genes in whole blood is associated with nearby rare structural variants

Author

Vanderstichele, Thomas, Burnham, Katie L., de Klein, Niek, Tardaguila, Manuel, Howell, Brittany, Walter, Klaudia, Kundu, Kousik, Koeppel, Jonas, Lee, Wanseon, Tokolyi, Alex, Persyn, Elodie, Nath, Artika P., Marten, Jonathan, Petrovski, Slavé, Roberts, David J., Di Angelantonio, Emanuele, Danesh, John, Berton, Alix, Platt, Adam, Butterworth, Adam S., Soranzo, Nicole, Parts, Leopold, Inouye, Michael, Paul, Dirk S., and Davenport, Emma E.

Published
2024
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2. eQTLs identify regulatory networks and drivers of variation in the individual response to sepsis

Author

Addison, Jenni, Galley, Helen, Hall, Sally, Roughton, Sian, Taylor, Jane, Tennant, Heather, Webster, Nigel, Guleri, Achyut, Waddington, Natalia, Arawwawala, Dilshan, Durcan, John, Mitchell-Inwang, Christine, Short, Alasdair, Smolen, Susan, Swan, Karen, Williams, Sarah, Errington, Emily, Gordon, Tony, Templeton, Maie, McCauley, Marie, Venatesh, Pyda, Ward, Geraldine, Baudouin, Simon, Grier, Sally, Hall, Elaine, Higham, Charley, Soar, Jasmeet, Brett, Stephen, Kitson, David, Moreno, Juan, Mountford, Laura, Wilson, Robert, Hall, Peter, Hewlett, Jackie, McKechnie, Stuart, Faras-Arraya, Roser, Garrard, Christopher, Hutton, Paula, Millo, Julian, Parsons, Penny, Smiths, Alex, Young, Duncan, Raymode, Parizade, Andreou, Prem, Bowrey, Sarah, Hales, Dawn, Kazembe, Sandra, Rich, Natalie, Roberts, Emma, Thompson, Jonathan, Fletcher, Simon, Glister, Georgina, Rosbergen, Melissa, Cuesta, Jeronimo Moreno, Bion, Julian, Carrera, Ronald, Lees, Sarah, Millar, Joanne, Mitchell, Natalie, Nilson, Annette, Perry, Elsa Jane, Ruel, Sebastian, Wilde, Jude, Willis, Heather, Atkinson, Jane, Brown, Abby, Jacques, Nicola, Kapila, Atul, Prowse, Heather, Bland, Martin, Bullock, Lynne, Harrison, Donna, Krige, Anton, Mills, Gary, Humphreys, John, Armitage, Kelsey, Laha, Shond, Baldwin, Jacqueline, Walsh, Angela, Doherty, Nicola, Drage, Stephen, Ortiz-Ruiz de Gordoa, Laura, Lowes, Sarah, Walsh, Helen, Calder, Verity, Swan, Catherine, Payne, Heather, Higgins, David, Andrews, Sarah, Mappleback, Sarah, Hinds, Charles, Watson, D., McLees, Eleanor, Purdy, Alice, Stotz, Martin, Ochelli-Okpue, Adaeze, Bonner, Stephen, Whitehead, Iain, Hugil, Keith, Goodridge, Victoria, Cawthor, Louisa, Kuper, Martin, Pahary, Sheik, Bellingan, Geoffrey, Marshall, Richard, Montgomery, Hugh, Ryu, Jung Hyun, Bercades, Georgia, Boluda, Susan, Bentley, Andrew, Mccalman, Katie, Jefferies, Fiona, Allcock, Alice, Burnham, Katie, Davenport, Emma, Geoghegan, Cyndi, Knight, Julian, Maugeri, Narelle, Mi, Yuxin, Radhakrishnan, Jayachandran, Burnham, Katie L., Milind, Nikhil, Lee, Wanseon, Kwok, Andrew J., Cano-Gamez, Kiki, Geoghegan, Cyndi G., Zhang, Ping, Soranzo, Nicole, Hinds, Charles J., Knight, Julian C., and Davenport, Emma E.

Published
2024
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3. The common VTE-protective G haplotype of F5 increases factor V-short, TFPI function, and risk of bleeding

Author

Sims, Matthew C., Gierula, Magdalena, Stephens, Jonathan C., Tokolyi, Alex, Stefanucci, Luca, Persyn, Elodie, Sun, Luanluan, Collins, Janine H., Davenport, Emma E., Di Angelantonio, Emanuele, Downes, Kate, Inouye, Michael, Paul, Dirk S., Thomas, Will, Tolios, Alexander, Ouwehand, Willem H., Gleadall, Nicholas S., Crawley, James T. B., Butterworth, Adam S., Frontini, Mattia, and Ahnström, Josefin

Published
2024
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5. An atlas of genetic scores to predict multi-omic traits

Author

Xu, Yu, Ritchie, Scott C., Liang, Yujian, Timmers, Paul R. H. J., Pietzner, Maik, Lannelongue, Loïc, Lambert, Samuel A., Tahir, Usman A., May-Wilson, Sebastian, Foguet, Carles, Johansson, Åsa, Surendran, Praveen, Nath, Artika P., Persyn, Elodie, Peters, James E., Oliver-Williams, Clare, Deng, Shuliang, Prins, Bram, Luan, Jian’an, Bomba, Lorenzo, Soranzo, Nicole, Di Angelantonio, Emanuele, Pirastu, Nicola, Tai, E. Shyong, van Dam, Rob M., Parkinson, Helen, Davenport, Emma E., Paul, Dirk S., Yau, Christopher, Gerszten, Robert E., Mälarstig, Anders, Danesh, John, Sim, Xueling, Langenberg, Claudia, Wilson, James F., Butterworth, Adam S., and Inouye, Michael

Published
2023
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8. A blood atlas of COVID-19 defines hallmarks of disease severity and specificity

Author

Ahern, David J., Ai, Zhichao, Ainsworth, Mark, Allan, Chris, Allcock, Alice, Angus, Brian, Ansari, M. Azim, Arancibia-Cárcamo, Carolina V., Aschenbrenner, Dominik, Attar, Moustafa, Baillie, J. Kenneth, Barnes, Eleanor, Bashford-Rogers, Rachael, Bashyal, Archana, Beer, Sally, Berridge, Georgina, Beveridge, Amy, Bibi, Sagida, Bicanic, Tihana, Blackwell, Luke, Bowness, Paul, Brent, Andrew, Brown, Andrew, Broxholme, John, Buck, David, Burnham, Katie L., Byrne, Helen, Camara, Susana, Candido Ferreira, Ivan, Charles, Philip, Chen, Wentao, Chen, Yi-Ling, Chong, Amanda, Clutterbuck, Elizabeth A., Coles, Mark, Conlon, Christopher P., Cornall, Richard, Cribbs, Adam P., Curion, Fabiola, Davenport, Emma E., Davidson, Neil, Davis, Simon, Dendrou, Calliope A., Dequaire, Julie, Dib, Lea, Docker, James, Dold, Christina, Dong, Tao, Downes, Damien, Drakesmith, Hal, Dunachie, Susanna J., Duncan, David A., Eijsbouts, Chris, Esnouf, Robert, Espinosa, Alexis, Etherington, Rachel, Fairfax, Benjamin, Fairhead, Rory, Fang, Hai, Fassih, Shayan, Felle, Sally, Fernandez Mendoza, Maria, Ferreira, Ricardo, Fischer, Roman, Foord, Thomas, Forrow, Aden, Frater, John, Fries, Anastasia, Gallardo Sanchez, Veronica, Garner, Lucy C., Geeves, Clementine, Georgiou, Dominique, Godfrey, Leila, Golubchik, Tanya, Gomez Vazquez, Maria, Green, Angie, Harper, Hong, Harrington, Heather A., Heilig, Raphael, Hester, Svenja, Hill, Jennifer, Hinds, Charles, Hird, Clare, Ho, Ling-Pei, Hoekzema, Renee, Hollis, Benjamin, Hughes, Jim, Hutton, Paula, Jackson-Wood, Matthew A., Jainarayanan, Ashwin, James-Bott, Anna, Jansen, Kathrin, Jeffery, Katie, Jones, Elizabeth, Jostins, Luke, Kerr, Georgina, Kim, David, Klenerman, Paul, Knight, Julian C., Kumar, Vinod, Kumar Sharma, Piyush, Kurupati, Prathiba, Kwok, Andrew, Lee, Angela, Linder, Aline, Lockett, Teresa, Lonie, Lorne, Lopopolo, Maria, Lukoseviciute, Martyna, Luo, Jian, Marinou, Spyridoula, Marsden, Brian, Martinez, Jose, Matthews, Philippa C., Mazurczyk, Michalina, McGowan, Simon, McKechnie, Stuart, Mead, Adam, Mentzer, Alexander J., Mi, Yuxin, Monaco, Claudia, Montadon, Ruddy, Napolitani, Giorgio, Nassiri, Isar, Novak, Alex, O'Brien, Darragh P., O'Connor, Daniel, O'Donnell, Denise, Ogg, Graham, Overend, Lauren, Park, Inhye, Pavord, Ian, Peng, Yanchun, Penkava, Frank, Pereira Pinho, Mariana, Perez, Elena, Pollard, Andrew J., Powrie, Fiona, Psaila, Bethan, Quan, T. Phuong, Repapi, Emmanouela, Revale, Santiago, Silva-Reyes, Laura, Richard, Jean-Baptiste, Rich-Griffin, Charlotte, Ritter, Thomas, Rollier, Christine S., Rowland, Matthew, Ruehle, Fabian, Salio, Mariolina, Sansom, Stephen Nicholas, Sanches Peres, Raphael, Santos Delgado, Alberto, Sauka-Spengler, Tatjana, Schwessinger, Ron, Scozzafava, Giuseppe, Screaton, Gavin, Seigal, Anna, Semple, Malcolm G., Sergeant, Martin, Simoglou Karali, Christina, Sims, David, Skelly, Donal, Slawinski, Hubert, Sobrinodiaz, Alberto, Sousos, Nikolaos, Stafford, Lizzie, Stockdale, Lisa, Strickland, Marie, Sumray, Otto, Sun, Bo, Taylor, Chelsea, Taylor, Stephen, Taylor, Adan, Thongjuea, Supat, Thraves, Hannah, Todd, John A., Tomic, Adriana, Tong, Orion, Trebes, Amy, Trzupek, Dominik, Tucci, Felicia Anna, Turtle, Lance, Udalova, Irina, Uhlig, Holm, van Grinsven, Erinke, Vendrell, Iolanda, Verheul, Marije, Voda, Alexandru, Wang, Guanlin, Wang, Lihui, Wang, Dapeng, Watkinson, Peter, Watson, Robert, Weinberger, Michael, Whalley, Justin, Witty, Lorna, Wray, Katherine, Xue, Luzheng, Yeung, Hing Yuen, Yin, Zixi, Young, Rebecca K., Youngs, Jonathan, Zhang, Ping, and Zurke, Yasemin-Xiomara

Published
2022
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10. Transcriptional reprogramming from innate immune functions to a pro-thrombotic signature by monocytes in COVID-19

Author

Maher, Allison K., Burnham, Katie L., Jones, Emma M., Tan, Michelle M. H., Saputil, Rocel C., Baillon, Laury, Selck, Claudia, Giang, Nicolas, Argüello, Rafael, Pillay, Clio, Thorley, Emma, Short, Charlotte-Eve, Quinlan, Rachael, Barclay, Wendy S., Cooper, Nichola, Taylor, Graham P., Davenport, Emma E., and Dominguez-Villar, Margarita

Published
2022
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11. Microarray analysis demonstrates up-regulation of the endothelin-1 gene with compensatory down-regulation of the ETA receptor gene in human portal vein.

Author

Owen, Nicola E., Williams, Thomas L., Maguire, Janet J., Kuc, Rhoda E., Davenport, Emma E., and Davenport, Anthony P.

Subjects
ENDOTHELIN receptors, LIVER regeneration, THROMBIN receptors, PORTAL vein, PREPROENDOTHELIN, DOWNREGULATION, TRANSCRIPTION factors, LIFE sciences
Abstract

This article discusses a study that analyzed gene expression in portal veins from patients with portal hypertension (PH) and cirrhosis. The study identified several genes that could be potential drug targets for the treatment of PH. The findings suggest that targeting genes involved in the endothelin pathway and G protein-coupled receptors could be beneficial in treating PH. The article also mentions the potential use of ETA receptor antagonists as a therapy for PH. Additionally, the document provides a list of references for further research on liver transplantation, portal hypertension, and the use of different medications in the treatment of cirrhosis. [Extracted from the article]

Published
2024
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12. Patient stratification using plasma cytokines and their regulators in sepsis: relationship to outcomes, treatment effect and leucocyte transcriptomic subphenotypes

Author

Antcliffe, David Benjamin, primary, Mi, Yuxin, additional, Santhakumaran, Shalini, additional, Burnham, Katie L, additional, Prevost, A Toby, additional, Ward, Josie K, additional, Marshall, Timothy J, additional, Bradley, Claire, additional, Al-Beidh, Farah, additional, Hutton, Paula, additional, McKechnie, Stuart, additional, Davenport, Emma E, additional, Hinds, Charles J, additional, O'Kane, Cecilia M, additional, McAuley, Daniel Francis, additional, Shankar-Hari, Manu, additional, Gordon, Anthony C, additional, and Knight, Julian C, additional

Published
2024
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14. High-throughput mass spectrometry maps the sepsis plasma proteome and differences in patient response.

Author

Mi, Yuxin, Burnham, Katie L., Charles, Philip D., Heilig, Raphael, Vendrell, Iolanda, Whalley, Justin, Torrance, Hew D., Antcliffe, David B., May, Shaun M., Neville, Matt J., Berridge, Georgina, Hutton, Paula, Geoghegan, Cyndi G., Radhakrishnan, Jayachandran, Nesvizhskii, Alexey I., Yu, Fengchao, Davenport, Emma E., McKechnie, Stuart, Davies, Roger, and O'Callaghan, David J. P.

Subjects
SEPSIS, MASS spectrometry, INDUCTIVELY coupled plasma mass spectrometry, LIQUID chromatography-mass spectrometry, TANDEM mass spectrometry
Abstract

Sepsis, the dysregulated host response to infection causing life-threatening organ dysfunction, is a global health challenge requiring better understanding of pathophysiology and new therapeutic approaches. Here, we applied high-throughput tandem mass spectrometry to delineate the plasma proteome for sepsis and comparator groups (noninfected critical illness, postoperative inflammation, and healthy volunteers) involving 2612 samples (from 1611 patients) and 4553 liquid chromatography–mass spectrometry analyses acquired through a single batch of continuous measurements, with a throughput of 100 samples per day. We show how this scale of data can delineate proteins, pathways, and coexpression modules in sepsis and be integrated with paired leukocyte transcriptomic data (837 samples from n = 649 patients). We mapped the plasma proteomic landscape of the host response in sepsis, including changes over time, and identified features relating to etiology, clinical phenotypes (including organ failures), and severity. This work reveals subphenotypes informative for sepsis response state, disease processes, and outcome; identifies potential biomarkers; and advances opportunities for a precision medicine approach to sepsis. Editor's summary: Sepsis is caused by an extreme immune response to infection and can damage organs and potentially lead to death. To better understand what happens to the body during sepsis, Mi et al. comprehensively profiled the plasma proteomes of ICU patients with sepsis. The longitudinal nature of their sampling allowed the authors to assess changes in the plasma proteome over time and to assess heterogeneity in patient responses. The group also profiled relevant comparator groups, including noninfected ICU patients, individuals with postoperative inflammation, and healthy individuals, allowing for the detection of sepsis-specific responses. This study offers insights into sepsis biology and a valuable resource for further research. —Catherine Charneski [ABSTRACT FROM AUTHOR]

Published
2024
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15. Genetic determinants of blood gene expression and splicing and their contribution to molecular phenotypes and health outcomes

Author

Tokolyi, Alex, primary, Persyn, Elodie, additional, Nath, Artika P., additional, Burnham, Katie L., additional, Marten, Jonathan, additional, Vanderstichele, Thomas, additional, Tardaguila, Manuel, additional, Stacey, David, additional, Farr, Ben, additional, Iyer, Vivek, additional, Jiang, Xilin, additional, Lambert, Samuel A., additional, Noell, Guillaume, additional, Quail, Michael A., additional, Rajan, Diana, additional, Ritchie, Scott C., additional, Sun, Benjamin B., additional, Thurston, Scott A.J., additional, Xu, Yu, additional, Whelan, Christopher D., additional, Runz, Heiko, additional, Petrovski, Slavé, additional, Gaffney, Daniel J., additional, Roberts, David J., additional, Di Angelantonio, Emanuele, additional, Peters, James E., additional, Soranzo, Nicole, additional, Danesh, John, additional, Butterworth, Adam S., additional, Inouye, Michael, additional, Davenport, Emma E., additional, and Paul, Dirk S., additional

Published
2023
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16. BurkHostGEN: a study protocol for evaluating variations in the Burkholderia pseudomallei and host genomes associated with melioidosis infection

Author

Angchagun, Kesorn, primary, Boonklang, Phumrapee, additional, Chomkatekaew, Chalita, additional, Pakdeerat, Sukritpong, additional, Wongsuwan, Gumphol, additional, Amornchai, Premjit, additional, Wuthiekanun, Vanaporn, additional, Panapipat, Salwaluk, additional, Ngernseng, Thatsanun, additional, Waithira, Naomi, additional, Walton, Steve, additional, Limmathurotsakul, Direk, additional, Surawong, Anoree, additional, Siriboon, Suwatthiya, additional, Chamnan, Parinya, additional, Chantratita, Narisara, additional, Dunachie, Susie, additional, Corander, Jukka, additional, Davenport, Emma E., additional, Knight, Julian, additional, Parkhill, Julian, additional, Peacock, Sharon J., additional, Thomson, Nicholas R., additional, Day, Nicholas P.J., additional, and Chewapreecha, Claire, additional

Published
2023
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17. A Transcriptomic Approach to Understand Patient Susceptibility to Pneumonia After Abdominal Surgery

Author

Torrance, Hew D, primary, Zhang, Ping, additional, Longbottom, E Rebecca, additional, Mi, Yuxin, additional, Whalley, Justin P, additional, Allcock, Alice, additional, Kwok, Andrew J, additional, Cano-Gamez, Eddie, additional, Geoghegan, Cyndi G, additional, Burnham, Katie L, additional, Antcliffe, David B, additional, Davenport, Emma E, additional, Pearse, Rupert M, additional, O’Dwyer, Michael J, additional, Hinds, Charles J, additional, Knight, Julian C, additional, and Gordon, Anthony C, additional

Published
2023
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18. Classification of patients with sepsis according to blood genomic endotype: a prospective cohort study

Author

de Beer, Friso M., Bos, Lieuwe D.J., Frencken, Jos F., Koster-Brouwer, Maria E., van de Groep, Kirsten, Verboom, Diana M., Glas, Gerie J., van Hooijdonk, Roosmarijn T.M., Hoogendijk, Arie J., Huson, Mischa A., Klouwenberg, Peter M. Klein, Ong, David S.Y., Schouten, Laura R.A., Straat, Marleen, Witteveen, Esther, Wieske, Luuk, Scicluna, Brendon P, van Vught, Lonneke A, Zwinderman, Aeilko H, Wiewel, Maryse A, Davenport, Emma E, Burnham, Katie L, Nürnberg, Peter, Schultz, Marcus J, Horn, Janneke, Cremer, Olaf L, Bonten, Marc J, Hinds, Charles J, Wong, Hector R, Knight, Julian C, and van der Poll, Tom

Published
2017
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22. Genome-wide association study of survival from sepsis due to pneumonia: an observational cohort study

Author

Rautanen, Anna, Mills, Tara C, Gordon, Anthony C, Hutton, Paula, Steffens, Michael, Nuamah, Rosamond, Chiche, Jean-Daniel, Parks, Tom, Chapman, Stephen J, Davenport, Emma E, Elliott, Katherine S, Bion, Julian, Lichtner, Peter, Meitinger, Thomas, Wienker, Thomas F, Caulfield, Mark J, Mein, Charles, Bloos, Frank, Bobek, Ilona, Cotogni, Paolo, Sramek, Vladimir, Sarapuu, Silver, Kobilay, Makbule, Ranieri, V Marco, Rello, Jordi, Sirgo, Gonzalo, Weiss, Yoram G, Russwurm, Stefan, Schneider, E Marion, Reinhart, Konrad, Holloway, Paul A H, Knight, Julian C, Garrard, Chris S, Russell, James A, Walley, Keith R, Stüber, Frank, Hill, Adrian V S, and Hinds, Charles J

Published
2015
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24. Inflammatory sub-phenotypes in sepsis: relationship to outcomes, treatment effect and transcriptomic sub-phenotypes

Author

Antcliffe, David B, primary, Mi, Yuxin, additional, Santhakumaran, Shalini, additional, Burnham, Katie L, additional, Prevost, A Toby, additional, Ward, Josie K, additional, Marshall, Timothy, additional, Bradley, Claire, additional, Al-Beidh, Farah, additional, Hutton, Paula, additional, McKechnie, Stuart, additional, Davenport, Emma E, additional, Hinds, Charles J, additional, O’Kane, Cecilia M, additional, McAuley, Daniel F, additional, Shankar-Hari, Manu, additional, Gordon, Anthony C, additional, and Knight, Julian C, additional

Published
2022
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26. Inducible apelin receptor knockdown reduces differentiation efficiency and contractility of hESC-derived cardiomyocytes

Author

Macrae, Robyn G C, primary, Colzani, Maria T, additional, Williams, Thomas L, additional, Bayraktar, Semih, additional, Kuc, Rhoda E, additional, Pullinger, Anna L, additional, Bernard, William G, additional, Robinson, Emma L, additional, Davenport, Emma E, additional, Maguire, Janet J, additional, Sinha, Sanjay, additional, and Davenport, Anthony P, additional

Published
2022
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27. An atlas of genetic scores to predict multi-omic traits

Author

Xu, Yu, primary, Ritchie, Scott C., additional, Liang, Yujian, additional, Timmers, Paul R. H. J., additional, Pietzner, Maik, additional, Lannelongue, Loïc, additional, Lambert, Samuel A., additional, Tahir, Usman A., additional, May-Wilson, Sebastian, additional, Johansson, Åsa, additional, Surendran, Praveen, additional, Nath, Artika P, additional, Persyn, Elodie, additional, Peters, James E., additional, Oliver-Williams, Clare, additional, Deng, Shuliang, additional, Prins, Bram, additional, Foguet, Carles, additional, Luan, Jian’an, additional, Bomba, Lorenzo, additional, Soranzo, Nicole, additional, Angelantonio, Emanuele Di, additional, Pirastu, Nicola, additional, Tai, E Shyong, additional, van Dam, Rob M, additional, Davenport, Emma E, additional, Paul, Dirk S., additional, Yau, Christopher, additional, Gerszten, Robert E., additional, Mälarstig, Anders, additional, Danesh, John, additional, Sim, Xueling, additional, Langenberg, Claudia, additional, Wilson, James F., additional, Butterworth, Adam S., additional, and Inouye, Michael, additional

Published
2022
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28. Transcriptional reprogramming from innate immune functions to a pro-thrombotic signature upon SARS-CoV-2 sensing by monocytes in COVID-19

Author

Maher, Allison K., primary, Burnham, Katie L., additional, Jones, Emma, additional, Baillon, Laury, additional, Selck, Claudia, additional, Giang, Nicolas, additional, Argüello, Rafael, additional, Short, Charlotte-Eve, additional, Quinlan, Rachael, additional, Barclay, Wendy S., additional, Cooper, Nichola, additional, Taylor, Graham P., additional, Davenport, Emma E., additional, and Dominguez-Villar, Margarita, additional

Published
2022
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29. Genetically personalised organ-specific metabolic models in health and disease

Author

Foguet, Carles, primary, Xu, Yu, additional, Ritchie, Scott C., additional, Lambert, Samuel A., additional, Persyn, Elodie, additional, Nath, Artika P., additional, Davenport, Emma E., additional, Roberts, David J., additional, Paul, Dirk S., additional, Angelantonio, Emanuele Di, additional, Danesh, John, additional, Butterworth, Adam S., additional, Yau, Christopher, additional, and Inouye, Michael, additional

Published
2022
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30. Inducible apelin receptor knockdown reduces differentiation efficiency and contractility of hESC-derived cardiomyocytes

Author

Macrae, Robyn GC, Colzani, Maria T, Williams, Thomas L, Bayraktar, Semih, Kuc, Rhoda E, Pullinger, Anna L, Bernard, William G, Robinson, Emma L, Davenport, Emma E, Maguire, Janet J, Sinha, Sanjay, Davenport, Anthony P, Macrae, Robyn GC [0000-0002-8129-7242], Pullinger, Anna L [0000-0002-3372-887X], Robinson, Emma L [0000-0002-4866-731X], Davenport, Anthony P [0000-0002-2096-3117], and Apollo - University of Cambridge Repository

Subjects
Adult, Apelin Receptors, Stem cell, Physiology, Human Embryonic Stem Cells, Cell Differentiation, Cardiomyocyte, Cardiovascular disease, Apelin receptor, Physiology (medical), Humans, Apelin, Myocytes, Cardiac, Cardiology and Cardiovascular Medicine, Embryonic Stem Cells
Abstract

Aims The apelin receptor, a G protein-coupled receptor, has emerged as a key regulator of cardiovascular development, physiology, and disease. However, there is a lack of suitable human in vitro models to investigate the apelinergic system in cardiovascular cell types. For the first time we have used human embryonic stem cell-derived cardiomyocytes (hESC-CMs) and a novel inducible knockdown system to examine the role of the apelin receptor in both cardiomyocyte development and to determine the consequences of loss of apelin receptor function as a model of disease. Methods and results Expression of the apelin receptor and its ligands in hESCs and hESC-CMs was determined. hESCs carrying a tetracycline-inducible short hairpin RNA targeting the apelin receptor were generated using the sOPTiKD system. Phenotypic assays characterized the consequences of either apelin receptor knockdown before hESC-CM differentiation (early knockdown) or in 3D engineered heart tissues as a disease model (late knockdown). hESC-CMs expressed the apelin signalling system at a similar level to the adult heart. Early apelin receptor knockdown decreased cardiomyocyte differentiation efficiency and prolonged voltage sensing, associated with asynchronous contraction. Late apelin receptor knockdown had detrimental consequences on 3D engineered heart tissue contractile properties, decreasing contractility and increasing stiffness. Conclusions We have successfully knocked down the apelin receptor, using an inducible system, to demonstrate a key role in hESC-CM differentiation. Knockdown in 3D engineered heart tissues recapitulated the phenotype of apelin receptor down-regulation in a failing heart, providing a potential platform for modelling heart failure and testing novel therapeutic strategies.

Published
2021

31. Inducible apelin receptor knockdown reduces differentiation efficiency and contractility of hESC-derived cardiomyocytes.

Author

Macrae, Robyn G C, Colzani, Maria T, Williams, Thomas L, Bayraktar, Semih, Kuc, Rhoda E, Pullinger, Anna L, Bernard, William G, Robinson, Emma L, Davenport, Emma E, Maguire, Janet J, Sinha, Sanjay, and Davenport, Anthony P

Subjects
APELIN, G protein coupled receptors, DOWNREGULATION, CARDIOVASCULAR development, CARDIOVASCULAR system
Abstract

Aims The apelin receptor, a G protein-coupled receptor, has emerged as a key regulator of cardiovascular development, physiology, and disease. However, there is a lack of suitable human in vitro models to investigate the apelinergic system in cardiovascular cell types. For the first time we have used human embryonic stem cell-derived cardiomyocytes (hESC-CMs) and a novel inducible knockdown system to examine the role of the apelin receptor in both cardiomyocyte development and to determine the consequences of loss of apelin receptor function as a model of disease. Methods and results Expression of the apelin receptor and its ligands in hESCs and hESC-CMs was determined. hESCs carrying a tetracycline-inducible short hairpin RNA targeting the apelin receptor were generated using the sOPTiKD system. Phenotypic assays characterized the consequences of either apelin receptor knockdown before hESC-CM differentiation (early knockdown) or in 3D engineered heart tissues as a disease model (late knockdown). hESC-CMs expressed the apelin signalling system at a similar level to the adult heart. Early apelin receptor knockdown decreased cardiomyocyte differentiation efficiency and prolonged voltage sensing, associated with asynchronous contraction. Late apelin receptor knockdown had detrimental consequences on 3D engineered heart tissue contractile properties, decreasing contractility and increasing stiffness. Conclusions We have successfully knocked down the apelin receptor, using an inducible system, to demonstrate a key role in hESC-CM differentiation. Knockdown in 3D engineered heart tissues recapitulated the phenotype of apelin receptor down-regulation in a failing heart, providing a potential platform for modelling heart failure and testing novel therapeutic strategies. [ABSTRACT FROM AUTHOR]

Published
2023
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32. An immune dysfunction score for stratification of patients with acute infection based on whole-blood gene expression.

Author

Cano-Gamez, Eddie, Burnham, Katie L., Goh, Cyndi, Allcock, Alice, Malick, Zunaira H., Overend, Lauren, Kwok, Andrew, Smith, David A., Peters-Sengers, Hessel, Antcliffe, David, McKechnie, Stuart, Scicluna, Brendon P., van der Poll, Tom, Gordon, Anthony C., Hinds, Charles J., Davenport, Emma E., Knight, Julian C., Webster, Nigel, Galley, Helen, and Taylor, Jane

Subjects
GENE expression, H1N1 influenza, COMMUNITY-acquired pneumonia, INFECTION, SEPSIS
Abstract

Dysregulated host responses to infection can lead to organ dysfunction and sepsis, causing millions of global deaths each year. To alleviate this burden, improved prognostication and biomarkers of response are urgently needed. We investigated the use of whole-blood transcriptomics for stratification of patients with severe infection by integrating data from 3149 samples from patients with sepsis due to community-acquired pneumonia or fecal peritonitis admitted to intensive care and healthy individuals into a gene expression reference map. We used this map to derive a quantitative sepsis response signature (SRSq) score reflective of immune dysfunction and predictive of clinical outcomes, which can be estimated using a 7- or 12-gene signature. Last, we built a machine learning framework, SepstratifieR, to deploy SRSq in adult and pediatric bacterial and viral sepsis, H1N1 influenza, and COVID-19, demonstrating clinically relevant stratification across diseases and revealing some of the physiological alterations linking immune dysregulation to mortality. Our method enables early identification of individuals with dysfunctional immune profiles, bringing us closer to precision medicine in infection. Stratifying sepsis: Predictors of severe infection could help physicians manage clinical care. Cano-Gamez et al. present an RNA-seq–based gene expression signature derived from patients with sepsis that generally captured patient prognosis with high sensitivity. Biologically, this signature corresponded to immune dysfunction. A machine learning framework based on the gene signature correctly stratified pediatric and adult patients with bacterial or viral sepsis, as well as patients with infection who did not meet sepsis criteria, including H1N1 influenza and COVID-19. This study may thus advance our ability to predict individual patient outcomes in sepsis. [ABSTRACT FROM AUTHOR]

Published
2022
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33. Blood leukocyte transcriptomes in Gram-positive and Gram-negative community-acquired pneumonia

Author

Pereverzeva, Liza, primary, Uhel, Fabrice, additional, Peters Sengers, Hessel, additional, Butler, Joe, additional, van Vught, Lonneke A., additional, Burnham, Katie L., additional, Davenport, Emma E., additional, Knight, Julian C., additional, Cremer, Olaf L., additional, Schultz, Marcus J., additional, Bonten, Marc M.J., additional, Scicluna, Brendon P., additional, and van der Poll, Tom, additional

Published
2021
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34. Interactions Between Genome‐Wide Genetic Factors and Smoking Influencing Risk of Systemic Lupus Erythematosus

Author

Cui, Jing, primary, Raychaudhuri, Soumya, additional, Karlson, Elizabeth W., additional, Speyer, Cameron, additional, Malspeis, Susan, additional, Guan, Hongshu, additional, Sparks, Jeffrey A., additional, Ni, Hongru, additional, Liu, Xinyi, additional, Stevens, Emma, additional, Williams, Jessica N., additional, Davenport, Emma E., additional, Knevel, Rachel, additional, and Costenbader, Karen H., additional

Published
2020
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35. A community approach to mortality prediction in sepsis via gene expression analysis

Author

Sweeney, Timothy E., primary, Perumal, Thanneer M., additional, Henao, Ricardo, additional, Nichols, Marshall, additional, Howrylak, Judith A., additional, Choi, Augustine M., additional, Bermejo-Martin, Jesús F., additional, Almansa, Raquel, additional, Tamayo, Eduardo, additional, Davenport, Emma E., additional, Burnham, Katie L., additional, Hinds, Charles J., additional, Knight, Julian C., additional, Woods, Christopher W., additional, Kingsmore, Stephen F., additional, Ginsburg, Geoffrey S., additional, Wong, Hector R., additional, Parnell, Grant P., additional, Tang, Benjamin, additional, Moldawer, Lyle L., additional, Moore, Frederick E., additional, Omberg, Larsson, additional, Khatri, Purvesh, additional, Tsalik, Ephraim L., additional, Mangravite, Lara M., additional, and Langley, Raymond J., additional

Published
2018
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36. Classification of patients with sepsis according to blood genomic endotype : a prospective cohort study

Author

Scicluna, Brendon P, Van Vught, Lonneke A., Zwinderman, Aeilko H, Wiewel, Maryse A, Davenport, Emma E, Burnham, Katie L, Nürnberg, Peter, Schultz, Marcus J., Horn, Janneke, Cremer, Olaf L, Bonten, Marc J, Hinds, Charles J, Wong, Hector R, Knight, Julian C., Van Der Poll, Tom, MARS consortium, Scicluna, Brendon P, Van Vught, Lonneke A., Zwinderman, Aeilko H, Wiewel, Maryse A, Davenport, Emma E, Burnham, Katie L, Nürnberg, Peter, Schultz, Marcus J., Horn, Janneke, Cremer, Olaf L, Bonten, Marc J, Hinds, Charles J, Wong, Hector R, Knight, Julian C., Van Der Poll, Tom, and MARS consortium

Published
2017

37. Classification of patients with sepsis according to blood genomic endotype: a prospective cohort study

Author

Scicluna, Brendon P., van Vught, Lonneke A., Zwinderman, Aeilko H., Wiewel, Maryse A., Davenport, Emma E., Burnham, Katie L., Nurnberg, Peter, Schultz, Marcus J., Horn, Janneke, Cremer, Olaf L., Bonten, Marc J., Hinds, Charles J., Wong, Hector R., Knight, Julian C., van der Poll, Tom, Scicluna, Brendon P., van Vught, Lonneke A., Zwinderman, Aeilko H., Wiewel, Maryse A., Davenport, Emma E., Burnham, Katie L., Nurnberg, Peter, Schultz, Marcus J., Horn, Janneke, Cremer, Olaf L., Bonten, Marc J., Hinds, Charles J., Wong, Hector R., Knight, Julian C., and van der Poll, Tom

Abstract

Background Host responses during sepsis are highly heterogeneous, which hampers the identification of patients at high risk of mortality and their selection for targeted therapies. In this study, we aimed to identify biologically relevant molecular endotypes in patients with sepsis. Methods This was a prospective observational cohort study that included consecutive patients admitted for sepsis to two intensive care units (ICUs) in the Netherlands between Jan 1, 2011, and July 20, 2012 (discovery and first validation cohorts) and patients admitted with sepsis due to community-acquired pneumonia to 29 ICUs in the UK (second validation cohort). We generated genome-wide blood gene expression profiles from admission samples and analysed them by unsupervised consensus clustering and machine learning. The primary objective of this study was to establish endotypes for patients with sepsis, and assess the association of these endotypes with clinical traits and survival outcomes. We also established candidate biomarkers for the endotypes to allow identification of patient endotypes in clinical practice. Findings The discovery cohort had 306 patients, the first validation cohort had 216, and the second validation cohort had 265 patients. Four molecular endotypes for sepsis, designated Mars1-4, were identified in the discovery cohort, and were associated with 28-day mortality (log-rank p=0.022). In the discovery cohort, the worst outcome was found for patients classified as having a Mars1 endotype, and at 28 days, 35 (39%) of 90 people with a Mars1 endotype had died (hazard ratio [HR] vs all other endotypes 1.86 [95% CI 1.21-2.86]; p=0.0045), compared with 23 (22%) of 105 people with a Mars2 endotype (HR 0.64 [0.40-1.04]; p=0.061), 16 (23%) of 71 people with a Mars3 endotype (HR 0.71 [0.41-1.22]; p=0.19), and 13 (33%) of 40 patients with a Mars4 endotype (HR 1.13 [0.63-2.04]; p=0.69). Analysis of the net reclassification improvement using a combined clinical and endotype model

Published
2017

38. Classification of patients with sepsis according to blood genomic endotype: a prospective cohort study

Author

Medische Staf Intensive Care, Infection & Immunity, Epi Infectieziekten, MMB, JC onderzoeksprogramma Infectieziekten, Scicluna, Brendon P, Van Vught, Lonneke A., Zwinderman, Aeilko H, Wiewel, Maryse A, Davenport, Emma E, Burnham, Katie L, Nürnberg, Peter, Schultz, Marcus J., Horn, Janneke, Cremer, Olaf L, Bonten, Marc J, Hinds, Charles J, Wong, Hector R, Knight, Julian C., Van Der Poll, Tom, MARS Consortium, Medische Staf Intensive Care, Infection & Immunity, Epi Infectieziekten, MMB, JC onderzoeksprogramma Infectieziekten, Scicluna, Brendon P, Van Vught, Lonneke A., Zwinderman, Aeilko H, Wiewel, Maryse A, Davenport, Emma E, Burnham, Katie L, Nürnberg, Peter, Schultz, Marcus J., Horn, Janneke, Cremer, Olaf L, Bonten, Marc J, Hinds, Charles J, Wong, Hector R, Knight, Julian C., Van Der Poll, Tom, and MARS Consortium

Published
2017

39. Classification of patients with sepsis according to blood genomic endotype: a prospective cohort study

Author

Scicluna, Brendon P, primary, van Vught, Lonneke A, additional, Zwinderman, Aeilko H, additional, Wiewel, Maryse A, additional, Davenport, Emma E, additional, Burnham, Katie L, additional, Nürnberg, Peter, additional, Schultz, Marcus J, additional, Horn, Janneke, additional, Cremer, Olaf L, additional, Bonten, Marc J, additional, Hinds, Charles J, additional, Wong, Hector R, additional, Knight, Julian C, additional, van der Poll, Tom, additional, de Beer, Friso M., additional, Bos, Lieuwe D.J., additional, Frencken, Jos F., additional, Koster-Brouwer, Maria E., additional, van de Groep, Kirsten, additional, Verboom, Diana M., additional, Glas, Gerie J., additional, van Hooijdonk, Roosmarijn T.M., additional, Hoogendijk, Arie J., additional, Huson, Mischa A., additional, Klouwenberg, Peter M. Klein, additional, Ong, David S.Y., additional, Schouten, Laura R.A., additional, Straat, Marleen, additional, Witteveen, Esther, additional, and Wieske, Luuk, additional

Published
2017
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40. Shared and Distinct Aspects of the Sepsis Transcriptomic Response to Fecal Peritonitis and Pneumonia

Author

Burnham, Katie L., primary, Davenport, Emma E., additional, Radhakrishnan, Jayachandran, additional, Humburg, Peter, additional, Gordon, Anthony C., additional, Hutton, Paula, additional, Svoren-Jabalera, Eduardo, additional, Garrard, Christopher, additional, Hill, Adrian V. S., additional, Hinds, Charles J., additional, and Knight, Julian C., additional

Published
2017
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41. Discovering in vivo cytokine eQTL interactions from a lupus clinical trial

Author

Davenport, Emma E., primary, Amariuta, Tiffany, additional, Gutierrez-Arcelus, Maria, additional, Slowikowski, Kamil, additional, Westra, Harm-Jan, additional, Luo, Yang, additional, Shen, Ciyue, additional, Rao, Deepak A., additional, Zhang, Ying, additional, Pearson, Stephen, additional, von Schack, David, additional, Beebe, Jean S., additional, Bing, Nan, additional, John, Sally, additional, Vincent, Michael S., additional, Zhang, Baohong, additional, and Raychaudhuri, Soumya, additional

Published
2017
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42. The common VTE-protective G haplotype of F5increases factor V-short, TFPI function, and risk of bleeding

Author

Sims, Matthew C., Gierula, Magdalena, Stephens, Jonathan C., Tokolyi, Alex, Stefanucci, Luca, Persyn, Elodie, Sun, Luanluan, Collins, Janine H., Davenport, Emma E., Di Angelantonio, Emanuele, Downes, Kate, Inouye, Michael, Paul, Dirk S., Thomas, Will, Tolios, Alexander, Ouwehand, Willem H., Gleadall, Nicholas S., Crawley, James T. B., Butterworth, Adam S., Frontini, Mattia, and Ahnström, Josefin

Abstract

•Individuals homozygous for the F5G haplotype (F5-G/G) have increased alternative F5splicing that leads to increased plasma FV-short levels.•F5-G/G individuals have a TFPI-dependent increase in lag time to thrombin generation, reduced VTE risk, and increased bleeding.

Published
2024
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44. Mortality prediction in sepsis via gene expression analysis: a community approach

Author

Sweeney, Timothy E, primary, Perumal, Thanneer M, additional, Henao, Ricardo, additional, Nichols, Marshall, additional, Howrylak, Judith A, additional, Choi, Augustine M, additional, Bermejo-Martin, Jesús F, additional, Almansa, Raquel, additional, Tamayo, Eduardo, additional, Davenport, Emma E, additional, Burnham, Katie L, additional, Hinds, Charles J, additional, Knight, Julian C, additional, Woods, Christopher W, additional, Kingsmore, Stephen F, additional, Ginsburg, Geoffrey S, additional, Wong, Hector R, additional, Parnell, Grant P, additional, Tang, Benjamin, additional, Moldawer, Lyle L, additional, Moore, Frederick E, additional, Omberg, Larsson, additional, Khatri, Purvesh, additional, Tsalik, Ephraim L, additional, Mangravite, Lara M, additional, and Langley, Raymond J, additional

Published
2016
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45. Factors influencing success of clinical genome sequencing across a broad spectrum of disorders

Author

UCL - SSS/IREC/NEFR - Pôle de Néphrologie, UCL - (SLuc) Service de néphrologie, McVean, Gilean, Taylor, Jenny C., Martin, Hilary C., Lise, Stefano, Broxholme, John, Cazier, Jean-Baptiste, Rimmer, Andy, Kanapin, Alexander, Lunter, Gerton, Fiddy, Simon, Allan, Chris, Aricescu, A. Radu, Attar, Moustafa, Babbs, Christian, Becq, Jennifer, Beeson, David, Bento, Celeste, Bignell, Patricia, Blair, Edward, Buckle, Veronica J., Bull, Katherine, Cais, Ondrej, Cario, Holger, Chapel, Helen, Copley, Richard R., Cornall, Richard, Craft, Jude, Dahan, Karin, Davenport, Emma E., Dendrou, Calliope, Devuyst, Olivier, Fenwick, Aimée L., Flint, Jonathan, Fugger, Lars, Gilbert, Rodney D., Goriely, Anne, Green, Angie, Greger, Ingo H., Grocock, Russell, Gruszczyk, Anja V., Hastings, Robert, Hatton, Edouard, Higgs, Doug, Hill, Adrian, Holmes, Chris, Howard, Malcolm, Hughes, Linda, Humburg, Peter, Johnson, David, Karpe, Fredrik, Kingsbury, Zoya, Kini, Usha, Knight, Julian C., Krohn, Jonathan, Lamble, Sarah, Langman, Craig, Lonie, Lorne, Luck, Joshua, McCarthy, Davis, McGowan, Simon J., McMullin, Mary Frances, Miller, Kerry A., Murray, Lisa, Németh, Andrea H., Nesbit, M. Andrew, Nutt, David, Ormondroyd, Elizabeth, Bang Oturai, Annette, Pagnamenta, Alistair, Patel, Smita Y., Percy, Melanie, Petousi, Nayia, Piazza, Paolo, Piret, Sian E., Polanco-Echeverry, Guadalupe, Popitsch, Niko, Powrie, Fiona, Pugh, Chris, Quek, Lynn, Robbins, Peter A., Robson, Kathryn, Russo, Alexandra, Sahgal, Natasha, Van Schouwenburg, Pauline A., Schuh, Anna, Silverman, Earl, Simmons, Alison, Sorensen, Per Soelberg, Sweeney, Elizabeth, Taylor, John, Thakker, Rajesh V., Tomlinson, Ian, Trebes, Amy, Twigg, Stephen R. F., Uhlig, Holm H., Vyas, Paresh, Vyse, Tim, Wall, Steven A., Watkins, Hugh, Whyte, Michael P., Witty, Lorna, Wright, Ben, UCL - SSS/IREC/NEFR - Pôle de Néphrologie, UCL - (SLuc) Service de néphrologie, McVean, Gilean, Taylor, Jenny C., Martin, Hilary C., Lise, Stefano, Broxholme, John, Cazier, Jean-Baptiste, Rimmer, Andy, Kanapin, Alexander, Lunter, Gerton, Fiddy, Simon, Allan, Chris, Aricescu, A. Radu, Attar, Moustafa, Babbs, Christian, Becq, Jennifer, Beeson, David, Bento, Celeste, Bignell, Patricia, Blair, Edward, Buckle, Veronica J., Bull, Katherine, Cais, Ondrej, Cario, Holger, Chapel, Helen, Copley, Richard R., Cornall, Richard, Craft, Jude, Dahan, Karin, Davenport, Emma E., Dendrou, Calliope, Devuyst, Olivier, Fenwick, Aimée L., Flint, Jonathan, Fugger, Lars, Gilbert, Rodney D., Goriely, Anne, Green, Angie, Greger, Ingo H., Grocock, Russell, Gruszczyk, Anja V., Hastings, Robert, Hatton, Edouard, Higgs, Doug, Hill, Adrian, Holmes, Chris, Howard, Malcolm, Hughes, Linda, Humburg, Peter, Johnson, David, Karpe, Fredrik, Kingsbury, Zoya, Kini, Usha, Knight, Julian C., Krohn, Jonathan, Lamble, Sarah, Langman, Craig, Lonie, Lorne, Luck, Joshua, McCarthy, Davis, McGowan, Simon J., McMullin, Mary Frances, Miller, Kerry A., Murray, Lisa, Németh, Andrea H., Nesbit, M. Andrew, Nutt, David, Ormondroyd, Elizabeth, Bang Oturai, Annette, Pagnamenta, Alistair, Patel, Smita Y., Percy, Melanie, Petousi, Nayia, Piazza, Paolo, Piret, Sian E., Polanco-Echeverry, Guadalupe, Popitsch, Niko, Powrie, Fiona, Pugh, Chris, Quek, Lynn, Robbins, Peter A., Robson, Kathryn, Russo, Alexandra, Sahgal, Natasha, Van Schouwenburg, Pauline A., Schuh, Anna, Silverman, Earl, Simmons, Alison, Sorensen, Per Soelberg, Sweeney, Elizabeth, Taylor, John, Thakker, Rajesh V., Tomlinson, Ian, Trebes, Amy, Twigg, Stephen R. F., Uhlig, Holm H., Vyas, Paresh, Vyse, Tim, Wall, Steven A., Watkins, Hugh, Whyte, Michael P., Witty, Lorna, and Wright, Ben

Abstract

To assess factors influencing the success of whole-genome sequencing for mainstream clinical diagnosis, we sequenced 217 individuals from 156 independent cases or families across a broad spectrum of disorders in whom previous screening had identified no pathogenic variants. We quantified the number of candidate variants identified using different strategies for variant calling, filtering, annotation and prioritization. We found that jointly calling variants across samples, filtering against both local and external databases, deploying multiple annotation tools and using familial transmission above biological plausibility contributed to accuracy. Overall, we identified disease-causing variants in 21% of cases, with the proportion increasing to 34% (23/68) for mendelian disorders and 57% (8/14) in family trios. We also discovered 32 potentially clinically actionable variants in 18 genes unrelated to the referral disorder, although only 4 were ultimately considered reportable. Our results demonstrate the value of genome sequencing for routine clinical diagnosis but also highlight many outstanding challenges.

Published
2015

46. Factors influencing success of clinical genome sequencing across a broad spectrum of disorders

Author

Taylor, Jenny C, Martin, Hilary C, Lise, Stefano, Broxholme, John, Cazier, Jean-Baptiste, Rimmer, Andy, Kanapin, Alexander, Lunter, Gerton, Fiddy, Simon, Allan, Chris, Aricescu, A Radu, Attar, Moustafa, Babbs, Christian, Becq, Jennifer, Beeson, David, Bento, Celeste, Bignell, Patricia, Blair, Edward, Buckle, Veronica J, Bull, Katherine, Cais, Ondrej, Cario, Holger, Chapel, Helen, Copley, Richard R, Cornall, Richard, Craft, Jude, Dahan, Karin, Davenport, Emma E, Dendrou, Calliope, Devuyst, Olivier, Fenwick, Aimée L, Flint, Jonathan, Fugger, Lars, Gilbert, Rodney D, Goriely, Anne, Green, Angie, Greger, Ingo H, Grocock, Russell, Gruszczyk, Anja V, Hastings, Robert, Hatton, Edouard, Higgs, Doug, Hill, Adrian, Holmes, Chris, Howard, Malcolm, Hughes, Linda, Humburg, Peter, Johnson, David, Karpe, Fredrik, Kingsbury, Zoya, Kini, Usha, Knight, Julian C, Krohn, Jonathan, Lamble, Sarah, Langman, Craig, Lonie, Lorne, Luck, Joshua, McCarthy, Davis, McGowan, Simon J, McMullin, Mary Frances, Miller, Kerry A, Murray, Lisa, Németh, Andrea H, Nesbit, M Andrew, Nutt, David, Ormondroyd, Elizabeth, Oturai, Annette Bang, Pagnamenta, Alistair, Patel, Smita Y, Percy, Melanie, Petousi, Nayia, Piazza, Paolo, Piret, Sian E, Polanco-Echeverry, Guadalupe, Popitsch, Niko, Powrie, Fiona, Pugh, Chris, Quek, Lynn, Robbins, Peter A, Robson, Kathryn, Russo, Alexandra, Sahgal, Natasha, van Schouwenburg, Pauline A, Schuh, Anna, Silverman, Earl, Simmons, Alison, Sørensen, Per Soelberg, Sweeney, Elizabeth, Taylor, John, Thakker, Rajesh V, Tomlinson, Ian, Trebes, Amy, Twigg, Stephen R F, Uhlig, Holm H, Vyas, Paresh, Vyse, Tim, Wall, Steven A, Watkins, Hugh, Whyte, Michael P, Witty, Lorna, Wright, Ben, Yau, Chris, Buck, David, Humphray, Sean, Ratcliffe, Peter J, Bell, John I, Wilkie, Andrew O M, Bentley, David, Donnelly, Peter, McVean, Gilean, Taylor, Jenny C, Martin, Hilary C, Lise, Stefano, Broxholme, John, Cazier, Jean-Baptiste, Rimmer, Andy, Kanapin, Alexander, Lunter, Gerton, Fiddy, Simon, Allan, Chris, Aricescu, A Radu, Attar, Moustafa, Babbs, Christian, Becq, Jennifer, Beeson, David, Bento, Celeste, Bignell, Patricia, Blair, Edward, Buckle, Veronica J, Bull, Katherine, Cais, Ondrej, Cario, Holger, Chapel, Helen, Copley, Richard R, Cornall, Richard, Craft, Jude, Dahan, Karin, Davenport, Emma E, Dendrou, Calliope, Devuyst, Olivier, Fenwick, Aimée L, Flint, Jonathan, Fugger, Lars, Gilbert, Rodney D, Goriely, Anne, Green, Angie, Greger, Ingo H, Grocock, Russell, Gruszczyk, Anja V, Hastings, Robert, Hatton, Edouard, Higgs, Doug, Hill, Adrian, Holmes, Chris, Howard, Malcolm, Hughes, Linda, Humburg, Peter, Johnson, David, Karpe, Fredrik, Kingsbury, Zoya, Kini, Usha, Knight, Julian C, Krohn, Jonathan, Lamble, Sarah, Langman, Craig, Lonie, Lorne, Luck, Joshua, McCarthy, Davis, McGowan, Simon J, McMullin, Mary Frances, Miller, Kerry A, Murray, Lisa, Németh, Andrea H, Nesbit, M Andrew, Nutt, David, Ormondroyd, Elizabeth, Oturai, Annette Bang, Pagnamenta, Alistair, Patel, Smita Y, Percy, Melanie, Petousi, Nayia, Piazza, Paolo, Piret, Sian E, Polanco-Echeverry, Guadalupe, Popitsch, Niko, Powrie, Fiona, Pugh, Chris, Quek, Lynn, Robbins, Peter A, Robson, Kathryn, Russo, Alexandra, Sahgal, Natasha, van Schouwenburg, Pauline A, Schuh, Anna, Silverman, Earl, Simmons, Alison, Sørensen, Per Soelberg, Sweeney, Elizabeth, Taylor, John, Thakker, Rajesh V, Tomlinson, Ian, Trebes, Amy, Twigg, Stephen R F, Uhlig, Holm H, Vyas, Paresh, Vyse, Tim, Wall, Steven A, Watkins, Hugh, Whyte, Michael P, Witty, Lorna, Wright, Ben, Yau, Chris, Buck, David, Humphray, Sean, Ratcliffe, Peter J, Bell, John I, Wilkie, Andrew O M, Bentley, David, Donnelly, Peter, and McVean, Gilean

Abstract

To assess factors influencing the success of whole-genome sequencing for mainstream clinical diagnosis, we sequenced 217 individuals from 156 independent cases or families across a broad spectrum of disorders in whom previous screening had identified no pathogenic variants. We quantified the number of candidate variants identified using different strategies for variant calling, filtering, annotation and prioritization. We found that jointly calling variants across samples, filtering against both local and external databases, deploying multiple annotation tools and using familial transmission above biological plausibility contributed to accuracy. Overall, we identified disease-causing variants in 21% of cases, with the proportion increasing to 34% (23/68) for mendelian disorders and 57% (8/14) in family trios. We also discovered 32 potentially clinically actionable variants in 18 genes unrelated to the referral disorder, although only 4 were ultimately considered reportable. Our results demonstrate the value of genome sequencing for routine clinical diagnosis but also highlight many outstanding challenges.

Published
2015

47. Factors influencing success of clinical genome sequencing across a broad spectrum of disorders

Author

Taylor, Jenny C, primary, Martin, Hilary C, additional, Lise, Stefano, additional, Broxholme, John, additional, Cazier, Jean-Baptiste, additional, Rimmer, Andy, additional, Kanapin, Alexander, additional, Lunter, Gerton, additional, Fiddy, Simon, additional, Allan, Chris, additional, Aricescu, A Radu, additional, Attar, Moustafa, additional, Babbs, Christian, additional, Becq, Jennifer, additional, Beeson, David, additional, Bento, Celeste, additional, Bignell, Patricia, additional, Blair, Edward, additional, Buckle, Veronica J, additional, Bull, Katherine, additional, Cais, Ondrej, additional, Cario, Holger, additional, Chapel, Helen, additional, Copley, Richard R, additional, Cornall, Richard, additional, Craft, Jude, additional, Dahan, Karin, additional, Davenport, Emma E, additional, Dendrou, Calliope, additional, Devuyst, Olivier, additional, Fenwick, Aimée L, additional, Flint, Jonathan, additional, Fugger, Lars, additional, Gilbert, Rodney D, additional, Goriely, Anne, additional, Green, Angie, additional, Greger, Ingo H, additional, Grocock, Russell, additional, Gruszczyk, Anja V, additional, Hastings, Robert, additional, Hatton, Edouard, additional, Higgs, Doug, additional, Hill, Adrian, additional, Holmes, Chris, additional, Howard, Malcolm, additional, Hughes, Linda, additional, Humburg, Peter, additional, Johnson, David, additional, Karpe, Fredrik, additional, Kingsbury, Zoya, additional, Kini, Usha, additional, Knight, Julian C, additional, Krohn, Jonathan, additional, Lamble, Sarah, additional, Langman, Craig, additional, Lonie, Lorne, additional, Luck, Joshua, additional, McCarthy, Davis, additional, McGowan, Simon J, additional, McMullin, Mary Frances, additional, Miller, Kerry A, additional, Murray, Lisa, additional, Németh, Andrea H, additional, Nesbit, M Andrew, additional, Nutt, David, additional, Ormondroyd, Elizabeth, additional, Oturai, Annette Bang, additional, Pagnamenta, Alistair, additional, Patel, Smita Y, additional, Percy, Melanie, additional, Petousi, Nayia, additional, Piazza, Paolo, additional, Piret, Sian E, additional, Polanco-Echeverry, Guadalupe, additional, Popitsch, Niko, additional, Powrie, Fiona, additional, Pugh, Chris, additional, Quek, Lynn, additional, Robbins, Peter A, additional, Robson, Kathryn, additional, Russo, Alexandra, additional, Sahgal, Natasha, additional, van Schouwenburg, Pauline A, additional, Schuh, Anna, additional, Silverman, Earl, additional, Simmons, Alison, additional, Sørensen, Per Soelberg, additional, Sweeney, Elizabeth, additional, Taylor, John, additional, Thakker, Rajesh V, additional, Tomlinson, Ian, additional, Trebes, Amy, additional, Twigg, Stephen R F, additional, Uhlig, Holm H, additional, Vyas, Paresh, additional, Vyse, Tim, additional, Wall, Steven A, additional, Watkins, Hugh, additional, Whyte, Michael P, additional, Witty, Lorna, additional, Wright, Ben, additional, Yau, Chris, additional, Buck, David, additional, Humphray, Sean, additional, Ratcliffe, Peter J, additional, Bell, John I, additional, Wilkie, Andrew O M, additional, Bentley, David, additional, Donnelly, Peter, additional, and McVean, Gilean, additional

Published
2015
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50. Microarray analysis demonstrates up-regulation of the endothelin-1 gene with compensatory down-regulation of the ETA receptor gene in human portal vein.

Author

Owen NE, Williams TL, Maguire JJ, Kuc RE, Davenport EE, and Davenport AP

Subjects
Adult, Female, Humans, Male, Middle Aged, Down-Regulation, Liver Transplantation, Up-Regulation, Endothelin-1 genetics, Endothelin-1 metabolism, Hypertension, Portal genetics, Hypertension, Portal metabolism, Liver Cirrhosis genetics, Liver Cirrhosis metabolism, Liver Cirrhosis pathology, Portal Vein metabolism, Portal Vein pathology, Receptor, Endothelin A genetics, Receptor, Endothelin A metabolism
Abstract

High blood pressure in the portal vein, portal hypertension (PH), is the final common pathway in liver cirrhosis regardless of aetiology. Complications from PH are the major cause of morbidity and mortality in these patients. Current drug therapy to reduce portal pressure is mainly limited to β-adrenergic receptor blockade but approximately 40% of patients do not respond. Our aim was to use microarray to measure the expression of ∼20,800 genes in portal vein from patients with PH undergoing transplantation for liver cirrhosis (PH, n=12) versus healthy vessels (control, n=9) to identify potential drug targets to improve therapy. Expression of 9,964 genes above background was detected in portal vein samples. Comparing PH veins versus control (adjusted P-value < 0.05, fold change > 1.5) identified 548 up-regulated genes and 1,996 down-regulated genes. The 2,544 differentially expressed genes were subjected to pathway analysis. We identified 49 significantly enriched pathways. The endothelin pathway was ranked the tenth most significant, the only vasoconstrictive pathway to be identified. ET-1 gene (EDN1) was significantly up-regulated, consistent with elevated levels of ET-1 peptide previously measured in PH and cirrhosis. ETA receptor gene (EDNRA) was significantly down-regulated, consistent with an adaptive response to increased peptide levels in the portal vein but there was no change in the ETB gene (EDNRB). The results provide further support for evaluating the efficacy of ETA receptor antagonists as a potential therapy in addition to β-blockers in patients with PH and cirrhosis., (© 2024 The Author(s).)

Published
2024
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