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1. Mendelian randomisation and experimental medicine approaches to IL-6 as a drug target in PAH

Author

Toshner, Mark, Church, Colin, Harbaum, Lars, Rhodes, Christopher, Villar Moreschi, Sofia S, Liley, James, Jones, Rowena, Arora, Amit, Batai, Ken, Desai, Ankit A, Coghlan, John G, Gibbs, J Simon R, Gor, Dee, Gräf, Stefan, Harlow, Louise, Hernandez-Sanchez, Jules, Howard, Luke S, Humbert, Marc, Karnes, Jason, Kiely, David G, Kittles, Rick, Knightbridge, Emily, Lam, Brian, Lutz, Katie A, Nichols, William C, Pauciulo, Michael W, Pepke-Zaba, Joanna, Suntharalingam, Jay, Soubrier, Florent, Trembath, Richard C, Schwantes-An, Tae-Hwi L, Wort, S John, Wilkins, Martin, Gaine, Sean, Morrell, Nicholas W, Corris, Paul A, Toshner, Mark [0000-0002-3969-6143], Villar, Sofia [0000-0001-7755-2637], Jones, Rowena [0000-0002-4551-2320], Graf, Stefan [0000-0002-1315-8873], Lam, Brian [0000-0002-3638-9025], Morrell, Nicholas [0000-0001-5700-9792], Apollo - University of Cambridge Repository, and British Heart Foundation

Subjects
Adult, Male, Pulmonary Arterial Hypertension, Biomedical Research, Interleukin-6, Respiratory System, Uniphy Clinical Trials Network, Middle Aged, Treatment Outcome, Humans, Familial Primary Pulmonary Hypertension, Female, 11 Medical and Health Sciences, Aged
Abstract

Inflammation and dysregulated immunity are important in the development of pulmonary arterial hypertension. Compelling preclinical data supports the therapeutic blockade of interleukin-6 signalling.We conducted an open-label phase-II study of intravenous tocilizumab (8 mg·kg-1) over 6 months in group 1 pulmonary arterial hypertension. Co-primary endpoints were safety, defined by incidence and severity of adverse events, and change in pulmonary vascular resistance. Separately, a Mendelian randomisation study was undertaken on 11,744 individuals with European ancestry including 2085 patients with idiopathic/heritable disease for the IL6R variant (rs7529229), known to associate with circulating IL6R levels.Twenty-nine patients (M/F 10/19; mean age 54.9[SD11.4]) were recruited. Nineteen had heritable/idiopathic and ten connective tissue disease associated pulmonary arterial hypertension. Six were withdrawn prior to drug administration. Twenty-three patients received at least one dose of tocilizumab. Tocilizumab was discontinued in 4 patients due to serious adverse events. There were no deaths. Despite evidence of target engagement in plasma interleukin-6 and C-reactive protein levels, both intention-to-treat and modified intention-to-treat analyses demonstrated no change in pulmonary vascular resistance. Inflammatory markers did not predict treatment response. Mendelian randomisation did not support an effect of the lead IL6R variant on risk of pulmonary arterial hypertension (OR 0.99, p=0.88).Adverse events were consistent with the known safety profile of tocilizumab. Tocilizumab did not show any consistent treatment effect.

Published
2022
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2. Bayesian Inference Associates Rare KDR Variants with Specific Phenotypes in Pulmonary Arterial Hypertension

Author

Emilia M. Swietlik, Daniel Greene, Na Zhu, Karyn Megy, Marcella Cogliano, Smitha Rajaram, Divya Pandya, Tobias Tilly, Katie A. Lutz, Carrie C.L. Welch, Michael W. Pauciulo, Laura Southgate, Jennifer M. Martin, Carmen M. Treacy, Christopher J. Penkett, Jonathan C. Stephens, Harm J. Bogaard, Colin Church, Gerry Coghlan, Anna W. Coleman, Robin Condliffe, Christina A. Eichstaedt, Mélanie Eyries, Henning Gall, Stefano Ghio, Barbara Girerd, Ekkehard Grünig, Simon Holden, Luke Howard, Marc Humbert, David G. Kiely, Gabor Kovacs, Jim Lordan, Rajiv D. Machado, Robert V. MacKenzie Ross, Colm McCabe, Shahin Moledina, David Montani, Horst Olschewski, Joanna Pepke-Zaba, Laura Price, Christopher J. Rhodes, Werner Seeger, Florent Soubrier, Jay Suntharalingam, Mark R. Toshner, Anton Vonk Noordegraaf, John Wharton, James M. Wild, Stephen John Wort, Allan Lawrie, Martin R. Wilkins, Richard C. Trembath, Yufeng Shen, Wendy K. Chung, Andrew J. Swift, William C. Nichols, Nicholas W. Morrell, Stefan Gräf, Stephen Abbs, Lara Abulhoul, Julian Adlard, Munaza Ahmed, Timothy J. Aitman, Hana Alachkar, David J. Allsup, Philip Ancliff, Richard Antrobus, Ruth Armstrong, Gavin Arno, Sofie Ashford, William J. Astle, Anthony Attwood, Paul Aurora, Christian Babbs, Chiara Bacchelli, Tamam Bakchoul, Siddharth Banka, Tadbir Bariana, Julian Barwell, Joana Batista, Helen E. Baxendale, Phil L. Beales, David L. Bennett, Agnieszka Bierzynska, Tina Biss, Maria A.K. Bitner-Glindzicz, Graeme C. Black, Marta Bleda, Iulia Blesneac, Detlef Bockenhauer, Sara Boyce, John R. Bradley, Gerome Breen, Paul Brennan, Carole Brewer, Matthew Brown, Andrew C. Browning, Michael J. Browning, Rachel J. Buchan, Matthew S. Buckland, Teofila Bueser, Carmen Bugarin Diz, John Burn, Siobhan O. Burns, Oliver S. Burren, Nigel Burrows, Carolyn Campbell, Gerald Carr-White, Keren Carss, Ruth Casey, Mark J. Caulfield, Jenny Chambers, John Chambers, Melanie M.Y. Chan, Floria Cheng, Patrick F. Chinnery, Manali Chitre, Martin T. Christian, Jill Clayton-Smith, Maureen Cleary, Naomi Clements Brod, Elizabeth Colby, Trevor R.P. Cole, Janine Collins, Peter W. Collins, Cecilia J. Compton, H. Terence Cook, Stuart Cook, Nichola Cooper, Paul A. Corris, Nicola S. Curry, Matthew J. Daniels, Mehul Dattani, Louise C. Daugherty, John Davis, Anthony De Soyza, Sri V.V. Deevi, Timothy Dent, Charu Deshpande, Eleanor F. Dewhurst, Peter H. Dixon, Sofia Douzgou, Kate Downes, Anna M. Drazyk, Elizabeth Drewe, Daniel Duarte, Tina Dutt, J. David M. Edgar, Karen Edwards, William Egner, Melanie N. Ekani, Perry Elliott, Wendy N. Erber, Marie Erwood, Maria C. Estiu, Dafydd Gareth Evans, Gillian Evans, Tamara Everington, Hiva Fassihi, Remi Favier, Debra Fletcher, Frances A. Flinter, R. Andres Floto, Tom Fowler, James Fox, Amy J. Frary, Courtney E. French, Kathleen Freson, Mattia Frontini, Abigail Furnell, Daniel P. Gale, Vijeya Ganesan, Michael Gattens, Hossein-Ardeschir Ghofrani, J. Simon R. Gibbs, Kate Gibson, Kimberly C. Gilmour, Nicholas S. Gleadall, Sarah Goddard, Keith Gomez, Pavels Gordins, David Gosal, Jodie Graham, Luigi Grassi, Lynn Greenhalgh, Andreas Greinacher, Paolo Gresele, Philip Griffiths, Sofia Grigoriadou, Detelina Grozeva, Mark Gurnell, Scott Hackett, Charaka Hadinnapola, Rosie Hague, William M. Hague, Matthias Haimel, Matthew Hall, Helen L. Hanson, Eshika Haque, Kirsty Harkness, Andrew R. Harper, Claire L. Harris, Daniel Hart, Ahamad Hassan, Grant Hayman, Alex Henderson, Archana Herwadkar, Jonathan Hoffman, Rita Horvath, Henry Houlden, Arjan C. Houweling, Fengyuan Hu, Gavin Hudson, Aarnoud P. Huissoon, Matthew Hurles, Melita Irving, Louise Izatt, Roger James, Sally A. Johnson, Stephen Jolles, Jennifer Jolley, Dragana Josifova, Neringa Jurkute, Mary A. Kasanicki, Hanadi Kazkaz, Rashid Kazmi, Peter Kelleher, Anne M Kelly, Wilf Kelsall, Carly Kempster, Nathalie Kingston, Nils Koelling, Myrto Kostadima, Ania Koziell, Roman Kreuzhuber, Taco W. Kuijpers, Ajith Kumar, Dinakantha Kumararatne, Manju A. Kurian, Michael A. Laffan, Fiona Lalloo, Michele Lambert, Hana Lango Allen, D. Mark Layton, Claire Lentaigne, Tracy Lester, Adam P. Levine, Rachel Linger, Hilary Longhurst, Lorena E. Lorenzo, Eleni Louka, Paul A. Lyons, Bella Madan, Eamonn R. Maher, Jesmeen Maimaris, Samantha Malka, Sarah Mangles, Rutendo Mapeta, Kevin J. Marchbank, Stephen Marks, Hugh S. Markus, Hanns-Ulrich Marschall, Andrew Marshall, Mary Mathias, Emma Matthews, Heather Maxwell, Paul McAlinden, Mark I. McCarthy, Harriet McKinney, Stuart Meacham, Adam J. Mead, Sarju G. Mehta, Michel Michaelides, Carolyn Millar, Shehla N. Mohammed, Anthony T. Moore, Monika Mozere, Keith W. Muir, Andrew D. Mumford, Andrea H. Nemeth, William G. Newman, Michael Newnham, Sadia Noorani, Paquita Nurden, Jennifer O’Sullivan, Samya Obaji, Chris Odhams, Steven Okoli, Andrea Olschewski, Kai Ren Ong, S. Helen Oram, Elizabeth Ormondroyd, Willem H. Ouwehand, Claire Palles, Sofia Papadia, Soo-Mi Park, David Parry, Smita Patel, Joan Paterson, Andrew Peacock, Simon H. Pearce, Kathelijne Peerlinck, Romina Petersen, Clarissa Pilkington, Kenneth E.S. Poole, Bethan Psaila, Angela Pyle, Richard Quinton, Shamima Rahman, Anupama Rao, F. Lucy Raymond, Paula J. Rayner-Matthews, Augusto Rendon, Tara Renton, Andrew S.C. Rice, Alex Richter, Leema Robert, Irene Roberts, Sarah J. Rose, Robert Ross-Russell, Catherine Roughley, Noemi B.A. Roy, Deborah M. Ruddy, Omid Sadeghi-Alavijeh, Moin A. Saleem, Nilesh Samani, Crina Samarghitean, Alba Sanchis-Juan, Ravishankar B. Sargur, Robert N. Sarkany, Simon Satchell, Sinisa Savic, Genevieve Sayer, John A. Sayer, Laura Scelsi, Andrew M. Schaefer, Sol Schulman, Richard Scott, Marie Scully, Claire Searle, Arjune Sen, W.A. Carrock Sewell, Denis Seyres, Neil Shah, Olga Shamardina, Susan E. Shapiro, Adam C. Shaw, Keith Sibson, Lucy Side, Ilenia Simeoni, Michael A. Simpson, Matthew C. Sims, Suthesh Sivapalaratnam, Damian Smedley, Katherine R. Smith, Kenneth G.C. Smith, Katie Snape, Nicole Soranzo, Olivera Spasic-Boskovic, Simon Staines, Emily Staples, Hannah Stark, Kathleen E. Stirrups, Alex Stuckey, Petros Syrris, R. Campbell Tait, Kate Talks, Rhea Y.Y. Tan, Jenny C. Taylor, John M. Taylor, James E. Thaventhiran, Andreas C. Themistocleous, David Thomas, Ellen Thomas, Moira J. Thomas, Patrick Thomas, Kate Thomson, Adrian J. Thrasher, Chantal Thys, Marc Tischkowitz, Catherine Titterton, Cheng-Hock Toh, Ian P. Tomlinson, Matthew Traylor, Paul Treadaway, Salih Tuna, Ernest Turro, Philip Twiss, Tom Vale, Chris Van Geet, Natalie van Zuydam, Anthony M Vandersteen, Marta Vazquez-Lopez, Julie von Ziegenweidt, Annette Wagner, Quinten Waisfisz, Neil Walker, Suellen M. Walker, James S. Ware, Hugh Watkins, Christopher Watt, Andrew R. Webster, Lucy Wedderburn, Wei Wei, Steven B. Welch, Julie Wessels, Sarah K. Westbury, John-Paul Westwood, Deborah Whitehorn, James Whitworth, Andrew O.M. Wilkie, Catherine Williamson, Brian T. Wilson, Edwin K.S. Wong, Nicholas Wood, Yvette Wood, Christopher Geoffrey Woods, Emma R. Woodward, Austen Worth, Michael Wright, Katherine Yates, Patrick F.K. Yong, Timothy Young, Ping Yu, Patrick Yu-Wai-Man, Eliska Zlamalova, Russel Hirsch, R. James White, Marc Simon, David Badesch, Erika Rosenzweig, Charles Burger, Murali Chakinala, Thenappan Thenappan, Greg Elliott, Robert Simms, Harrison Farber, Robert Frantz, Jean Elwing, Nicholas Hill, Dunbar Ivy, James Klinger, Steven Nathan, Ronald Oudiz, Ivan Robbins, Robert Schilz, Terry Fortin, Jeffrey Wilt, Delphine Yung, Eric Austin, Ferhaan Ahmad, Nitin Bhatt, Tim Lahm, Adaani Frost, Zeenat Safdar, Zia Rehman, Robert Walter, Fernando Torres, Sahil Bakshi, Stephen Archer, Rahul Argula, Christopher Barnett, Raymond Benza, Ankit Desai, Veeranna Maddipati, University of Cambridge [UK] (CAM), Columbia University [New York], University of Sheffield [Sheffield], University of Cincinnati (UC), St George's, University of London, Vrije Universiteit Amsterdam [Amsterdam] (VU), Golden Jubilee National Hospital, Glasgow, Royal Free Hospital [London, UK], Heidelberg University Hospital [Heidelberg], Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Technische Hochschule Mittelhessen - University of Applied Sciences [Giessen] (THM), Fondazione IRCCS Policlinico San Matteo, Hypertension pulmonaire : physiopathologie et innovation thérapeutique (HPPIT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Universität Heidelberg [Heidelberg], Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Imperial College London, Royal Hallamshire Hospital, University of Graz, Freeman Hospital, Royal United Hospitals Bath (RUH), Great Ormond Street Hospital for Children [London] (GOSH), Royal Papworth Hospital, Cambridge Biomedical Campus, Cambridge, United Kingdom., King‘s College London, Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Karl-Franzens-Universität [Graz, Autriche], Pulmonary medicine, ACS - Pulmonary hypertension & thrombosis, Swietlik, Emilia [0000-0002-4095-8489], Megy, Karyn [0000-0002-2826-3879], Tilly, Tobias [0000-0002-6762-5342], Stephens, Jonathan [0000-0003-2020-9330], Toshner, Mark [0000-0002-3969-6143], Morrell, Nicholas [0000-0001-5700-9792], Graf, Stefan [0000-0002-1315-8873], Apollo - University of Cambridge Repository, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Karl-Franzens-Universität Graz, HAL-SU, Gestionnaire, British Heart Foundation, and The Academy of Medical Sciences

Subjects
0301 basic medicine, Candidate gene, Cardiac & Cardiovascular Systems, genetic association studies, 030204 cardiovascular system & hematology, Biology, Bayesian inference, 03 medical and health sciences, 0302 clinical medicine, Missing heritability problem, pulmonary hypertension, medicine, Family history, Gene, Genetics & Heredity, Genetics, family history, Science & Technology, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Kinase insert domain receptor, computed tomography, General Medicine, Original Articles, medicine.disease, Pulmonary hypertension, Phenotype, 3. Good health, 030104 developmental biology, Cardiovascular System & Cardiology, ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, Life Sciences & Biomedicine, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, vascular endothelial growth factor receptor
Abstract

Supplemental Digital Content is available in the text., Background: Approximately 25% of patients with pulmonary arterial hypertension (PAH) have been found to harbor rare mutations in disease-causing genes. To identify missing heritability in PAH, we integrated deep phenotyping with whole-genome sequencing data using Bayesian statistics. Methods: We analyzed 13 037 participants enrolled in the NBR study (NIHR BioResource—Rare Diseases), of which 1148 were recruited to the PAH domain. To test for genetic associations between genes and selected phenotypes of pulmonary hypertension, we used the Bayesian rare variant association method BeviMed. Results: Heterozygous, high impact, likely loss-of-function variants in the kinase insert domain receptor (KDR) gene were strongly associated with significantly reduced transfer coefficient for carbon monoxide (posterior probability=0.989) and older age at diagnosis (posterior probability=0.912). We also provide evidence for familial segregation of a rare nonsense KDR variant with these phenotypes. On computed tomographic imaging of the lungs, a range of parenchymal abnormalities were observed in the 5 patients harboring these predicted deleterious variants in KDR. Four additional PAH cases with rare likely loss-of-function variants in KDR were independently identified in the US PAH Biobank cohort with similar phenotypic characteristics. Conclusions: The Bayesian inference approach allowed us to independently validate KDR, which encodes for the VEGFR2 (vascular endothelial growth factor receptor 2), as a novel PAH candidate gene. Furthermore, this approach specifically associated high impact likely loss-of-function variants in the genetically constrained gene with distinct phenotypes. These findings provide evidence for KDR being a clinically actionable PAH gene and further support the central role of the vascular endothelium in the pathobiology of PAH.

Published
2020

3. Biological heterogeneity in idiopathic pulmonary arterial hypertension identified through unsupervised transcriptomic profiling of whole blood

Author

Kariotis, S, Jammeh, E, Swietlik, EM, Pickworth, JA, Rhodes, CJ, Otero, P, Wharton, J, Iremonger, J, Dunning, MJ, Pandya, D, Mascarenhas, TS, Errington, N, Thompson, AAR, Romanoski, CE, Rischard, F, Garcia, JGN, Yuan, JX-J, An, T-HS, Desai, AA, Coghlan, G, Lordan, J, Corris, PA, Howard, LS, Condliffe, R, Kiely, DG, Church, C, Pepke-Zaba, J, Toshner, M, Wort, S, Graf, S, Morrell, NW, Wilkins, MR, Lawrie, A, Wang, D, Bleda, M, Hadinnapola, C, Haimel, M, Auckland, K, Tilly, T, Martin, JM, Yates, K, Treacy, CM, Day, M, Greenhalgh, A, Shipley, D, Peacock, AJ, Irvine, V, Kennedy, F, Moledina, S, MacDonald, L, Tamvaki, E, Barnes, A, Cookson, V, Chentouf, L, Ali, S, Othman, S, Ranganathan, L, Gibbs, JSR, DaCosta, R, Pinguel, J, Dormand, N, Parker, A, Stokes, D, Ghedia, D, Tan, Y, Ngcozana, T, Wanjiku, I, Polwarth, G, Mackenzie Ross, RV, Suntharalingam, J, Grover, M, Kirby, A, Grove, A, White, K, Seatter, A, Creaser-Myers, A, Walker, S, Roney, S, Elliot, CA, Charalampopoulos, A, Sabroe, I, Hameed, A, Armstrong, I, Hamilton, N, Rothman, AMK, Swift, AJ, Wild, JM, Soubrier, F, Eyries, M, Humbert, M, Montani, D, Girerd, B, Scelsi, L, Ghio, S, Gall, H, Ghofrani, A, Bogaard, HJ, Noordegraaf, AV, Houweling, AC, Veld, AHI, Schotte, G, Kariotis, Sokratis [0000-0001-9993-6017], Pickworth, Josephine A [0000-0002-7199-364X], Rhodes, Christopher J [0000-0002-4962-3204], Wharton, John [0000-0001-8110-2575], Iremonger, James [0000-0003-3953-8812], Dunning, Mark J [0000-0002-8853-9435], Errington, Niamh [0000-0001-6768-7394], Thompson, AA Roger [0000-0002-0717-4551], Howard, Luke S [0000-0003-2822-210X], Graf, Stefan [0000-0002-1315-8873], Wilkins, Martin R [0000-0003-3926-1171], Lawrie, Allan [0000-0003-4192-9505], Wang, Dennis [0000-0003-0068-1005], Apollo - University of Cambridge Repository, Gräf, Stefan [0000-0002-1315-8873], Pickworth, Josephine A. [0000-0002-7199-364X], Rhodes, Christopher J. [0000-0002-4962-3204], Dunning, Mark J. [0000-0002-8853-9435], Thompson, A. A. Roger [0000-0002-0717-4551], Howard, Luke S. [0000-0003-2822-210X], Wilkins, Martin R. [0000-0003-3926-1171], Pulmonary medicine, ACS - Pulmonary hypertension & thrombosis, Human genetics, and ACS - Atherosclerosis & ischemic syndromes

Subjects
HYPOXIA-INDUCED PROLIFERATION, OPERATED CALCIUM-ENTRY, Classification and taxonomy, Science, PROGNOSTIC IMPACT, General Physics and Astronomy, Down-Regulation, 631/114/2404, General Biochemistry, Genetics and Molecular Biology, 38/91, Functional clustering, Genomic analysis, 631/114/1386, 631/1647/2217, Humans, Familial Primary Pulmonary Hypertension, HLA-DP beta-Chains, RISK SCORE CALCULATOR, OUTCOMES, Pulmonary Arterial Hypertension, Science & Technology, Multidisciplinary, Gene Expression Profiling, 692/4019/592/75, article, 49/39, General Chemistry, Multidisciplinary Sciences, IRON-DEFICIENCY, Cardiovascular diseases, UK National PAH Cohort Study Consortium, REGISTRY, ASSESSMENTS, SURVIVAL, Science & Technology - Other Topics, Transcriptome, 5-Aminolevulinate Synthetase
Abstract

Idiopathic pulmonary arterial hypertension (IPAH) is a rare but fatal disease diagnosed by right heart catheterisation and the exclusion of other forms of pulmonary arterial hypertension, producing a heterogeneous population with varied treatment response. Here we show unsupervised machine learning identification of three major patient subgroups that account for 92% of the cohort, each with unique whole blood transcriptomic and clinical feature signatures. These subgroups are associated with poor, moderate, and good prognosis. The poor prognosis subgroup is associated with upregulation of the ALAS2 and downregulation of several immunoglobulin genes, while the good prognosis subgroup is defined by upregulation of the bone morphogenetic protein signalling regulator NOG, and the C/C variant of HLA-DPA1/DPB1 (independently associated with survival). These findings independently validated provide evidence for the existence of 3 major subgroups (endophenotypes) within the IPAH classification, could improve risk stratification and provide molecular insights into the pathogenesis of IPAH., Idiopathic pulmonary arterial hypertension is a rare and fatal disease with a heterogeneous treatment response. Here the authors show that unsupervised machine learning of whole blood transcriptomes from 359 patients with idiopathic pulmonary arterial hypertension identifies 3 subgroups (endophenotypes) that improve risk stratification and provide new molecular insights.

Published
2020

4. Whole Blood RNA Profiles Associated with Pulmonary Arterial Hypertension and Clinical Outcome

Author

Rhodes, Christopher J, Otero-Núñez, Pablo, Wharton, John, Swietlik, Emilia M, Kariotis, Sokratis, Harbaum, Lars, Dunning, Mark J, Elinoff, Jason M, Errington, Niamh, Thomson, AA Roger, Iremonger, James, Coghlan, J Gerry, Corris, Paul A, Howard, Luke S, Kiely, David G, Church, Colin, Pepke-Zaba, Joanna, Toshner, Mark, Wort, Stephen J, Desai, Ankit A, Humbert, Marc, Nichols, William C, Southgate, Laura, Trégouët, David-Alexandre, Trembath, Richard C, Prokopenko, Inga, Gräf, Stefan, Morrell, Nicholas W, Wang, Dennis, Lawrie, Allan, Wilkins, Martin R, NIHR BioResource – Rare Diseases PAH Consortium And The UK National PAH Cohort Study Consortium, Swietlik, Emilia [0000-0002-4095-8489], Toshner, Mark [0000-0002-3969-6143], Graf, Stefan [0000-0002-1315-8873], Morrell, Nicholas [0000-0001-5700-9792], and Apollo - University of Cambridge Repository

Subjects
pulmonary arterial hypertension, RNAseq, whole blood RNA
Abstract

RATIONALE: Idiopathic and hereditary pulmonary arterial hypertension (PAH) are rare but comprise a genetically heterogeneous patient group. RNA-sequencing linked to the underlying genetic architecture can be used to better understand the underlying pathology by identifying key signalling pathways and stratify patients more robustly according to clinical risk. OBJECTIVES: Using a three-stage design of RNA discovery, RNA validation/model construction and model validation to define a set of PAH-associated RNAs and a single summarising RNA model score. To define genes most likely to be involved in disease development, we performed Mendelian randomisation (MR) analysis. METHODS: RNA-sequencing was performed on whole blood samples from 359 patients with idiopathic, heritable and drug-induced PAH and 72 age- and sex-matched healthy volunteers. The score was evaluated against disease severity markers including survival analysis using all-cause mortality from diagnosis. MR used known eQTL and summary statistics from a PAH GWAS. MEASUREMENTS AND MAIN RESULTS: We identified 507 genes with differential RNA expression in PAH patients compared to controls. A model of 25 RNAs was able to distinguish PAH with 87% accuracy (AUC 95% CI: 0.791-0.945) in model validation. The RNA model score was associated with disease severity and long-term survival (p=4.66x10-6) in PAH. MR detected an association between SMAD5 levels and PAH disease susceptibility (OR:0.317, 95%CI:0.129-0.776, p=0.012). CONCLUSIONS: A whole blood RNA signature of PAH, which includes RNAs relevant to disease pathogenesis, associates with disease severity and identifies patients with poor clinical outcomes. Genetic variants associated with lower SMAD5 expression may increase susceptibility to PAH.

Published
2020
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5. Characterization of GDF2 Mutations and Levels of BMP9 and BMP10 in Pulmonary Arterial Hypertension

Author

Christopher J. Rhodes, Allan Lawrie, Robert V. MacKenzie Ross, Mark Toshner, Mélanie Eyries, Werner Seeger, Richard M. Salmon, Stefano Ghio, Laura Scelsi, Stephen J. Wort, Gabor Kovacs, Florent Soubrier, J. Simon R. Gibbs, Richard C. Trembath, Jennifer M. Martin, Nicholas W. Morrell, Matthias Haimel, Gerry Coghlan, Marc Humbert, Jay Suntharalingam, Charaka Hadinnapola, Cesare Danesino, Willem H. Ouwehand, Louise C. Daugherty, Carmen M. Treacy, David G. Kiely, Andrea Olschewski, Joanna Pepke-Zaba, Deborah Whitehorn, Anton Vonk Noordegraaf, Andrew J. Peacock, Robin Condliffe, Horst Olschewski, Paul A. Corris, Joshua Hodgson, Hossein Ardeschir Ghofrani, Arjan C. Houweling, Colin Church, Jingxu Guo, Stefan Gräf, Barbara Girerd, Katherine Yates, Harm Jan Bogaard, Ivana Nikolic, Luke S. Howard, Henning Gall, Laura Southgate, Olga Shamardina, Emilia M. Swietlik, Marta Bleda, Rajiv D. Machado, Inga Prokopenko, John Wharton, James Liley, Simon Holden, Paul B. Yu, Martin R. Wilkins, Shahin Moledina, David Montani, Paul D. Upton, Wei Li, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Swietlik, Emilia [0000-0002-4095-8489], Guo, Jingxu [0000-0002-1568-4842], Shamardina, Olga [0000-0003-4994-2157], Ouwehand, Willem [0000-0002-7744-1790], Toshner, Mark [0000-0002-3969-6143], Li, Wei [0000-0002-1924-3120], Graf, Stefan [0000-0002-1315-8873], Upton, Paul [0000-0003-2716-4921], Morrell, Nicholas [0000-0001-5700-9792], Apollo - University of Cambridge Repository, Pulmonary medicine, ACS - Pulmonary hypertension & thrombosis, Human genetics, APH - Quality of Care, ACS - Atherosclerosis & ischemic syndromes, and British Heart Foundation

Subjects
Pulmonary and Respiratory Medicine, Adult, Male, medicine.medical_specialty, Heterozygote, DNA Copy Number Variations, [SDV]Life Sciences [q-bio], Respiratory System, Mutation, Missense, GDF2, Critical Care and Intensive Care Medicine, Bone morphogenetic protein, BMP9, 03 medical and health sciences, 0302 clinical medicine, Sex Factors, Critical Care Medicine, Sex factors, Internal medicine, General & Internal Medicine, pulmonary arterial hypertension, medicine, Growth Differentiation Factor 2, Humans, In patient, 030212 general & internal medicine, Respiratory system, 11 Medical and Health Sciences, Science & Technology, business.industry, Case-control study, Heterozygote advantage, Middle Aged, 3. Good health, Transport protein, BMP10, Protein Transport, Endocrinology, 030228 respiratory system, Case-Control Studies, Bone Morphogenetic Proteins, Female, business, Life Sciences & Biomedicine
Abstract

International audience; Rationale: Recently, rare heterozygous mutations in GDF2 were identified in patients with pulmonary arterial hypertension (PAH). GDF2 encodes the circulating BMP (bone morphogenetic protein) type 9, which is a ligand for the BMP2 receptor.Objectives: Here we determined the functional impact of GDF2 mutations and characterized plasma BMP9 and BMP10 levels in patients with idiopathic PAH.Methods: Missense BMP9 mutant proteins were expressed in vitro and the impact on BMP9 protein processing and secretion, endothelial signaling, and functional activity was assessed. Plasma BMP9 and BMP10 levels and activity were assayed in patients with PAH with GDF2 variants and in control subjects. Levels were also measured in a larger cohort of control subjects (n = 120) and patients with idiopathic PAH (n = 260).Measurements and Main Results: We identified a novel rare variation at the GDF2 and BMP10 loci, including copy number variation. In vitro, BMP9 missense proteins demonstrated impaired cellular processing and secretion. Patients with PAH who carried these mutations exhibited reduced plasma levels of BMP9 and reduced BMP activity. Unexpectedly, plasma BMP10 levels were also markedly reduced in these individuals. Although overall BMP9 and BMP10 levels did not differ between patients with PAH and control subjects, BMP10 levels were lower in PAH females. A subset of patients with PAH had markedly reduced plasma levels of BMP9 and BMP10 in the absence of GDF2 mutations.Conclusions: Our findings demonstrate that GDF2 mutations result in BMP9 loss of function and are likely causal. These mutations lead to reduced circulating levels of both BMP9 and BMP10. These findings support therapeutic strategies to enhance BMP9 or BMP10 signaling in PAH.

Published
2020

6. Phenotypic Characterization of EIF2AK4 Mutation Carriers in a Large Cohort of Patients Diagnosed Clinically With Pulmonary Arterial Hypertension

Author

Harm Jan Bogaard, Richard C. Trembath, Florent Soubrier, Allan Lawrie, Robin Condliffe, Jennifer M. Martin, Nicholas W. Morrell, Heritable Pah, Nicholas Screaton, Jay Suntharalingam, Robert V. MacKenzie Ross, David G. Kiely, Matthias Haimel, Colin Church, Stefan Gräf, Stephen J. Wort, Paula Rayner-Matthews, Peter Dorfmüller, Andrew Peacock, Marc Humbert, Katherine Yates, Andrew J. Swift, Laura Southgate, Olga Shamardina, Paul A. Corris, Charaka Hadinnapola, Mark Toshner, Rajiv D. Machado, Mark Southwood, Martin R. Wilkins, John Wharton, Shahin Moledina, Simon Holden, Joanna Pepke-Zaba, Anton Vonk Noordegraaf, Gerry Coghlan, Michael Newnham, Carmen M. Treacy, Stephen D. Preston, Jules Hernández-Sánchez, Barbara Girerd, Simon Gibbs, Marta Bleda, David Montani, British Heart Foundation, RS: CARIM - R1.04 - Clinical thrombosis and haemostasis, MUMC+: DA CDL Algemeen (9), Med Microbiol, Infect Dis & Infect Prev, Biochemie, RS: CARIM - R1.03 - Cell biochemistry of thrombosis and haemostasis, Hadinnapola, Charaka [0000-0002-7794-3432], Haimel, Matthias [0000-0002-0320-0214], Shamardina, Olga [0000-0003-4994-2157], Toshner, Mark [0000-0002-3969-6143], Graf, Stefan [0000-0002-1315-8873], Morrell, Nicholas [0000-0001-5700-9792], Apollo - University of Cambridge Repository, Pulmonary medicine, ACS - Pulmonary hypertension & thrombosis, and APH - Quality of Care

Subjects
Male, CAPILLARY HEMANGIOMATOSIS, Cardiac & Cardiovascular Systems, Heredity, DNA Mutational Analysis, 030204 cardiovascular system & hematology, Cohort Studies, NIHR BioResource–Rare Diseases Consortium, UK National Cohort Study of Idiopathic and Heritable PAH, 0302 clinical medicine, VENOOCCLUSIVE-DISEASE, Gene Frequency, Risk Factors, pulmonary hypertension, Medicine, Familial Primary Pulmonary Hypertension, genetics, Prospective Studies, Prospective cohort study, 1102 Cardiorespiratory Medicine and Haematology, Middle Aged, Medical research, Protein-Serine-Threonine Kinases, DIFFUSION CAPACITY, 3. Good health, Pedigree, Europe, Phenotype, Predictive value of tests, Pulmonary venoocclusive disease, Female, Pulmonary Veno-Occlusive Disease, Cardiology and Cardiovascular Medicine, Life Sciences & Biomedicine, pulmonary veno-occlusive disease, CT, Adult, medicine.medical_specialty, genetics, human, hypertension, pulmonary, Hypertension, Pulmonary, hypertension, pulmonary, Protein Serine-Threonine Kinases, Pulmonary Artery, Bone Morphogenetic Protein Receptors, Type II, Article, 1117 Public Health and Health Services, 03 medical and health sciences, Young Adult, Predictive Value of Tests, Physiology (medical), Internal medicine, Humans, Arterial Pressure, Genetic Predisposition to Disease, human, Genetic Association Studies, Aged, Retrospective Studies, Science & Technology, pulmonary venoocclusive disease, business.industry, BMPR2, Retrospective cohort study, 1103 Clinical Sciences, medicine.disease, Pulmonary hypertension, Blood pressure, EIF2AK4, 030228 respiratory system, Peripheral Vascular Disease, Cardiovascular System & Hematology, REGISTRY, Physical therapy, Cardiovascular System & Cardiology, prognosis, mutation, business, Tomography, X-Ray Computed
Abstract

Background: Pulmonary arterial hypertension (PAH) is a rare disease with an emerging genetic basis. Heterozygous mutations in the gene encoding the bone morphogenetic protein receptor type 2 ( BMPR2 ) are the commonest genetic cause of PAH, whereas biallelic mutations in the eukaryotic translation initiation factor 2 alpha kinase 4 gene ( EIF2AK4 ) are described in pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis. Here, we determine the frequency of these mutations and define the genotype-phenotype characteristics in a large cohort of patients diagnosed clinically with PAH. Methods: Whole-genome sequencing was performed on DNA from patients with idiopathic and heritable PAH and with pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis recruited to the National Institute of Health Research BioResource–Rare Diseases study. Heterozygous variants in BMPR2 and biallelic EIF2AK4 variants with a minor allele frequency of sorting intolerant from tolerant predictions) were identified as potentially causal. Phenotype data from the time of diagnosis were also captured. Results: Eight hundred sixty-four patients with idiopathic or heritable PAH and 16 with pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis were recruited. Mutations in BMPR2 were identified in 130 patients (14.8%). Biallelic mutations in EIF2AK4 were identified in 5 patients with a clinical diagnosis of pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis. Furthermore, 9 patients with a clinical diagnosis of PAH carried biallelic EIF2AK4 mutations. These patients had a reduced transfer coefficient for carbon monoxide (K co ; 33% [interquartile range, 30%–35%] predicted) and younger age at diagnosis (29 years; interquartile range, 23–38 years) and more interlobular septal thickening and mediastinal lymphadenopathy on computed tomography of the chest compared with patients with PAH without EIF2AK4 mutations. However, radiological assessment alone could not accurately identify biallelic EIF2AK4 mutation carriers. Patients with PAH with biallelic EIF2AK4 mutations had a shorter survival. Conclusions: Biallelic EIF2AK4 mutations are found in patients classified clinically as having idiopathic and heritable PAH. These patients cannot be identified reliably by computed tomography, but a low K co and a young age at diagnosis suggests the underlying molecular diagnosis. Genetic testing can identify these misclassified patients, allowing appropriate management and early referral for lung transplantation.

Published
2017

7. Genetic determinants of risk in pulmonary arterial hypertension: international genome-wide association studies and meta-analysis

Author

Rhodes, Christopher J, Batai, Ken, Bleda, Marta, Haimel, Matthias, Southgate, Laura, Germain, Marine, Pauciulo, Michael W, Hadinnapola, Charaka, Aman, Jurjan, Girerd, Barbara, Arora, Amit, Knight, Jo, Hanscombe, Ken B, Karnes, Jason H, Kaakinen, Marika, Gall, Henning, Ulrich, Anna, Harbaum, Lars, Cebola, Inês, Ferrer, Jorge, Lutz, Katie, Swietlik, Emilia, Ahmad, Ferhaan, Amouyel, Philippe, Archer, Stephen L, Argula, Rahul, Austin, Eric D, Badesch, David, Bakshi, Sahil, Barnett, Christopher, Benza, Raymond, Bhatt, Nitin, Bogaard, Harm J, Burger, Charles D, Chakinala, Murali, Church, Colin, Coghlan, John G, Condliffe, Robin, Corris, Paul A, Danesino, Cesare, Debette, Stéphanie, Elliott, C Gregory, Elwing, Jean, Eyries, Melanie, Fortin, Terry, Franke, Andre, Frantz, Robert P, Frost, Adaani, Garcia, Joe GN, Ghio, Stefano, Ghofrani, Hossein-Ardeschir, Gibbs, J Simon R, Harley, John, He, Hua, Hill, Nicholas S, Hirsch, Russel, Houweling, Arjan C, Howard, Luke S, Ivy, Dunbar, Kiely, David G, Klinger, James, Kovacs, Gabor, Lahm, Tim, Laudes, Matthias, Machado, Rajiv D, MacKenzie Ross, Robert V, Marsolo, Keith, Martin, Lisa J, Moledina, Shahin, Montani, David, Nathan, Steven D, Newnham, Michael, Olschewski, Andrea, Olschewski, Horst, Oudiz, Ronald J, Ouwehand, Willem, Peacock, Andrew J, Pepke-Zaba, Joanna, Rehman, Zia, Robbins, Ivan, Roden, Dan M, Rosenzweig, Erika B, Saydain, Ghulam, Scelsi, Laura, Schilz, Robert, Seeger, Werner, Shaffer, Christian M, Simms, Robert W, Simon, Marc, Sitbon, Olivier, Suntharalingam, Jay, Tang, Haiyang, Tchourbanov, Alexander Y, Thenappan, Thenappan, Torres, Fernando, Toshner, Mark, Treacy, Carmen M, Vonk Noordegraaf, Anton, Waisfisz, Quinten, Walsworth, Anna K, Walter, Robert E, Wharton, John, White, R James, Wilt, Jeffrey, Wort, Stephen J, Yung, Delphine, Lawrie, Allan, Humbert, Marc, Soubrier, Florent, Trégouët, David-Alexandre, Prokopenko, Inga, Kittles, Richard, Graf, Stefan, Nichols, William C, Trembath, Richard C, Desai, Ankit A, Morrell, Nicholas, Wilkins, Martin R, UK NIHR BioResource Rare Diseases Consortium, UK PAH Cohort Study Consortium, US PAH Biobank Consortium, Apollo-University Of Cambridge Repository, Swietlik, Emilia [0000-0002-4095-8489], Ouwehand, Willem [0000-0002-7744-1790], Toshner, Mark [0000-0002-3969-6143], Graf, Stefan [0000-0002-1315-8873], Morrell, Nicholas [0000-0001-5700-9792], and Apollo - University of Cambridge Repository

Subjects
Male, Pulmonary Arterial Hypertension, US PAH Biobank Consortium, Genotyping Techniques, UK PAH Cohort Study Consortium, Genetic Variation, Middle Aged, HLA-DP alpha-Chains, Risk Assessment, Survival Analysis, Polymorphism, Single Nucleotide, UK NIHR BioResource Rare Diseases Consortium, SOXF Transcription Factors, Humans, Genetic Predisposition to Disease, Female, HLA-DP beta-Chains, Signal Transduction, Genome-Wide Association Study
Abstract

Background\ud Rare genetic variants cause pulmonary arterial hypertension, but the contribution of common genetic variation to disease risk and natural history is poorly characterised. We tested for genome-wide association for pulmonary arterial hypertension in large international cohorts and assessed the contribution of associated regions to outcomes.\ud \ud Methods\ud We did two separate genome-wide association studies (GWAS) and a meta-analysis of pulmonary arterial hypertension. These GWAS used data from four international case-control studies across 11 744 individuals with European ancestry (including 2085 patients). One GWAS used genotypes from 5895 whole-genome sequences and the other GWAS used genotyping array data from an additional 5849 individuals. Cross-validation of loci reaching genome-wide significance was sought by meta-analysis. Conditional analysis corrected for the most significant variants at each locus was used to resolve signals for multiple associations. We functionally annotated associated variants and tested associations with duration of survival. All-cause mortality was the primary endpoint in survival analyses.\ud \ud Findings\ud A locus near SOX17 (rs10103692, odds ratio 1·80 [95% CI 1·55–2·08], p=5·13 × 10–15) and a second locus in HLA-DPA1 and HLA-DPB1 (collectively referred to as HLA-DPA1/DPB1 here; rs2856830, 1·56 [1·42–1·71], p=7·65 × 10–20) within the class II MHC region were associated with pulmonary arterial hypertension. The SOX17 locus had two independent signals associated with pulmonary arterial hypertension (rs13266183, 1·36 [1·25–1·48], p=1·69 × 10–12; and rs10103692). Functional and epigenomic data indicate that the risk variants near SOX17 alter gene regulation via an enhancer active in endothelial cells. Pulmonary arterial hypertension risk variants determined haplotype-specific enhancer activity, and CRISPR-mediated inhibition of the enhancer reduced SOX17 expression. The HLA-DPA1/DPB1 rs2856830 genotype was strongly associated with survival. Median survival from diagnosis in patients with pulmonary arterial hypertension with the C/C homozygous genotype was double (13·50 years [95% CI 12·07 to >13·50]) that of those with the T/T genotype (6·97 years [6·02–8·05]), despite similar baseline disease severity.\ud \ud Interpretation\ud This is the first study to report that common genetic variation at loci in an enhancer near SOX17 and in HLA-DPA1/DPB1 is associated with pulmonary arterial hypertension. Impairment of SOX17 function might be more common in pulmonary arterial hypertension than suggested by rare mutations in SOX17. Further studies are needed to confirm the association between HLA typing or rs2856830 genotyping and survival, and to determine whether HLA typing or rs2856830 genotyping improves risk stratification in clinical practice or trials.\ud \ud Funding\ud UK NIHR, BHF, UK MRC, Dinosaur Trust, NIH/NHLBI, ERS, EMBO, Wellcome Trust, EU, AHA, ACClinPharm, Netherlands CVRI, Dutch Heart Foundation, Dutch Federation of UMC, Netherlands OHRD and RNAS, German DFG, German BMBF, APH Paris, INSERM, Université Paris-Sud, and French ANR.

Published
2019

8. Genome-wide identification and characterisation of human DNA replication origins by initiation site sequencing (ini-seq)

Author

Langley, Alexander R, Gräf, Stefan, Smith, James C, Krude, Torsten, Graf, Stefan [0000-0002-1315-8873], Krude, Torsten [0000-0002-1842-1933], and Apollo - University of Cambridge Repository

Subjects
DNA Replication, Genome, Human, genetic processes, Chromosome Mapping, Computational Biology, High-Throughput Nucleotide Sequencing, Replication Origin, DNA, Genomics, Sequence Analysis, DNA, Genome Integrity, Repair and Replication, Cell Line, Tumor, Humans, natural sciences, Nucleotide Motifs, Transcription Initiation Site
Abstract

Next-generation sequencing has enabled the genome-wide identification of human DNA replication origins. However, different approaches to mapping replication origins, namely (i) sequencing isolated small nascent DNA strands (SNS-seq); (ii) sequencing replication bubbles (bubble-seq) and (iii) sequencing Okazaki fragments (OK-seq), show only limited concordance. To address this controversy, we describe here an independent high-resolution origin mapping technique that we call initiation site sequencing (ini-seq). In this approach, newly replicated DNA is directly labelled with digoxigenin-dUTP near the sites of its initiation in a cell-free system. The labelled DNA is then immunoprecipitated and genomic locations are determined by DNA sequencing. Using this technique we identify >25,000 discrete origin sites at sub-kilobase resolution on the human genome, with high concordance between biological replicates. Most activated origins identified by ini-seq are found at transcriptional start sites and contain G-quadruplex (G4) motifs. They tend to cluster in early-replicating domains, providing a correlation between early replication timing and local density of activated origins. Origins identified by ini-seq show highest concordance with sites identified by SNS-seq, followed by OK-seq and bubble-seq. Furthermore, germline origins identified by positive nucleotide distribution skew jumps overlap with origins identified by ini-seq and OK-seq more frequently and more specifically than do sites identified by either SNS-seq or bubble-seq.

Published
2016

9. Response by Hadinnapola et al to Letter Regarding Article, 'Phenotypic Characterization of EIF2AK4 Mutation Carriers in a Large Cohort of Patients Diagnosed Clinically With Pulmonary Arterial Hypertension'

Author

Hadinnapola, Charaka, Gräf, Stefan, Morrell, Nicholas W, Graf, Stefan [0000-0002-1315-8873], Morrell, Nicholas [0000-0001-5700-9792], and Apollo - University of Cambridge Repository

Subjects
Cohort Studies, Hypertension, Pulmonary, Mutation, Humans, Familial Primary Pulmonary Hypertension, Protein Serine-Threonine Kinases
Published
2018
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10. Selective enhancement of endothelial BMPR-II with BMP9 reverses pulmonary arterial hypertension

Author

Janine Mary Wilkinson, Nicholas W. Morrell, Paul D. Upton, Kylie M Drake, Mark L. Ormiston, Lai Ming Yung, Stephen D Moore, Matthias Mueller, Stefan Gräf, Lu Long, Rajiv D. Machado, Mark Southwood, Bernd Kinzel, Micheala A. Aldred, Xudong Yang, Paul B. Yu, Graf, Stefan [0000-0002-1315-8873], Upton, Paul [0000-0003-2716-4921], Morrell, Nicholas [0000-0001-5700-9792], and Apollo - University of Cambridge Repository

Subjects
Male, Aging, Cell Membrane Permeability, Endothelium, Transcription, Genetic, Systole, Heart Ventricles, Hypertension, Pulmonary, Immunoblotting, GDF2, Apoptosis, 030204 cardiovascular system & hematology, Biology, Pulmonary Artery, Bone morphogenetic protein, Bone Morphogenetic Protein Receptors, Type II, Article, General Biochemistry, Genetics and Molecular Biology, Rats, Sprague-Dawley, 03 medical and health sciences, 0302 clinical medicine, medicine, polycyclic compounds, Growth Differentiation Factor 2, Animals, Humans, Bone morphogenetic protein receptor, Gene Knock-In Techniques, Phosphorylation, Receptor, 030304 developmental biology, 0303 health sciences, Monocrotaline, Gene Expression Profiling, C521 Medical Microbiology, JNK Mitogen-Activated Protein Kinases, Endothelial Cells, General Medicine, medicine.disease, Pulmonary hypertension, BMPR2, Rats, Mice, Inbred C57BL, medicine.anatomical_structure, Immunology, Cancer research, A100 Pre-clinical Medicine, Signal transduction, Densitometry
Abstract

Genetic evidence implicates the loss of bone morphogenetic protein type II receptor (BMPR-II) signaling in the endothelium as an initiating factor in pulmonary arterial hypertension (PAH). However, selective targeting of this signaling pathway using BMP ligands has not yet been explored as a therapeutic strategy. Here, we identify BMP9 as the preferred ligand for preventing apoptosis and enhancing monolayer integrity in both pulmonary arterial endothelial cells and blood outgrowth endothelial cells from subjects with PAH who bear mutations in the gene encoding BMPR-II, BMPR2. Mice bearing a heterozygous knock-in allele of a human BMPR2 mutation, R899X, which we generated as an animal model of PAH caused by BMPR-II deficiency, spontaneously developed PAH. Administration of BMP9 reversed established PAH in these mice, as well as in two other experimental PAH models, in which PAH develops in response to either monocrotaline or VEGF receptor inhibition combined with chronic hypoxia. These results demonstrate the promise of direct enhancement of endothelial BMP signaling as a new therapeutic strategy for PAH.

Published
2018
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11. HGVA: the Human Genome Variation Archive

Author

Swaathi Kandasamy, Joaquín Tárraga, Ignacio Medina, Wasim Bari, Jacobo Coll, Joaquín Dopazo, Pedro Furió-Tarí, Matthias Haimel, Stefan Gräf, Antonio Rueda, Marta Bleda, Augusto Rendon, Javier Santoyo López, Haimel, Matthias [0000-0002-0320-0214], Graf, Stefan [0000-0002-1315-8873], Rendon Restrepo, Augusto [0000-0001-8994-0039], Apollo - University of Cambridge Repository, [Lopez, Javier] Genom England, Charterhouse Sq, London EC1M 6BQ, England, [Coll, Jacobo] Genom England, Charterhouse Sq, London EC1M 6BQ, England, [Furio-Tari, Pedro] Genom England, Charterhouse Sq, London EC1M 6BQ, England, [Bari, Wasim] Genom England, Charterhouse Sq, London EC1M 6BQ, England, [Rueda, Antonio] Genom England, Charterhouse Sq, London EC1M 6BQ, England, [Rendon, Augusto] Genom England, Charterhouse Sq, London EC1M 6BQ, England, [Haimel, Matthias] Univ Cambridge, Dept Haematol, Cambridge CB2 0PT, England, [Kandasamy, Swaathi] Univ Cambridge, Dept Haematol, Cambridge CB2 0PT, England, [Bleda, Marta] Univ Cambridge, Dept Haematol, Cambridge CB2 0PT, England, [Graf, Stefan] Univ Cambridge, Dept Haematol, Cambridge CB2 0PT, England, [Rendon, Augusto] Univ Cambridge, Dept Haematol, Cambridge CB2 0PT, England, [Haimel, Matthias] Univ Cambridge, Dept Med, Cambridge CB2 0QQ, England, [Bleda, Marta] Univ Cambridge, Dept Med, Cambridge CB2 0QQ, England, [Graf, Stefan] Univ Cambridge, Dept Med, Cambridge CB2 0QQ, England, [Haimel, Matthias] Cambridge Univ Hosp, NIHR BioResource Rare Dis, CambridgeBiomed Campus, Cambridge CB2 0QQ, England, [Bleda, Marta] Cambridge Univ Hosp, NIHR BioResource Rare Dis, CambridgeBiomed Campus, Cambridge CB2 0QQ, England, [Graf, Stefan] Cambridge Univ Hosp, NIHR BioResource Rare Dis, CambridgeBiomed Campus, Cambridge CB2 0QQ, England, [Tarraga, Joaquin] Univ Cambridge, UIS, HPC Serv, Cambridge CB3 0FB, England, [Medina, Ignacio] Univ Cambridge, UIS, HPC Serv, Cambridge CB3 0FB, England, [Dopazo, Joaquin] Hosp Virgen Rocio, Clin Bioinformat Area, FPS, Seville 41013, Spain, [Dopazo, Joaquin] Hosp Virgen Rocio, FPS, Funct Genom Node INB, Seville 41013, Spain, [Dopazo, Joaquin] Hosp Virgen Rocio, Bioinformat Rare Dis BiER, FPS, Ctr Invest Biomed Red Enfermedades Raras CIBERER, Seville 41013, Spain, Spanish Ministry of Economy and Competitiveness, 'Instituto de Salud Carlos III' (ISCIII) 'Plataforma de Recursos Biomoleculares y Bioinformaticos', European Regional Development Funds (ERDF) [EU H2020-INFRADEV-1-1 ELIXIR-EXCELERATE], National Institute for Health Research (NIHR) England, MINECO (SPAIN), and National Institute for Health Research (NIHR)

Subjects
0301 basic medicine, Genetic-variation, Population, Biology, Guidelines, JavaScript, Genome, 03 medical and health sciences, Annotation, User-Computer Interface, 0302 clinical medicine, Genetics, Humans, 1000 Genomes Project, education, computer.programming_language, education.field_of_study, Internet, business.industry, Ontology, Genome, Human, Variants, Genetic Variation, Python (programming language), Data science, 030104 developmental biology, ComputingMethodologies_PATTERNRECOGNITION, Knowledge base, Web Server Issue, Human genome, business, computer, 030217 neurology & neurosurgery, Software
Abstract

High-profile genomic variation projects like the 1000 Genomes project or the Exome Aggregation Consortium, are generating a wealth of human genomic variation knowledge which can be used as an essential reference for identifying disease-causing genotypes. However, accessing these data, contrasting the various studies and integrating those data in downstream analyses remains cumbersome. The Human Genome Variation Archive (HGVA) tackles these challenges and facilitates access to genomic data for key reference projects in a clean, fast and integrated fashion. HGVA provides an efficient and intuitive web-interface for easy data mining, a comprehensive RESTful API and client libraries in Python, Java and JavaScript for fast programmatic access to its knowledge base. HGVA calculates population frequencies for these projects and enriches their data with variant annotation provided by CellBase, a rich and fast annotation solution. HGVA serves as a proof-of-concept of the genome analysis developments being carried out by the University of Cambridge together with UK's 100 000 genomes project and the National Institute for Health Research BioResource Rare-Diseases, in particular, deploying open-source for Computational Biology (OpenCB) software platform for storing and analyzing massive genomic datasets.

Published
2017

12. Plasma metabolomics implicates modified transfer RNAs and altered bioenergetics in the outcomes of pulmonary arterial hypertension

Author

Rhodes, CJ, Ghataorhe, P, Wharton, J, Rue-Albrecht, KC, Hadinnapola, C, Watson, G, Bleda, M, Haimel, M, Coghlan, G, Corris, PA, Howard, LS, Kiely, DG, Peacock, AJ, Pepke-Zaba, J, Toshner, MR, Wort, SJ, Gibbs, JSR, Lawrie, A, Gräf, S, Morrell, NW, Wilkins, MR, Hadinnapola, Charaka [0000-0002-7794-3432], Haimel, Matthias [0000-0002-0320-0214], Toshner, Mark [0000-0002-3969-6143], Graf, Stefan [0000-0002-1315-8873], Morrell, Nicholas [0000-0001-5700-9792], and Apollo - University of Cambridge Repository

Subjects
Adult, Male, Hypertension, Pulmonary, Middle Aged, Prognosis, metabolomics, Young Adult, Treatment Outcome, RNA, Transfer, pulmonary circulation, Original Research Articles, ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, Humans, metabolome, Female, Energy Metabolism, metabolism, Aged
Abstract

Supplemental Digital Content is available in the text., Background: Pulmonary arterial hypertension (PAH) is a heterogeneous disorder with high mortality. Methods: We conducted a comprehensive study of plasma metabolites using ultraperformance liquid chromatography mass spectrometry to identify patients at high risk of early death, to identify patients who respond well to treatment, and to provide novel molecular insights into disease pathogenesis. Results: Fifty-three circulating metabolites distinguished well-phenotyped patients with idiopathic or heritable PAH (n=365) from healthy control subjects (n=121) after correction for multiple testing (P

Published
2016

13. Towards a molecular classification of pulmonary arterial hypertension

Author

Nicholas W. Morrell, Stefan Gräf, Graf, Stefan [0000-0002-1315-8873], Morrell, Nicholas [0000-0001-5700-9792], and Apollo - University of Cambridge Repository

Subjects
0301 basic medicine, Pulmonary and Respiratory Medicine, medicine.medical_specialty, business.industry, Hypertension, Pulmonary, Physiology, medicine.disease, Pulmonary hypertension, 03 medical and health sciences, 030104 developmental biology, Molecular classification, Internal medicine, medicine, Cardiology, Humans, Familial primary pulmonary hypertension, Familial Primary Pulmonary Hypertension, business
Abstract

This editorial discusses recent advances in understanding the genetic basis of pulmonary arterial hypertension http://ow.ly/mmfi303fvCu

Published
2016

14. BMPR2 mutations and survival in pulmonary arterial hypertension: an individual participant data meta-analysis

Author

Evans, Jonathan D. W., Girerd, Barbara, Montani, David, Wang, Xiao Jian, Austin, Eric D., Elliott, Greg, Asano, Koichiro, Grünig, Ekkehard, Yan, Yi, Jing, Zhi Cheng, Wheeler, Lisa A., Nakayama, Ikue, Satoh, Toru, Eichstaedt, Christina, Hinderhofer, Katrin, Wolf, Matthias, Rosenzweig, Erika B., Chung, Wendy K., Soubrier, Florent, Simonneau, Gérald, Sitbon, Olivier, Gräf, Stefan, Kaptoge, Stephen, Di Angelantonio, Emanuele, Humbert, Marc, Morrell, Nicholas W., GALIE', NAZZARENO, MANES, ALESSANDRA, PALAZZINI, MASSIMILIANO, Graf, Stefan [0000-0002-1315-8873], Kaptoge, Stephen [0000-0002-1155-4872], Di Angelantonio, Emanuele [0000-0001-8776-6719], Morrell, Nicholas [0000-0001-5700-9792], Apollo - University of Cambridge Repository, Evans, Jonathan D.W., Girerd, Barbara, Montani, David, Wang, Xiao-Jian, Galiè, Nazzareno, Austin, Eric D., Elliott, Greg, Asano, Koichiro, Grünig, Ekkehard, Yan, Yi, Jing, Zhi-Cheng, Manes, Alessandra, Palazzini, Massimiliano, Wheeler, Lisa A., Nakayama, Ikue, Satoh, Toru, Eichstaedt, Christina, Hinderhofer, Katrin, Wolf, Matthia, Rosenzweig, Erika B., Chung, Wendy K., Soubrier, Florent, Simonneau, Gérald, Sitbon, Olivier, Gräf, Stefan, Kaptoge, Stephen, Di Angelantonio, Emanuele, Humbert, Marc, and Morrell, Nicholas W

Subjects
Adult, Male, Pulmonary hypertension, geneticas, Hypertension, Pulmonary, Articles, Middle Aged, Bone Morphogenetic Protein Receptors, Type II, Prognosis, Survival Rate, Young Adult, Mutation, Humans, Familial Primary Pulmonary Hypertension, Female, Lung Transplantation, Proportional Hazards Models
Abstract

BACKGROUND: Mutations in the gene encoding the bone morphogenetic protein receptor type II (BMPR2) are the commonest genetic cause of pulmonary arterial hypertension (PAH). However, the effect of BMPR2 mutations on clinical phenotype and outcomes remains uncertain. METHODS: We analysed individual participant data of 1550 patients with idiopathic, heritable, and anorexigen-associated PAH from eight cohorts that had been systematically tested for BMPR2 mutations. The primary outcome was the composite of death or lung transplantation. All-cause mortality was the secondary outcome. Hazard ratios (HRs) for death or transplantation and all-cause mortality associated with the presence of BMPR2 mutation were calculated using Cox proportional hazards models stratified by cohort. FINDINGS: Overall, 448 (29%) of 1550 patients had a BMPR2 mutation. Mutation carriers were younger at diagnosis (mean age 35·4 [SD 14·8] vs 42·0 [17·8] years), had a higher mean pulmonary artery pressure (60·5 [13·8] vs 56·4 [15·3] mm Hg) and pulmonary vascular resistance (16·6 [8·3] vs 12·9 [8·3] Wood units), and lower cardiac index (2·11 [0·69] vs 2·51 [0·92] L/min per m(2); all p

Published
2015

15. The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroups

Author

Curtis, Christina, Shah, Sohrab P, Chin, Suet-Feung, Turashvili, Gulisa, Rueda, Oscar M, Dunning, Mark J, Speed, Doug, Lynch, Andy G, Samarajiwa, Shamith, Yuan, Yinyin, Gräf, Stefan, Ha, Gavin, Haffari, Gholamreza, Bashashati, Ali, Russell, Roslin, McKinney, Steven, METABRIC Group, Langerød, Anita, Green, Andrew, Provenzano, Elena, Wishart, Gordon, Pinder, Sarah, Watson, Peter, Markowetz, Florian, Murphy, Leigh, Ellis, Ian, Purushotham, Arnie, Børresen-Dale, Anne-Lise, Brenton, James D, Tavaré, Simon, Caldas, Carlos, Aparicio, Samuel, Chin, Suet-Feung [0000-0001-5697-1082], Rueda Palacio, Oscar [0000-0003-0008-4884], Dunning, Mark [0000-0002-8853-9435], Lynch, Andy [0000-0002-7876-7338], Samarajiwa, Shamith [0000-0003-1046-0601], Graf, Stefan [0000-0002-1315-8873], Markowetz, Florian [0000-0002-2784-5308], Brenton, James [0000-0002-5738-6683], and Apollo - University of Cambridge Repository

Subjects
DNA Copy Number Variations, Genome, Human, MAP Kinase Kinase 4, Gene Expression Profiling, Breast Neoplasms, Genomics, Kaplan-Meier Estimate, Prognosis, Polymorphism, Single Nucleotide, Gene Expression Regulation, Neoplastic, Treatment Outcome, Humans, Female, Gene Regulatory Networks, Protein Phosphatase 2, Genes, Neoplasm
Abstract

The elucidation of breast cancer subgroups and their molecular drivers requires integrated views of the genome and transcriptome from representative numbers of patients. We present an integrated analysis of copy number and gene expression in a discovery and validation set of 997 and 995 primary breast tumours, respectively, with long-term clinical follow-up. Inherited variants (copy number variants and single nucleotide polymorphisms) and acquired somatic copy number aberrations (CNAs) were associated with expression in ~40% of genes, with the landscape dominated by cis- and trans-acting CNAs. By delineating expression outlier genes driven in cis by CNAs, we identified putative cancer genes, including deletions in PPP2R2A, MTAP and MAP2K4. Unsupervised analysis of paired DNA–RNA profiles revealed novel subgroups with distinct clinical outcomes, which reproduced in the validation cohort. These include a high-risk, oestrogen-receptor-positive 11q13/14 cis-acting subgroup and a favourable prognosis subgroup devoid of CNAs. Trans-acting aberration hotspots were found to modulate subgroup-specific gene networks, including a TCR deletion-mediated adaptive immune response in the ‘CNA-devoid’ subgroup and a basal-specific chromosome 5 deletion-associated mitotic network. Our results provide a novel molecular stratification of the breast cancer population, derived from the impact of somatic CNAs on the transcriptome.

Published
2012

16. Ensembl 2008

Author

Flicek, P, Aken, BL, Beal, K, Ballester, B, Caccamo, M, Chen, Y, Clarke, L, Coates, G, Cunningham, F, Cutts, T, Down, T, Dyer, SC, Eyre, T, Fitzgerald, S, Fernandez-Banet, J, Gräf, S, Haider, S, Hammond, M, Holland, R, Howe, KL, Howe, K, Johnson, N, Jenkinson, A, Kähäri, A, Keefe, D, Kokocinski, F, Kulesha, E, Lawson, D, Longden, I, Megy, K, Meidl, P, Overduin, B, Parker, A, Pritchard, B, Prlic, A, Rice, S, Rios, D, Schuster, M, Sealy, I, Slater, G, Smedley, D, Spudich, G, Trevanion, S, Vilella, AJ, Vogel, J, White, S, Wood, M, Birney, E, Cox, T, Curwen, V, Durbin, R, Fernandez-Suarez, XM, Herrero, J, Hubbard, TJP, Kasprzyk, A, Proctor, G, Smith, J, Ureta-Vidal, A, Searle, S, Graf, Stefan [0000-0002-1315-8873], Megy, Karyn [0000-0002-2826-3879], and Apollo - University of Cambridge Repository

Subjects
Internet, Mice, User-Computer Interface, ComputingMethodologies_PATTERNRECOGNITION, Databases, Genetic, Computer Graphics, Animals, Humans, Genomics, Regulatory Elements, Transcriptional, Software
Abstract

The Ensembl project (http://www.ensembl.org) is a comprehensive genome information system featuring an integrated set of genome annotation, databases and other information for chordate and selected model organism and disease vector genomes. As of release 47 (October 2007), Ensembl fully supports 35 species, with preliminary support for six additional species. New species in the past year include platypus and horse. Major additions and improvements to Ensembl since our previous report include extensive support for functional genomics data in the form of a specialized functional genomics database, genome-wide maps of protein-DNA interactions and the Ensembl regulatory build; support for customization of the Ensembl web interface through the addition of user accounts and user groups; and increased support for genome resequencing. We have also introduced new comparative genomics-based data mining options and report on the continued development of our software infrastructure.

Published
2008

17. Optimized design and assessment of whole genome tiling arrays

Author

Martijn A. Huynen, Fiona G. G. Nielsen, Ewan Birney, Stefan Kurtz, Paul Flicek, Henk Stunnenberg, Stefan Gräf, Graf, Stefan [0000-0002-1315-8873], and Apollo - University of Cambridge Repository

Subjects
Statistics and Probability, Quality Control, Source code, Energy and redox metabolism [NCMLS 4], Genetics and epigenetic pathways of disease [NCMLS 6], Bioinformatics, media_common.quotation_subject, Biology, computer.software_genre, Biochemistry, Genome, Article, Set (abstract data type), Greedy algorithm, Molecular Biology, media_common, Tiling array, Chromosome Mapping, Equipment Design, Sequence Analysis, DNA, Microarray Analysis, Substring, Computer Science Applications, Equipment Failure Analysis, Computational Mathematics, Mitochondrial medicine [IGMD 8], Computational Theory and Mathematics, Computer-Aided Design, Noise (video), Data mining, DNA microarray, DNA Probes, Cellular energy metabolism [UMCN 5.3], Algorithm, computer, Algorithms
Abstract

Motivation: Recent advances in microarray technologies have made it feasible to interrogate whole genomes with tiling arrays and this technique is rapidly becoming one of the most important high-throughput functional genomics assays. For large mammalian genomes, analyzing oligonucleotide tiling array data is complicated by the presence of non-unique sequences on the array, which increases the overall noise in the data and may lead to false positive results due to cross-hybridization. The ability to create custom microarrays using maskless array synthesis has led us to consider ways to optimize array design characteristics for improving data quality and analysis. We have identified a number of design parameters to be optimized including uniqueness of the probe sequences within the whole genome, melting temperature and self-hybridization potential. Results: We introduce the uniqueness score, U, a novel quality measure for oligonucleotide probes and present a method to quickly compute it. We show that U is equivalent to the number of shortest unique substrings in the probe and describe an efficient greedy algorithm to design mammalian whole genome tiling arrays using probes that maximize U. Using the mouse genome, we demonstrate how several optimizations influence the tiling array design characteristics. With a sensible set of parameters, our designs cover 78% of the mouse genome including many regions previously considered ‘untilable’ due to the presence of repetitive sequence. Finally, we compare our whole genome tiling array designs with commercially available designs. Availability: Source code is available under an open source license from http://www.ebi.ac.uk/~graef/arraydesign/ Contact: [email protected]

Published
2007

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