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Your search keyword '"Valentina Iotchkova"' showing total 11 results
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11 results on '"Valentina Iotchkova"'

1. Neutrophil lymphocyte ratio as an indicator for disease progression in Idiopathic Pulmonary Fibrosis

Author

Ling-Pei Ho, Rosie Barker, Harriet Bothwell, Andrea Pereira, Rachel K Hoyles, Rachel Benamore, Kritica Dwivedi, Andrew Achaiah, Amila Rathnapala, and Valentina Iotchkova

Subjects
Medicine, Diseases of the respiratory system, RC705-779
Abstract

Rationale Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disease. Patients present at different stages and disease course is varied. Blood monocytes have been linked to all-cause mortality, and neutrophils to progression to IPF in patients with the indeterminate for usual interstitial pneumonia CT pattern.Objective To determine association between blood monocytes, neutrophils and lymphocytes levels (and their derived indexes), with lung function decline and mortality in IPF.Methods We performed a retrospective analysis of an IPF cohort (n=128) who had their first clinical visit at the Oxford Interstitial Lung Disease Service between 2013 and 2017. Association between blood monocytes, neutrophils, lymphocytes and derived indexes (within 4 months of visit) and decline in forced vital capacity (FVC) and all-cause mortality were assessed using Cox proportional hazard regression analysis. Kaplan-Meier analysis was used to assess time-to-event for 10% FVC decline and mortality for patients dichotomised to high and low leucocyte counts.Results Median length of follow-up was 31.0 months (IQR 16.2–42.4); 41.4% demonstrated FVC decline >10% per year and 43.8% died. In multivariate models (incorporating age, gender and initial FVC%), raised neutrophils, lymphopaenia and neutrophil:lymphocyte ratio were associated with FVC decline (p≤0.01); while both monocytes and neutrophil levels (and their derived indexes) were associated with all-cause mortality (p≤0.01). Kaplan-Meier analysis also showed association between neutrophils and its derived indexes but not monocyte, with FVC decline.Conclusion Blood neutrophil and lymphopaenia are more sensitive than monocytes as prognostic indicators of disease progression in those with established IPF.

Published
2022
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3. Blood leukocyte levels as potential prognostic markers in IPF

Author

Ling-Pei Ho, Rachel K. Hoyles, Kritica Dwivedi, Rosia Barker, Armila Rathnapala, Andrew Achaiah, Harriet Bothwell, Valentina Iotchkova, and Andrea Pereira

Subjects
Oncology, medicine.medical_specialty, business.industry, Internal medicine, medicine, business
Published
2021

4. Genetic perturbation of PU.1 binding and chromatin looping at neutrophil enhancers associates with autoimmune disease

Author

Hannes Ponstingl, Simone Ecker, Manuel Tardaguila, Samantha Farrow, Paul Flicek, Valentina Iotchkova, Ben Farr, Mattia Frontini, Lu Chen, Nicole Soranzo, Louella Vasquez, Peter Fraser, David J. Richardson, Alice L. Mann, Avik Datta, Daniel Mead, Heather Elding, Kate Downes, Klaudia Walter, Tomi Pastinen, Kousik Kundu, Biola-Maria Javierre, Mikhail Spivakov, Ying Sims, Stephen Watt, Frances Burden, Laura Clarke, Walter, Klaudia [0000-0003-4448-0301], Kundu, Kousik [0000-0002-1019-8351], Ecker, Simone [0000-0001-5648-1710], Iotchkova, Valentina [0000-0001-5057-0210], Mead, Daniel [0000-0001-7717-4330], Ponstingl, Hannes [0000-0001-7573-1703], Richardson, David [0000-0003-0247-9118], Flicek, Paul [0000-0002-3897-7955], Clarke, Laura [0000-0002-5989-6898], Fraser, Peter [0000-0002-0041-1227], Javierre, Biola-Maria [0000-0002-8682-6748], Spivakov, Mikhail [0000-0002-0383-3943], Soranzo, Nicole [0000-0003-1095-3852], and Apollo - University of Cambridge Repository

Subjects
0301 basic medicine, Male, Neutrophils, 45/43, General Physics and Astronomy, 631/250/262, 0302 clinical medicine, Transcriptional regulation, Promoter Regions, Genetic, Innate immunity, Multidisciplinary, article, 49/39, Middle Aged, Acquired immune system, Chromatin, Cell biology, Enhancer Elements, Genetic, Chromatin Immunoprecipitation Sequencing, Female, Adult, Science, Quantitative Trait Loci, Biology, Chromatin structure, General Biochemistry, Genetics and Molecular Biology, Autoimmune Diseases, 03 medical and health sciences, Young Adult, Immune system, Proto-Oncogene Proteins, 631/208/200, medicine, Humans, Enhancer, Gene, Aged, 45/91, Autoimmune disease, Innate immune system, General Chemistry, 631/337/100/101, medicine.disease, Gene regulation, 631/208/199, 030104 developmental biology, Gene Expression Regulation, Trans-Activators, Gene expression, 38/15, 030217 neurology & neurosurgery
Abstract

Funder: MS is funded by Medical Research Council (MC-A652-5QA20), Funder: This work was supported by the Wellcome Trust grant (206194) and EU FP7 High Impact Project BLUEPRINT (HEALTH-F5-2011-282510), Neutrophils play fundamental roles in innate immune response, shape adaptive immunity, and are a potentially causal cell type underpinning genetic associations with immune system traits and diseases. Here, we profile the binding of myeloid master regulator PU.1 in primary neutrophils across nearly a hundred volunteers. We show that variants associated with differential PU.1 binding underlie genetically-driven differences in cell count and susceptibility to autoimmune and inflammatory diseases. We integrate these results with other multi-individual genomic readouts, revealing coordinated effects of PU.1 binding variants on the local chromatin state, enhancer-promoter contacts and downstream gene expression, and providing a functional interpretation for 27 genes underlying immune traits. Collectively, these results demonstrate the functional role of PU.1 and its target enhancers in neutrophil transcriptional control and immune disease susceptibility.

Published
2021

5. S79 Prevalence of the indeterminate for UIP CT feature and potential link between monocyte and neutrophil levels and progression to IPF – a single centre analysis

Author

Rachel K. Hoyles, Amila Rathnapala, Andrea Pereira, Andrew Achaiah, Rosie Barker, Kritica Dwivedi, LP Ho, Harriet Bothwell, and Valentina Iotchkova

Subjects
medicine.medical_specialty, Proportional hazards model, business.industry, Disease, Guideline, respiratory system, medicine.disease, Gastroenterology, respiratory tract diseases, Idiopathic pulmonary fibrosis, FEV1/FVC ratio, DLCO, Internal medicine, Cohort, Medicine, Indeterminate, business
Abstract

Introduction Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disease with poor prognosis. Identifying patients early may allow intervention which could limit progression. The ‘indeterminate for UIP’ (iUIP) CT pattern could be a precursor to IPF. Aims To evaluate prevalence and progression of patients with ‘iUIP’ to a clinical diagnosis of IPF, and explore factors contributing to progression. Methods We performed a retrospective analysis of an IPF cohort seen in the Oxford ILD Service between 2013–2017. We analysed all HRCTs performed for each patient up to August 2019. HRCT images were re-categorised according to the 2018 IPF guideline to identify those with iUIP CT pattern. These were categorised as ‘non-progressors’ or ‘progressors’ depending on whether there has been change in CT scan in terms of extent of disease or change in pattern of disease to ‘definite’ or ‘probable’ UIP pattern.Radiological features, lung function trends, haematological data and patient demographics were examined to explore potential contribution to progression using a univariate Cox proportional hazard model. Results 230 individual patients with a clinical diagnosis of IPF were screened. 48 (21%) cases with iUIP pattern were identified. 32 patients had at least one follow-on CT scan. Of these evaluable cases, 23 (71%) demonstrated progression and 9 (29%) cases demonstrated no progression. Of the progressors; 26% (6 cases) demonstrated increase in extent of iUIP (over 3.1 ±0.8 yrs), 48% (11 cases) progressed to ‘probable UIP’ (over 3.8 ±1.6 yrs) and 26% progressed to ‘definite UIP’ (4.1 ±2.4 yrs). All those with ‘definite’ or ‘probable UIP’ were diagnosed as IPF by ILD MDT. Using Cox regression, CT-contemporaneous monocyte count >0.90 × 103/μL [HR 3.9 (1.3–12), p=0.017] and neutrophils >7.5 × 103/µl [HR 43 (4.2–430), p=0.001] were significantly associated with progression to IPF. There was also trend towards male gender, lower baseline FVC and TLCO, presence of GGO on CT and ex-smoker status in the progressor group. Conclusion 53% of evaluable iUIP patients progressed to a clinical diagnosis of IPF over 3.9 years (±1.9). Baseline monocyte (>0.90 × 103/μL) and neutrophil (>7.5 × 103/µl) counts were significantly associated with progression. These data provide a single-centre analysis of the evolution of patients with iUIP CT pattern, and first signal for potential factors associated with progression to IPF.

Published
2021

6. Incidence of symptomatic, image-confirmed venous thromboembolism following hospitalization for COVID-19 with 90-day follow-up

Author

Akshay Shah, Joshua Morton, Susan Shapiro, Paraskevi Untiveros, Gavinda Sangha, Nicola Curry, Valentina Iotchkova, Sarah Jaafar, and Richard A. Salisbury

Subjects
Diagnostic Imaging, Male, medicine.medical_specialty, Time Factors, medicine.drug_class, Low molecular weight heparin, 030204 cardiovascular system & hematology, law.invention, Thrombosis and Hemostasis, 03 medical and health sciences, 0302 clinical medicine, Randomized controlled trial, law, Internal medicine, medicine, Humans, 030212 general & internal medicine, Blood coagulation test, Aged, Retrospective Studies, Aged, 80 and over, business.industry, SARS-CoV-2, Medical record, Incidence (epidemiology), Incidence, COVID-19, Disease Management, Retrospective cohort study, Hematology, Venous Thromboembolism, Middle Aged, medicine.disease, Thrombosis, Hospitalization, England, Observational study, Female, Blood Coagulation Tests, Disease Susceptibility, Symptom Assessment, business, Biomarkers, Follow-Up Studies
Abstract

Key Points The rate of symptomatic VTE in patients after hospitalization for COVID-19 was 2.6% at 42 days after discharge. Bleeding is a significant cause of morbidity in addition to thrombosis in patients admitted with COVID-19., Although COVID-19 has been reported to be associated with high rates of venous thromboembolism (VTE), the risk of VTE and bleeding after hospitalization for COVID-19 remains unclear, and the optimal hospital VTE prevention strategy is not known. We collected retrospective observational data on thrombosis and bleeding in 303 consecutive adult patients admitted to the hospital for at least 24 hours for COVID-19. Patients presenting with VTE on admission were excluded. Data were collected until 90 days after admission or known death by using medical records and an established national VTE network. Maximal level of care was ward based in 78% of patients, with 22% requiring higher dependency care (12% noninvasive ventilation, 10% invasive ventilation). Almost all patients (97.0%) received standard thromboprophylaxis or were already receiving therapeutic anticoagulation (17.5%). Symptomatic image-confirmed VTE occurred in 5.9% of patients during index hospitalization, and in 7.2% at 90 days after admission (23.9% in patients requiring higher dependency care); half the events were isolated segmental or subsegmental defects on lung imaging. Bleeding occurred in 13 patients (4.3%) during index hospitalization (1.3% had major bleeding). The majority of bleeds occurred in patients on the general ward, and 6 patients were receiving treatment-dose anticoagulation, highlighting the need for caution in intensifying standard thromboprophylaxis strategies. Of 152 patients discharged from the hospital without an indication for anticoagulation, 97% did not receive thromboprophylaxis after discharge, and 3% received 7 days of treatment with low molecular weight heparin after discharge. The rate of symptomatic VTE in this group at 42 days after discharge was 2.6%, highlighting the need for large prospective randomized controlled trials of thromboprophylaxis after discharge in COVID-19., Visual Abstract

Published
2020

7. Type-1 IFN primed monocytes in pathogenesis of idiopathic pulmonary fibrosis

Author

Yuejuan Zheng, Jan Rehwinkel, Karl Blirando, Nasullah K Alham, Victoria St Noble, Emily Fraser, Emmanouela Repapi, Neil Ashley, Joseph M D Rastrick, Agne Antanaviciute, Colin Clelland, Rachel E. Rigby, Stephen S. Taylor, Rachel K. Hoyles, Ling-Pei Ho, Chaitanya Vuppusetty, Clare S. Hardman, Laura Denney, Valentina Iotchkova, and Rachel Benamore

Subjects
CD64, Lung, business.industry, Disease, respiratory system, medicine.disease, respiratory tract diseases, Pathogenesis, Idiopathic pulmonary fibrosis, Immune system, medicine.anatomical_structure, Fibrosis, Immunology, medicine, business, Ex vivo
Abstract

Idiopathic pulmonary fibrosis (IPF) is the most severe form of lung fibrosis. It is progressive, and has an extremely poor outcome and limited treatment options. The disease exclusively affects the lungs, and thus less attention has been focused on blood-borne immune cells. which could be a more effective therapeutic target than lung-based cells. Here, we questioned if circulating monocytes, which has been shown to be increased in IPF, bore abnormalities that might contribute to its pathogenesis. We found that levels of circulating monocytes correlated directly with the extent of fibrosis in the lungs, and increased further during acute clinical deterioration. Monocytes in IPF were phenotypically distinct, displaying increased expression of CD64, a type 1 IFN gene expression signature and a greater magnitude of type 1 IFN response when stimulated. These abnormalities were accompanied by markedly raised CSF-1 levels in the serum, prolonged survival of monocytesex vivo, and increased numbers of monocytes in lung tissue. Our study defines the key monocytic abnormalities in IPF, proposing type 1 IFN-primed monocytes as a potential driver of an aberrant repair response and fibrosis. It provides a rationale for targeting monocytes and identifies monocytic CD64 as a potential specific therapeutic target for IPF.

Published
2020
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8. Variation in PU.1 binding and chromatin looping at neutrophil enhancers influences autoimmune disease susceptibility

Author

Laura Clarke, Hannes Ponstingl, Manuel Tardaguila, Lu Chen, Tomi Pastinen, Javierre B-M., Stephen B. Watt, Mattia Frontini, Nicole Soranzo, Mikhail Spivakov, Ben Farr, Louella Vasquez, Frances Burden, Alice L. Mann, David J. Richardson, Heather Elding, Ying Yan, Kousik Kundu, S. Farrow, Paul Flicek, Klaudia Walter, Avik Datta, Daniel Mead, Simone Ecker, Kate Downes, Valentina Iotchkova, and Peter Fraser

Subjects
Genetics, Autoimmune disease, Cell type, Myeloid, medicine.anatomical_structure, Immune system, Gene expression, medicine, Disease, Biology, Enhancer, medicine.disease, Chromatin
Abstract

Neutrophils play fundamental roles in innate inflammatory response, shape adaptive immunity1, and have been identified as a potentially causal cell type underpinning genetic associations with immune system traits and diseases2,3 The majority of these variants are non-coding and the underlying mechanisms are not fully understood. Here, we profiled the binding of one of the principal myeloid transcriptional regulators, PU.1, in primary neutrophils across nearly a hundred volunteers, and elucidate the coordinated genetic effects of PU.1 binding variation, local chromatin state, promoter-enhancer interactions and gene expression. We show that PU.1 binding and the associated chain of molecular changes underlie genetically-driven differences in cell count and autoimmune disease susceptibility. Our results advance interpretation for genetic loci associated with neutrophil biology and immune disease.

Published
2019
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9. Bi-allelic Loss-of-Function CACNA1B Mutations in Progressive Epilepsy-Dyskinesia

Author

Kathleen M. Gorman, Esther Meyer, Detelina Grozeva, Egidio Spinelli, Amy McTague, Alba Sanchis-Juan, Keren J. Carss, Emily Bryant, Adi Reich, Amy L. Schneider, Ronit M. Pressler, Michael A. Simpson, Geoff D. Debelle, Evangeline Wassmer, Jenny Morton, Diana Sieciechowicz, Eric Jan-Kamsteeg, Alex R. Paciorkowski, Mary D. King, J. Helen Cross, Annapurna Poduri, Heather C. Mefford, Ingrid E. Scheffer, Tobias B. Haack, Gary McCullagh, John J. Millichap, Gemma L. Carvill, Jill Clayton-Smith, Eamonn R. Maher, F. Lucy Raymond, Manju A. Kurian, Jeremy F. McRae, Stephen Clayton, Tomas W. Fitzgerald, Joanna Kaplanis, Elena Prigmore, Diana Rajan, Alejandro Sifrim, Stuart Aitken, Nadia Akawi, Mohsan Alvi, Kirsty Ambridge, Daniel M. Barrett, Tanya Bayzetinova, Philip Jones, Wendy D. Jones, Daniel King, Netravathi Krishnappa, Laura E. Mason, Tarjinder Singh, Adrian R. Tivey, Munaza Ahmed, Uruj Anjum, Hayley Archer, Ruth Armstrong, Jana Awada, Meena Balasubramanian, Siddharth Banka, Diana Baralle, Angela Barnicoat, Paul Batstone, David Baty, Chris Bennett, Jonathan Berg, Birgitta Bernhard, A. Paul Bevan, Maria Bitner-Glindzicz, Edward Blair, Moira Blyth, David Bohanna, Louise Bourdon, David Bourn, Lisa Bradley, Angela Brady, Simon Brent, Carole Brewer, Kate Brunstrom, David J. Bunyan, John Burn, Natalie Canham, Bruce Castle, Kate Chandler, Elena Chatzimichali, Deirdre Cilliers, Angus Clarke, Susan Clasper, Virginia Clowes, Andrea Coates, Trevor Cole, Irina Colgiu, Amanda Collins, Morag N. Collinson, Fiona Connell, Nicola Cooper, Helen Cox, Lara Cresswell, Gareth Cross, Yanick Crow, Mariella D’Alessandro, Tabib Dabir, Rosemarie Davidson, Sally Davies, Dylan de Vries, John Dean, Charu Deshpande, Gemma Devlin, Abhijit Dixit, Angus Dobbie, Alan Donaldson, Dian Donnai, Deirdre Donnelly, Carina Donnelly, Angela Douglas, Sofia Douzgou, Alexis Duncan, Jacqueline Eason, Sian Ellard, Ian Ellis, Frances Elmslie, Karenza Evans, Sarah Everest, Tina Fendick, Richard Fisher, Frances Flinter, Nicola Foulds, Andrew Fry, Alan Fryer, Carol Gardiner, Lorraine Gaunt, Neeti Ghali, Richard Gibbons, Harinder Gill, Judith Goodship, David Goudie, Emma Gray, Andrew Green, Philip Greene, Lynn Greenhalgh, Susan Gribble, Rachel Harrison, Lucy Harrison, Victoria Harrison, Rose Hawkins, Liu He, Stephen Hellens, Alex Henderson, Sarah Hewitt, Lucy Hildyard, Emma Hobson, Simon Holden, Muriel Holder, Susan Holder, Georgina Hollingsworth, Tessa Homfray, Mervyn Humphreys, Jane Hurst, Ben Hutton, Stuart Ingram, Melita Irving, Lily Islam, Andrew Jackson, Joanna Jarvis, Lucy Jenkins, Diana Johnson, Elizabeth Jones, Dragana Josifova, Shelagh Joss, Beckie Kaemba, Sandra Kazembe, Rosemary Kelsell, Bronwyn Kerr, Helen Kingston, Usha Kini, Esther Kinning, Gail Kirby, Claire Kirk, Emma Kivuva, Alison Kraus, Dhavendra Kumar, V. K. Ajith Kumar, Katherine Lachlan, Wayne Lam, Anne Lampe, Caroline Langman, Melissa Lees, Derek Lim, Cheryl Longman, Gordon Lowther, Sally A. Lynch, Alex Magee, Eddy Maher, Alison Male, Sahar Mansour, Karen Marks, Katherine Martin, Una Maye, Emma McCann, Vivienne McConnell, Meriel McEntagart, Ruth McGowan, Kirsten McKay, Shane McKee, Dominic J. McMullan, Susan McNerlan, Catherine McWilliam, Sarju Mehta, Kay Metcalfe, Anna Middleton, Zosia Miedzybrodzka, Emma Miles, Shehla Mohammed, Tara Montgomery, David Moore, Sian Morgan, Hood Mugalaasi, Victoria Murday, Helen Murphy, Swati Naik, Andrea Nemeth, Louise Nevitt, Ruth Newbury-Ecob, Andrew Norman, Rosie O’Shea, Caroline Ogilvie, Kai-Ren Ong, Soo-Mi Park, Michael J. Parker, Chirag Patel, Joan Paterson, Stewart Payne, Daniel Perrett, Julie Phipps, Daniela T. Pilz, Martin Pollard, Caroline Pottinger, Joanna Poulton, Norman Pratt, Katrina Prescott, Sue Price, Abigail Pridham, Annie Procter, Hellen Purnell, Oliver Quarrell, Nicola Ragge, Raheleh Rahbari, Josh Randall, Julia Rankin, Lucy Raymond, Debbie Rice, Leema Robert, Eileen Roberts, Jonathan Roberts, Paul Roberts, Gillian Roberts, Alison Ross, Elisabeth Rosser, Anand Saggar, Shalaka Samant, Julian Sampson, Richard Sandford, Ajoy Sarkar, Susann Schweiger, Richard Scott, Ingrid Scurr, Ann Selby, Anneke Seller, Cheryl Sequeira, Nora Shannon, Saba Sharif, Charles Shaw-Smith, Emma Shearing, Debbie Shears, Eamonn Sheridan, Ingrid Simonic, Roldan Singzon, Zara Skitt, Audrey Smith, Kath Smith, Sarah Smithson, Linda Sneddon, Miranda Splitt, Miranda Squires, Fiona Stewart, Helen Stewart, Volker Straub, Mohnish Suri, Vivienne Sutton, Ganesh Jawahar Swaminathan, Elizabeth Sweeney, Kate Tatton-Brown, Cat Taylor, Rohan Taylor, Mark Tein, I. Karen Temple, Jenny Thomson, Marc Tischkowitz, Susan Tomkins, Audrey Torokwa, Becky Treacy, Claire Turner, Peter Turnpenny, Carolyn Tysoe, Anthony Vandersteen, Vinod Varghese, Pradeep Vasudevan, Parthiban Vijayarangakannan, Julie Vogt, Emma Wakeling, Sarah Wallwark, Jonathon Waters, Astrid Weber, Diana Wellesley, Margo Whiteford, Sara Widaa, Sarah Wilcox, Emily Wilkinson, Denise Williams, Nicola Williams, Louise Wilson, Geoff Woods, Christopher Wragg, Michael Wright, Laura Yates, Michael Yau, Chris Nellåker, Michael Parker, Helen V. Firth, Caroline F. Wright, David R. FitzPatrick, Jeffrey C. Barrett, Matthew E. Hurles, Saeed Al Turki, Carl Anderson, Richard Anney, Dinu Antony, Maria Soler Artigas, Muhammad Ayub, Senduran Balasubramaniam, Inês Barroso, Phil Beales, Jamie Bentham, Shoumo Bhattacharya, Ewan Birney, Douglas Blackwood, Martin Bobrow, Elena Bochukova, Patrick Bolton, Rebecca Bounds, Chris Boustred, Gerome Breen, Mattia Calissano, Keren Carss, Krishna Chatterjee, Lu Chen, Antonio Ciampi, Sebhattin Cirak, Peter Clapham, Gail Clement, Guy Coates, David Collier, Catherine Cosgrove, Tony Cox, Nick Craddock, Lucy Crooks, Sarah Curran, David Curtis, Allan Daly, Aaron Day-Williams, Ian N.M. Day, Thomas Down, Yuanping Du, Ian Dunham, Sarah Edkins, Peter Ellis, David Evans, Sadaf Faroogi, Ghazaleh Fatemifar, David R. Fitzpatrick, Paul Flicek, James Flyod, A. Reghan Foley, Christopher S. Franklin, Marta Futema, Louise Gallagher, Matthias Geihs, Daniel Geschwind, Heather Griffin, Xueqin Guo, Xiaosen Guo, Hugh Gurling, Deborah Hart, Audrey Hendricks, Peter Holmans, Bryan Howie, Liren Huang, Tim Hubbard, Steve E. Humphries, Pirro Hysi, David K. Jackson, Yalda Jamshidi, Tian Jing, Chris Joyce, Jane Kaye, Thomas Keane, Julia Keogh, John Kemp, Karen Kennedy, Anja Kolb-Kokocinski, Genevieve Lachance, Cordelia Langford, Daniel Lawson, Irene Lee, Monkol Lek, Jieqin Liang, Hong Lin, Rui Li, Yingrui Li, Ryan Liu, Jouko Lönnqvist, Margarida Lopes, Valentina Iotchkova, Daniel MacArthur, Jonathan Marchini, John Maslen, Mangino Massimo, Iain Mathieson, Gaëlle Marenne, Peter McGuffin, Andrew McIntosh, Andrew G. McKechanie, Andrew McQuillin, Sarah Metrustry, Hannah Mitchison, Alireza Moayyeri, James Morris, Francesco Muntoni, Kate Northstone, Michael O'Donnovan, Alexandros Onoufriadis, Stephen O'Rahilly, Karim Oualkacha, Michael J. Owen, Aarno Palotie, Kalliope Panoutsopoulou, Victoria Parker, Jeremy R. Parr, Lavinia Paternoster, Tiina Paunio, Felicity Payne, Olli Pietilainen, Vincent Plagnol, Lydia Quaye, Michael A. Quail, Karola Rehnström, Susan Ring, Graham R.S. Ritchie, Nicola Roberts, David B. Savage, Peter Scambler, Stephen Schiffels, Miriam Schmidts, Nadia Schoenmakers, Robert K. Semple, Eva Serra, Sally I. Sharp, So-Youn Shin, David Skuse, Kerrin Small, Lorraine Southam, Olivera Spasic-Boskovic, David St Clair, Jim Stalker, Elizabeth Stevens, Beate St Pourcian, Jianping Sun, Jaana Suvisaari, Ionna Tachmazidou, Martin D. Tobin, Ana Valdes, Margriet Van Kogelenberg, Peter M. Visscher, Louise V. Wain, James T.R. Walters, Guangbiao Wang, Jun Wang, Yu Wang, Kirsten Ward, Elanor Wheeler, Tamieka Whyte, Hywel Williams, Kathleen A. Williamson, Crispian Wilson, Kim Wong, ChangJiang Xu, Jian Yang, Fend Zhang, Pingbo Zhang, Timothy Aitman, Hana Alachkar, Sonia Ali, Louise Allen, David Allsup, Gautum Ambegaonkar, Julie Anderson, Richard Antrobus, Gavin Arno, Gururaj Arumugakani, Sofie Ashford, William Astle, Antony Attwood, Steve Austin, Chiara Bacchelli, Tamam Bakchoul, Tadbir K. Bariana, Helen Baxendale, David Bennett, Claire Bethune, Shahnaz Bibi, Marta Bleda, Harm Boggard, Paula Bolton-Maggs, Claire Booth, John R. Bradley, Angie Brady, Matthew Brown, Michael Browning, Christine Bryson, Siobhan Burns, Paul Calleja, Jenny Carmichael, Mark Caulfield, Elizabeth Chalmers, Anita Chandra, Patrick Chinnery, Manali Chitre, Colin Church, Emma Clement, Naomi Clements-Brod, Gerry Coghlan, Peter Collins, Nichola Cooper, Amanda Creaser-Myers, Rosa DaCosta, Louise Daugherty, Sophie Davies, John Davis, Minka De Vries, Patrick Deegan, Sri V.V. Deevi, Lisa Devlin, Eleanor Dewhurst, Rainer Doffinger, Natalie Dormand, Elizabeth Drewe, David Edgar, William Egner, Wendy N. Erber, Marie Erwood, Tamara Everington, Remi Favier, Helen Firth, Debra Fletcher, James C. Fox, Amy Frary, Kathleen Freson, Bruce Furie, Abigail Furnell, Daniel Gale, Alice Gardham, Michael Gattens, Pavandeep K. Ghataorhe, Rohit Ghurye, Simon Gibbs, Kimberley Gilmour, Paul Gissen, Sarah Goddard, Keith Gomez, Pavel Gordins, Stefan Gräf, Daniel Greene, Alan Greenhalgh, Andreas Greinacher, Sofia Grigoriadou, Scott Hackett, Charaka Hadinnapola, Rosie Hague, Matthias Haimel, Csaba Halmagyi, Tracey Hammerton, Daniel Hart, Grant Hayman, Johan W.M. Heemskerk, Robert Henderson, Anke Hensiek, Yvonne Henskens, Archana Herwadkar, Fengyuan Hu, Aarnoud Huissoon, Marc Humbert, Roger James, Stephen Jolles, Rashid Kazmi, David Keeling, Peter Kelleher, Anne M. Kelly, Fiona Kennedy, David Kiely, Nathalie Kingston, Ania Koziell, Deepa Krishnakumar, Taco W. Kuijpers, Dinakantha Kumararatne, Manju Kurian, Michael A. Laffan, Michele P. Lambert, Hana Lango Allen, Allan Lawrie, Sara Lear, Claire Lentaigne, Ri Liesner, Rachel Linger, Hilary Longhurst, Lorena Lorenzo, Rajiv Machado, Rob Mackenzie, Robert MacLaren, Eamonn Maher, Jesmeen Maimaris, Sarah Mangles, Ania Manson, Rutendo Mapeta, Hugh S. Markus, Jennifer Martin, Larahmie Masati, Mary Mathias, Vera Matser, Anna Maw, Elizabeth McDermott, Coleen McJannet, Stuart Meacham, Sharon Meehan, Karyn Megy, Michel Michaelides, Carolyn M. Millar, Shahin Moledina, Anthony Moore, Nicholas Morrell, Andrew Mumford, Sai Murng, Elaine Murphy, Sergey Nejentsev, Sadia Noorani, Paquita Nurden, Eric Oksenhendler, Willem H. Ouwehand, Sofia Papadia, Alasdair Parker, John Pasi, Chris Patch, Jeanette Payne, Andrew Peacock, Kathelijne Peerlinck, Christopher J. Penkett, Joanna Pepke-Zaba, David J. Perry, Val Pollock, Gary Polwarth, Mark Ponsford, Waseem Qasim, Isabella Quinti, Stuart Rankin, Karola Rehnstrom, Evan Reid, Christopher J. Rhodes, Michael Richards, Sylvia Richardson, Alex Richter, Irene Roberts, Matthew Rondina, Catherine Roughley, Kevin Rue-Albrecht, Crina Samarghitean, Saikat Santra, Ravishankar Sargur, Sinisa Savic, Sol Schulman, Harald Schulze, Marie Scully, Suranjith Seneviratne, Carrock Sewell, Olga Shamardina, Debbie Shipley, Ilenia Simeoni, Suthesh Sivapalaratnam, Kenneth Smith, Aman Sohal, Laura Southgate, Simon Staines, Emily Staples, Hans Stauss, Penelope Stein, Jonathan Stephens, Kathleen Stirrups, Sophie Stock, Jay Suntharalingam, R. Campbell Tait, Kate Talks, Yvonne Tan, Jecko Thachil, James Thaventhiran, Ellen Thomas, Moira Thomas, Dorothy Thompson, Adrian Thrasher, Catherine Titterton, Cheng-Hock Toh, Mark Toshner, Carmen Treacy, Richard Trembath, Salih Tuna, Wojciech Turek, Ernest Turro, Chris Van Geet, Marijke Veltman, Julie von Ziegenweldt, Anton Vonk Noordegraaf, Ivy Wanjiku, Timothy Q. Warner, Hugh Watkins, Andrew Webster, Steve Welch, Sarah Westbury, John Wharton, Deborah Whitehorn, Martin Wilkins, Lisa Willcocks, Catherine Williamson, Geoffrey Woods, John Wort, Nigel Yeatman, Patrick Yong, Tim Young, Ping Yu, Paediatric Infectious Diseases / Rheumatology / Immunology, ARD - Amsterdam Reproduction and Development, Pediatric surgery, APH - Aging & Later Life, Molecular cell biology and Immunology, Pulmonary medicine, ACS - Pulmonary hypertension & thrombosis, and APH - Quality of Care

Subjects
0301 basic medicine, Male, Adolescent, Loss of Heterozygosity, Context (language use), Postnatal microcephaly, Neurotransmission, medicine.disease_cause, Bioinformatics, Synaptic Transmission, Loss of heterozygosity, 03 medical and health sciences, Epilepsy, 0302 clinical medicine, Calcium Channels, N-Type, Report, Genetics, medicine, Humans, Child, Genetics (clinical), Mutation, Dyskinesias, business.industry, Infant, medicine.disease, Hypotonia, Pedigree, 030104 developmental biology, Dyskinesia, Child, Preschool, Calcium, Female, medicine.symptom, business, 030217 neurology & neurosurgery
Abstract

© 2019 American Society of Human Genetics The occurrence of non-epileptic hyperkinetic movements in the context of developmental epileptic encephalopathies is an increasingly recognized phenomenon. Identification of causative mutations provides an important insight into common pathogenic mechanisms that cause both seizures and abnormal motor control. We report bi-allelic loss-of-function CACNA1B variants in six children from three unrelated families whose affected members present with a complex and progressive neurological syndrome. All affected individuals presented with epileptic encephalopathy, severe neurodevelopmental delay (often with regression), and a hyperkinetic movement disorder. Additional neurological features included postnatal microcephaly and hypotonia. Five children died in childhood or adolescence (mean age of death: 9 years), mainly as a result of secondary respiratory complications. CACNA1B encodes the pore-forming subunit of the pre-synaptic neuronal voltage-gated calcium channel Cav2.2/N-type, crucial for SNARE-mediated neurotransmission, particularly in the early postnatal period. Bi-allelic loss-of-function variants in CACNA1B are predicted to cause disruption of Ca2+ influx, leading to impaired synaptic neurotransmission. The resultant effect on neuronal function is likely to be important in the development of involuntary movements and epilepsy. Overall, our findings provide further evidence for the key role of Cav2.2 in normal human neurodevelopment.

Published
2018

10. Low-frequency variation in TP53 has large effects on head circumference and intracranial volume

Author

Dietmar Fernández-Orth, Nicholas J. Timpson, George Dedoussis, Beate St Pourcain, George Davey Smith, Chin Yang Shapland, Tim J Cole, Andrew P. Jackson, Valentina Iotchkova, Jordi Sunyer, Caroline Hayward, Eleftheria Zeggini, Josine L. Min, Fernando Rivadeneira, Simon E. Fisher, Carolina Medina-Gomez, Tarunveer S. Ahluwalia, Ioanna Tachmazidou, Janine F. Felix, Veronique Vitart, Jennifer Huffmann, James F. Wilson, Mònica Guxens, Bram P. Prins, Martine Vrijheid, Hans Bisgaard, Simon Haworth, Craig E. Pennell, Lærke Sass, Vincent W. V. Jaddoe, Louise Cleal, Klaus Bønnelykke, Paul R. H. J. Timmers, Klaudia Walter, Carol A. Wang, and UK10K consortium

Subjects
Adult, Male, medicine.medical_specialty, Adolescent, Cephalometry, Cranial growth, Biology, Article, White People, European descent, 03 medical and health sciences, 0302 clinical medicine, Gene Frequency, Intracranial volume, Internal medicine, Genetic variation, medicine, Humans, RNA, Messenger, Child, Allele frequency, Alleles, Aged, 030304 developmental biology, Aged, 80 and over, 0303 health sciences, Genome, Human, Skull, Gene Expression Regulation, Developmental, Genetic Variation, Middle Aged, Head circumference, Endocrinology, Developmental genetics, Genetic Loci, Female, Tumor Suppressor Protein p53, 030217 neurology & neurosurgery
Abstract

Cranial growth and development is a complex process which affects the closely related traits of head circumference (HC) and intracranial volume (ICV). The underlying genetic influences shaping these traits during the transition from childhood to adulthood are little understood, but might include both age-specific genetic factors and low-frequency genetic variation. Here, we model the developmental genetic architecture of HC, showing this is genetically stable and correlated with genetic determinants of ICV. Investigating up to 46,000 children and adults of European descent, we identify association with final HC and/or final ICV + HC at 9 novel common and low-frequency loci, illustrating that genetic variation from a wide allele frequency spectrum contributes to cranial growth. The largest effects are reported for low-frequency variants within TP53, with 0.5 cm wider heads in increaser-allele carriers versus non-carriers during mid-childhood, suggesting a previously unrecognized role of TP53 transcripts in human cranial development., Size and shape of the brain are, among others, influenced by the dimensions of the skull. Here, the authors report genome-wide association studies for head circumference and intracranial volume in children and adults and the identification of nine common or low-frequency variants associated with these traits.

Published
2018
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11. Mechanisms of Progression of Myeloid Preleukemia to Transformed Myeloid Leukemia in Children with Down Syndrome

Author

Yasuhide Hayashi, Jan-Henning Klusmann, M Labuhn, Udo Oppermann, Alison Kennedy, Sören Matzk, David Samulowski, Marie-Laure Yaspo, Takashi Taga, Irene Roberts, Raj Bhayadia, C Scheer, Leila N. Varghese, Mitchell J. Weiss, Dirk Heckl, Kelly J. Perkins, Thomas Risch, Vyacheslav Amstislavskiy, John D. Crispino, Etsuro Ito, Peter J. Campbell, Seishi Ogawa, Jeffrey W. Taub, Bilyana Stoilova, Stefan N. Constantinescu, Adrian Schwarzer, Dirk Reinhardt, Paresh Vyas, Kenichi Yoshida, Elli Papaemmanuil, Marlen Metzner, Valentina Iotchkova, Catherine Garnett, David Cruz Hernandez, UCL - SSS/DDUV/SIGN - Cell signalling, and UCL - (SLuc) Service d'hématologie

Subjects
0301 basic medicine, Cancer Research, Myeloid, Transcription, Genetic, Chromosomes, Human, Pair 21, Down syndrome, Preleukemia, Medizin, cancer transformation, preleukemia, CRISPR screen, Cytokine Receptor Common beta Subunit, 0302 clinical medicine, Mice, Inbred NOD, GATA1 Transcription Factor, Exome, Gene Expression Regulation, Leukemic, Myeloid leukemia, GATA1, 3. Good health, medicine.anatomical_structure, Cell Transformation, Neoplastic, Phenotype, Oncology, Leukemia, Myeloid, 030220 oncology & carcinogenesis, Disease Progression, Cytokine receptor, Mice, Transgenic, Biology, Article, Leukemoid Reaction, 03 medical and health sciences, stomatognathic system, medicine, Biomarkers, Tumor, Animals, Humans, Genetic Predisposition to Disease, Acute myeloid leukemia, business.industry, Cell Biology, medicine.disease, Mice, Inbred C57BL, Disease Models, Animal, 030104 developmental biology, HEK293 Cells, Cancer cell, Mutation, Cancer research, Down Syndrome, business, Trisomy, 030215 immunology
Abstract

Summary Myeloid leukemia in Down syndrome (ML-DS) clonally evolves from transient abnormal myelopoiesis (TAM), a preleukemic condition in DS newborns. To define mechanisms of leukemic transformation, we combined exome and targeted resequencing of 111 TAM and 141 ML-DS samples with functional analyses. TAM requires trisomy 21 and truncating mutations in GATA1; additional TAM variants are usually not pathogenic. By contrast, in ML-DS, clonal and subclonal variants are functionally required. We identified a recurrent and oncogenic hotspot gain-of-function mutation in myeloid cytokine receptor CSF2RB. By a multiplex CRISPR/Cas9 screen in an in vivo murine TAM model, we tested loss-of-function of 22 recurrently mutated ML-DS genes. Loss of 18 different genes produced leukemias that phenotypically, genetically, and transcriptionally mirrored ML-DS.

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