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1. Successful integration of newborn genetic testing into UK routine screening using prospective consent to determine eligibility for clinical trials

Author

Owen Martyn Bendor-Samuel, Tabitha Wishlade, Louise Willis, Parvinder Aley, Edward Choi, Rachel Craik, Yama Mujadidi, Ginny Mounce, Fenella Roseman, Arancha De La Horra Gozalo, James Bland, Nazia Taj, Ian Smith, Anette-Gabriele Ziegler, Ezio Bonifacio, Christiane Winkler, Florian Haupt, John A Todd, Laurent Servais, Matthew D Snape, and Manu Vatish

Subjects
Informed Consent, Original research, paediatrics, genetics, endocrinology, neonatology, Infant, Newborn, COVID-19, United Kingdom, ddc, Diabetes Mellitus, Type 1, Pregnancy, Communicable Disease Control, Pediatrics, Perinatology and Child Health, Humans, Female, Prospective Studies, Genetic Testing
Abstract

ObjectiveINGR1D (INvestigating Genetic Risk for type 1 Diabetes) was a type 1 diabetes (T1D) genetic screening study established to identify participants for a primary prevention trial (POInT, Primary Oral Insulin Trial).MethodsThe majority of participants were recruited by research midwives in antenatal clinics from 18 weeks’ gestation. Using the NHS Newborn Bloodspot Screening Programme (NBSP) infrastructure, participants enrolled in INGR1D had an extra sample taken from their day 5 bloodspot card sent for T1D genetic screening. Those at an increased risk of T1D were informed of the result, given education about T1D and the opportunity to take part in POInT.ResultsBetween April 2018 and November 2020, 66% of women approached about INGR1D chose to participate. 15 660 babies were enrolled into INGR1D and 14 731 blood samples were processed. Of the processed samples, 157 (1%) had confirmed positive results, indicating an increased risk of T1D, of whom a third (n=49) enrolled into POInT (20 families were unable to participate in POInT due to COVID-19 lockdown restrictions).ConclusionThe use of prospective consent to perform personalised genetic testing on samples obtained through the routine NBSP represents a novel mechanism for clinical genetic research in the UK and provides a model for further population-based genetic studies in the newborn.

Published
2022

2. Investigation of hospital discharge cases and SARS-CoV-2 introduction into Lothian care homes

Author

S. Cotton, M.P. McHugh, R. Dewar, J.G. Haas, K. Templeton, Samuel C. Robson, Thomas R. Connor, Nicholas J. Loman, Tanya Golubchik, Rocio T. Martinez Nunez, David Bonsall, Andrew Rambaut, Luke B. Snell, Rich Livett, Catherine Ludden, Sally Corden, Eleni Nastouli, Gaia Nebbia, Ian Johnston, Jacqui A. Prieto, Kordo Saeed, David K. Jackson, Catherine Houlihan, Dan Frampton, William L. Hamilton, Adam A. Witney, Giselda Bucca, Cassie F. Pope, Catherine Moore, Emma C. Thomson, Teresa Cutino-Moguel, Ewan M. Harrison, Colin P. Smith, Fiona Rogan, Shaun M. Beckwith, Abigail Murray, Dawn Singleton, Kirstine Eastick, Liz A. Sheridan, Paul Randell, Leigh M. Jackson, Cristina V. Ariani, Sónia Gonçalves, Derek J. Fairley, Matthew W. Loose, Joanne Watkins, Samuel Moses, Sam Nicholls, Matthew Bull, Roberto Amato, Darren L. Smith, David M. Aanensen, Jeffrey C. Barrett, Beatrix Kele, Dinesh Aggarwal, James G. Shepherd, Martin D. Curran, Surendra Parmar, Matthew D. Parker, Catryn Williams, Sharon Glaysher, Anthony P. Underwood, Matthew Bashton, Nicole Pacchiarini, Katie F. Loveson, Matthew Byott, Alessandro M. Carabelli, Kate E. Templeton, Sharon J. Peacock, Thushan I. de Silva, Dennis Wang, Cordelia F. Langford, John Sillitoe, Rory N. Gunson, Simon Cottrell, Justin O’Grady, Dominic Kwiatkowski, Patrick J. Lillie, Nicholas Cortes, Nathan Moore, Claire Thomas, Phillipa J. Burns, Tabitha W. Mahungu, Steven Liggett, Angela H. Beckett, Matthew TG. Holden, Lisa J. Levett, Husam Osman, Mohammed O. Hassan-Ibrahim, David A. Simpson, Meera Chand, Ravi K. Gupta, Alistair C. Darby, Steve Paterson, Oliver G. Pybus, Erik M. Volz, Daniela de Angelis, David L. Robertson, Andrew J. Page, Inigo Martincorena, Louise Aigrain, Andrew R. Bassett, Nick Wong, Yusri Taha, Michelle J. Erkiert, Michael H. Spencer Chapman, Rebecca Dewar, Martin P. McHugh, Siddharth Mookerjee, Stephen Aplin, Matthew Harvey, Thea Sass, Helen Umpleby, Helen Wheeler, James P. McKenna, Ben Warne, Joshua F. Taylor, Yasmin Chaudhry, Rhys Izuagbe, Aminu S. Jahun, Gregory R. Young, Claire McMurray, Clare M. McCann, Andrew Nelson, Scott Elliott, Hannah Lowe, Anna Price, Matthew R. Crown, Sara Rey, Sunando Roy, Ben Temperton, Sharif Shaaban, Andrew R. Hesketh, Kenneth G. Laing, Irene M. Monahan, Judith Heaney, Emanuela Pelosi, Siona Silviera, Eleri Wilson-Davies, Helen Fryer, Helen Adams, Louis du Plessis, Rob Johnson, William T. Harvey, Joseph Hughes, Richard J. Orton, Lewis G. Spurgin, Yann Bourgeois, Chris Ruis, Áine O'Toole, Marina Gourtovaia, Theo Sanderson, Christophe Fraser, Jonathan Edgeworth, Judith Breuer, Stephen L. Michell, John A. Todd, Michaela John, David Buck, Kavitha Gajee, Gemma L. Kay, David Heyburn, Themoula Charalampous, Adela Alcolea-Medina, Katie Kitchman, Alan McNal, David T. Pritch, Samir Dervisevic, Peter Muir, Esther Robinson, Barry B. Vipond, Newara A. Ramadan, Christopher Jeanes, Danni Weldon, Jana Catalan, Neil Jones, Ana da Silva Filipe, Chris Williams, Marc Fuchs, Julia Miskelly, Aaron R. Jeffries, Karen Oliver, Naomi R. Park, Amy Ash, Cherian Koshy, Magdalena Barrow, Sarah L. Buchan, Anna Mantzouratou, Gemma Clark, Christopher W. Holmes, Sharon Campbell, Thomas Davis, Ngee Keong Tan, Julianne R. Brown, Kathryn A. Harris, Stephen P. Kidd, Paul R. Grant, Li Xu-McCrae, Alison Cox, Pinglawathee Madona, Marcus Pond, Paul A. Randell, Karen T. Withell, Cheryl Williams, Clive Graham, Rebecca Denton-Smith, Emma Swindells, Robyn Turnbull, Tim J. Sloan, Andrew Bosworth, Stephanie Hutchings, Hannah M. Pymont, Anna Casey, Liz Ratcliffe, Christopher R. Jones, Bridget A. Knight, Tanzina Haque, Jennifer Hart, Dianne Irish-Tavares, Eric Witele, Craig Mower, Louisa K. Watson DipHE, Jennifer Collins, Gary Eltringham, Dorian Crudgington, Ben Macklin, Miren Iturriza-Gomara, Anita O. Lucaci, Patrick C. McClure, Matthew Carlile, Nadine Holmes, Christopher Moore, Nathaniel Storey, Stefan Rooke, Gonzalo Yebra, Noel Craine, Malorie Perry, Nabil-Fareed Alikhan, Stephen Bridgett, Kate F. Cook, Christopher Fearn, Salman Goudarzi, Ronan A. Lyons, Thomas Williams, Sam T. Haldenby, Jillian Durham, Steven Leonard, Robert M. Davies, Rahul Batra, Beth Blane, Moira J. Spyer, Perminder Smith, Mehmet Yavus, Rachel J. Williams, Adhyana IK. Mahanama, Buddhini Samaraweera, Sophia T. Girgis, Samantha E. Hansford, Angie Green, Charlotte Beaver, Katherine L. Bellis, Matthew J. Dorman, Sally Kay, Liam Prestwood, Shavanthi Rajatileka, Joshua Quick, Radoslaw Poplawski, Nicola Reynolds, Andrew Mack, Arthur Morriss, Thomas Whalley, Bindi Patel, Iliana Georgana, Myra Hosmillo, Malte L. Pinckert, Joanne Stockton, John H. Henderson, Amy Hollis, William Stanley, Wen C. Yew, Richard Myers, Alicia Thornton, Alexander Adams, Tara Annett, Hibo Asad, Alec Birchley, Jason Coombes, Johnathan M. Evans, Laia Fina, Bree Gatica-Wilcox, Lauren Gilbert, Lee Graham, Jessica Hey, Ember Hilvers, Sophie Jones, Hannah Jones, Sara Kumziene-Summerhayes, Caoimhe McKerr, Jessica Powell, Georgia Pugh, Sarah Taylor, Alexander J. Trotter, Charlotte A. Williams, Leanne M. Kermack, Benjamin H. Foulkes, Marta Gallis, Hailey R. Hornsby, Stavroula F. Louka, Manoj Pohare, Paige Wolverson, Peijun Zhang, George MacIntyre-Cockett, Amy Trebes, Robin J. Moll, Lynne Ferguson, Emily J. Goldstein, Alasdair Maclean, Rachael Tomb, Igor Starinskij, Laura Thomson, Joel Southgate, Moritz UG. Kraemer, Jayna Raghwani, Alex E. Zarebski, Olivia Boyd, Lily Geidelberg, Chris J. Illingworth, Chris Jackson, David Pascall, Sreenu Vattipally, Timothy M. Freeman, Sharon N. Hsu, Benjamin B. Lindsey, Keith James, Kevin Lewis, Gerry Tonkin-Hill, Jaime M. Tovar-Corona, MacGregor Cox, Khalil Abudahab, Mirko Menegazzo, Ben EW. Taylor, Corin A. Yeats, Afrida Mukaddas, Derek W. Wright, Leonardo de Oliveira Martins, Rachel Colquhoun, Verity Hill, Ben Jackson, J.T. McCrone, Nathan Medd, Emily Scher, Jon-Paul Keatley, Tanya Curran, Sian Morgan, Patrick Maxwell, Ken Smith, Sahar Eldirdiri, Anita Kenyon, Alison H. Holmes, James R. Price, Tim Wyatt, Alison E. Mather, Timofey Skvortsov, John A. Hartley, Martyn Guest, Christine Kitchen, Ian Merrick, Robert Munn, Beatrice Bertolusso, Jessica Lynch, Gabrielle Vernet, Stuart Kirk, Elizabeth Wastnedge, Rachael Stanley, Giles Idle, Declan T. Bradley, Nicholas F. Killough, Jennifer Poyner, Matilde Mori, Owen Jones, Victoria Wright, Ellena Brooks, Carol M. Churcher, Laia Delgado Callico, Mireille Fragakis, Katerina Galai, Andrew Jermy, Sarah Judges, Anna Markov, Georgina M. McManus, Kim S. Smith, Peter MD. Thomas-McEwen, Elaine Westwick, Stephen W. Attwood, Frances Bolt, Alisha Davies, Elen De Lacy, Fatima Downing, Sue Edwards, Lizzie Meadows, Sarah Jeremiah, Nikki Smith, Luke Foulser, Amita Patel, Louise Berry, Tim Boswell, Vicki M. Fleming, Hannah C. Howson-Wells, Amelia Joseph, Manjinder Khakh, Michelle M. Lister, Paul W. Bird, Karlie Fallon, Thomas Helmer, Claire L. McMurray, Mina Odedra, Jessica Shaw, Julian W. Tang, Nicholas J. Willford, Victoria Blakey, Veena Raviprakash, Nicola Sheriff, Lesley-Anne Williams, Theresa Feltwell, Luke Bedford, James S. Cargill, Warwick Hughes, Jonathan Moore, Susanne Stonehouse, Laura Atkinson, Jack CD. Lee, Divya Shah, Natasha Ohemeng-Kumi, John Ramble, Jasveen Sehmi, Rebecca Williams, Wendy Chatterton, Monika Pusok, William Everson, Anibolina Castigador, Emily Macnaughton, Kate El Bouzidi, Temi Lampejo, Malur Sudhanva, Cassie Breen, Graciela Sluga, Shazaad SY. Ahmad, Ryan P. George, Nicholas W. Machin, Debbie Binns, Victoria James, Rachel Blacow, Lindsay Coupland, Louise Smith, Edward Barton, Debra Padgett, Garren Scott, Aidan Cross, Mariyam Mirfenderesky, Jane Greenaway, Kevin Cole, Phillip Clarke, Nichola Duckworth, Sarah Walsh, Kelly Bicknell, Robert Impey, Sarah Wyllie, Richard Hopes, Chloe Bishop, Vicki Chalker, Ian Harrison, Laura Gifford, Zoltan Molnar, Cressida Auckland, Cariad Evans, Kate Johnson, David G. Partridge, Mohammad Raza, Paul Baker, Stephen Bonner, Sarah Essex, Leanne J. Murray, Andrew I. Lawton, Shirelle Burton-Fanning, Brendan AI. Payne, Sheila Waugh, Andrea N. Gomes, Maimuna Kimuli, Darren R. Murray, Paula Ashfield, Donald Dobie, Fiona Ashford, Angus Best, Liam Crawford, Nicola Cumley, Megan Mayhew, Oliver Megram, Jeremy Mirza, Emma Moles-Garcia, Benita Percival, Megan Driscoll, Leah Ensell, Helen L. Lowe, Laurentiu Maftei, Matteo Mondani, Nicola J. Chaloner, Benjamin J. Cogger, Lisa J. Easton, Hannah Huckson, Jonathan Lewis, Sarah Lowdon, Cassandra S. Malone, Florence Munemo, Manasa Mutingwende, Roberto Nicodemi, Olga Podplomyk FD, Thomas Somassa, Andrew Beggs, Alex Richter, Claire Cormie, Joana Dias, Sally Forrest, Ellen E. Higginson, Mailis Maes, Jamie Young, Rose K. Davidson, Kathryn A. Jackson, Alexander J. Keeley, Jonathan Ball, Timothy Byaruhanga, Joseph G. Chappell, Jayasree Dey, Jack D. Hill, Emily J. Park, Arezou Fanaie, Rachel A. Hilson, Geraldine Yaze, Stephanie Lo, Safiah Afifi, Robert Beer, Joshua Maksimovic, Kathryn McCluggage, Karla Spellman, Catherine Bresner, William Fuller, Angela Marchbank, Trudy Workma, Ekaterina Shelest, Johnny Debebe, Fei Sang, Sarah Francois, Bernardo Gutierrez, Tetyana I. Vasylyeva, Flavia Flaviani, Manon Ragonnet-Cronin, Katherine L. Smollett, Alice Broos, Daniel Mair, Jenna Nichols, Kyriaki Nomikou, Lily Tong, Ioulia Tsatsani, Sarah O'Brien, Steven Rushton, Roy Sanderson, Jon Perkins, Seb Cotton, Abbie Gallagher, Elias Allara, Clare Pearson, David Bibby, Gavin Dabrer, Nicholas Ellaby, Eileen Gallagher, Jonathan Hubb, Angie Lackenby, David Lee, Nikos Manesis, Tamyo Mbisa, Steven Platt, Katherine A. Twohig, Mari Morgan, Alp Aydin, David J. Baker, Ebenezer Foster-Nyarko, Sophie J. Prosolek, Steven Rudder, Chris Baxter, Sílvia F. Carvalho, Deborah Lavin, Arun Mariappan, Clara Radulescu, Aditi Singh, Miao Tang, Helen Morcrette, Nadua Bayzid, Marius Cotic, Carlos E. Balcazar, Michael D. Gallagher, Daniel Maloney, Thomas D. Stanton, Kathleen A. Williamson, Robin Manley, Michelle L. Michelsen, Christine M. Sambles, David J. Studholme, Joanna Warwick-Dugdale, Richard Eccles, Matthew Gemmell, Richard Gregory, Margaret Hughes, Charlotte Nelson, Lucille Rainbow, Edith E. Vamos, Hermione J. Webster, Mark Whitehead, Claudia Wierzbicki, Adrienn Angyal, Luke R. Green, Max Whiteley, Emma Betteridge, Iraad F. Bronner, Ben W. Farr, Scott Goodwin, Stefanie V. Lensing, Shane A. McCarthy, Michael A. Quail, Diana Rajan, Nicholas M. Redshaw, Carol Scott, Lesley Shirley, Scott AJ. Thurston, Will Rowe, Amy Gaskin, Thanh Le-Viet, James Bonfield, Jennifier Liddle, Andrew Whitwham, University of St Andrews. School of Medicine, University of St Andrews. Infection and Global Health Division, and Apollo - University of Cambridge Repository

Subjects
Microbiology (medical), MCC, Introduction, SARS-CoV-2, NDAS, COVID-19, Care homes, General Medicine, NIS, Patient Discharge, Hospitals, Hospitalization, Infectious Diseases, SDG 3 - Good Health and Well-being, RA0421, RA0421 Public health. Hygiene. Preventive Medicine, Humans, Hospital discharge
Abstract

COG-UK is supported by funding from the MRC part of UK Research & Innovation, the National Institute of Health Research (Grant code MC_PC_19027), and Genome Research Limited, operating as the Welcome Sanger Institute. Background The first epidemic wave of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) in Scotland resulted in high case numbers and mortality in care homes. In Lothian, over one-third of care homes reported an outbreak, while there was limited testing of hospital patients discharged to care homes. Aim To investigate patients discharged from hospitals as a source of SARS-CoV-2 introduction into care homes during the first epidemic wave. Methods A clinical review was performed for all patients discharges from hospitals to care homes from 1st March 2020 to 31st May 2020. Episodes were ruled out based on coronavirus disease 2019 (COVID-19) test history, clinical assessment at discharge, whole-genome sequencing (WGS) data and an infectious period of 14 days. Clinical samples were processed for WGS, and consensus genomes generated were used for analysis using Cluster Investigation and Virus Epidemiological Tool software. Patient timelines were obtained using electronic hospital records. Findings In total, 787 patients discharged from hospitals to care homes were identified. Of these, 776 (99%) were ruled out for subsequent introduction of SARS-CoV-2 into care homes. However, for 10 episodes, the results were inconclusive as there was low genomic diversity in consensus genomes or no sequencing data were available. Only one discharge episode had a genomic, time and location link to positive cases during hospital admission, leading to 10 positive cases in their care home. Conclusion The majority of patients discharged from hospitals were ruled out for introduction of SARS-CoV-2 into care homes, highlighting the importance of screening all new admissions when faced with a novel emerging virus and no available vaccine. Publisher PDF

Published
2023

3. Circulating C-Peptide Levels in Living Children and Young People and Pancreatic β-Cell Loss in Pancreas Donors Across Type 1 Diabetes Disease Duration

Author

Alice L.J. Carr, Jamie R.J. Inshaw, Christine S. Flaxman, Pia Leete, Rebecca C. Wyatt, Lydia A. Russell, Matthew Palmer, Dmytro Prasolov, Thomas Worthington, Bethany Hull, Linda S. Wicker, David B. Dunger, Richard A. Oram, Noel G. Morgan, John A. Todd, Sarah J. Richardson, and Rachel E.J. Besser

Subjects
Diabetes Mellitus, Type 1, Adolescent, C-Peptide, Insulin-Secreting Cells, Endocrinology, Diabetes and Metabolism, Internal Medicine, Humans, Infant, Child, Pancreas, Tissue Donors
Abstract

C-peptide declines in type 1 diabetes, although many long-duration patients retain low, but detectable levels. Histological analyses confirm that β-cells can remain following type 1 diabetes onset. We explored the trends observed in C-peptide decline in the UK Genetic Resource Investigating Diabetes (UK GRID) cohort (N = 4,079), with β-cell loss in pancreas donors from the network for Pancreatic Organ donors with Diabetes (nPOD) biobank and the Exeter Archival Diabetes Biobank (EADB) (combined N = 235), stratified by recently reported age at diagnosis endotypes (

Published
2022

4. Identification of LZTFL1 as a candidate effector gene at a COVID-19 risk locus

Author

Stephen C. Hyde, Julian C. Knight, Fadi Issa, Amy Cross, Damien J. Downes, S N Sansom, Nigel A. Roberts, Peng Hua, Ron Schwessinger, Olga Mielczarek, C. De Andrea, Davies Joj., Altar M. Munis, Antony J. Cutler, Jim R. Hughes, Deborah R. Gill, Ignacio Melero, Jill M. Brown, and John A. Todd

Subjects
Male, Leucine zipper, Epithelial-Mesenchymal Transition, Locus (genetics), Genome-wide association study, Biology, Polymorphism, Single Nucleotide, 03 medical and health sciences, 0302 clinical medicine, Genetics, Humans, Allele, Enhancer, Lung, Gene, Transcription factor, 030304 developmental biology, 0303 health sciences, SARS-CoV-2, Effector, COVID-19, Epithelial Cells, 3. Good health, Case-Control Studies, 030220 oncology & carcinogenesis, Cancer research, Female, Chromosomes, Human, Pair 3, Genome-Wide Association Study, Transcription Factors
Abstract

The severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) disease (COVID-19) pandemic has caused millions of deaths worldwide. Genome-wide association studies identified the 3p21.31 region as conferring a twofold increased risk of respiratory failure. Here, using a combined multiomics and machine learning approach, we identify the gain-of-function risk A allele of an SNP, rs17713054G>A, as a probable causative variant. We show with chromosome conformation capture and gene-expression analysis that the rs17713054-affected enhancer upregulates the interacting gene, leucine zipper transcription factor like 1 (LZTFL1). Selective spatial transcriptomic analysis of lung biopsies from patients with COVID-19 shows the presence of signals associated with epithelial–mesenchymal transition (EMT), a viral response pathway that is regulated by LZTFL1. We conclude that pulmonary epithelial cells undergoing EMT, rather than immune cells, are likely responsible for the 3p21.31-associated risk. Since the 3p21.31 effect is conferred by a gain-of-function, LZTFL1 may represent a therapeutic target.

Published
2021

5. Analysis of overlapping genetic association in type 1 and type 2 diabetes

Author

Mark I. McCarthy, Francesco Cucca, Crouch Djm., Anubha Mahajan, M I Stefana, Inshaw Jrj., John A. Todd, and Carlo Sidore

Subjects
0301 basic medicine, False discovery rate, Systematic, Male, Genome-wide association study, Genotype, Endocrinology, Diabetes and Metabolism, Short Communication, Disease, Type 2 diabetes, 030105 genetics & heredity, Biology, Polymorphism, Single Nucleotide, Co-localisation, 03 medical and health sciences, Chromosome (genetic algorithm), Internal Medicine, medicine, Genetics, Insulin, Humans, Genetic Predisposition to Disease, Allele, Alleles, Genetic Association Studies, Genetic association, Type 1 diabetes, Statistics, medicine.disease, United Kingdom, 030104 developmental biology, Analyses, Diabetes Mellitus, Type 1, Diabetes Mellitus, Type 2, Italy, Etiology, Female
Abstract

Aims/hypothesisGiven the potential shared aetiology between type 1 and type 2 diabetes, we aimed to identify any genetic regions associated with both diseases. For associations where there is a shared signal and the allele that increases risk to one disease also increases risk to the other, inference about shared aetiology could be made, with the potential to develop therapeutic strategies to treat or prevent both diseases simultaneously. Alternatively, if a genetic signal colocalises with divergent effect directions, it could provide valuable biological insight into how the association affects the two diseases differently.MethodsUsing publicly available type 2 diabetes summary statistics from a genomewide association study (GWAS) meta-analysis of European ancestry individuals (74,124 cases and 824,006 controls) and type 1 diabetes GWAS summary statistics from a meta-analysis of studies on individuals from the UK and Sardinia (7,467 cases and 10,218 controls), we identified all regions of 0.5 Mb that contained variants associated with both diseases (false discovery ratecoloc. Any association with a colocalisation posterior probability of ≥0.9 was considered a genuine shared association with both diseases.ResultsOf the 81 association signals from 42 genetic regions that showed association with both type 1 and type 2 diabetes, four association signals colocalised between both diseases (posterior probability ≥0.9): (i) chromosome 16q23.1, near Chymotripsinogen B1 (CTRB1) / Breast Cancer Anti-Estrogen Resistance Protein 1 (BCAR1), which has been previously identified; (ii) chromosome 11p15.5, near the Insulin (INS) gene; (iii) chromosome 4p16.3, near Transmembrane protein 129 (TMEM129), and (iv) chromosome 1p31.3, near Phosphoglucomutase 1 (PGM1). In each of these regions, the effect of genetic variants on type 1 diabetes was in the opposite direction to the effect on type 2 diabetes. Use of additional datasets also supported the previously identified colocalisation on chromosome 9p24.2, near the GLIS Family Zinc Finger Protein 3 (GLIS3) gene, in this case with a concordant direction of effect.Conclusions/interpretationThat four of five association signals that colocalise between type 1 diabetes and type 2 diabetes are in opposite directions suggests a complex genetic relationship between the two diseases.Research in ContextWhat is already known about this subject?Other than insulin, there are currently no treatments for both type 1 and type 2 diabetes.Findings that genetic variants near the GLIS3 gene increase risk of both type 1 and type 2 diabetes have indicated shared genetic mechanisms at the level of the pancreatic β cell.What is the key question?By examining chromosome regions associated with both diseases, are there any more variants that affect risk of both diseases and could support common mechanisms and repositioning of therapeutics between the diseases?What are the new findings?At current sample sizes, there is evidence that five genetic variants in different chromosome regions impact risk of developing both diseases.However, four of these variants have the opposite direction of effect in type 1 diabetes compared to type 2 diabetes, with only one, near GLIS3, having a concordant direction of effect.How might this impact on clinical practise in the foreseeable future?Genetic findings have furthered research in type 1 and type 2 diabetes independently, and suggest therapeutic strategies. However, our current investigation into their shared genetics suggests that repositioning of current type 2 diabetes treatments into type 1 diabetes may not be straightforward.

Published
2021

6. Low-dose IL-2 reduces IL-21

Author

Jia-Yuan, Zhang, Fiona, Hamey, Dominik, Trzupek, Marius, Mickunas, Mercede, Lee, Leila, Godfrey, Jennie H M, Yang, Marcin L, Pekalski, Jane, Kennet, Frank, Waldron-Lynch, Mark L, Evans, Timothy I M, Tree, Linda S, Wicker, John A, Todd, and Ricardo C, Ferreira

Subjects
Diabetes Mellitus, Type 1, T-Lymphocytes, Anti-Inflammatory Agents, Humans, Gene Expression, Interleukin-2
Abstract

Despite early clinical successes, the mechanisms of action of low-dose interleukin-2 (LD-IL-2) immunotherapy remain only partly understood. Here we examine the effects of interval administration of low-dose recombinant IL-2 (iLD-IL-2) in type 1 diabetes using high-resolution single-cell multiomics and flow cytometry on longitudinally-collected peripheral blood samples. Our results confirm that iLD-IL-2 selectively expands thymic-derived FOXP3

Published
2022

7. Thymocyte regulatory variant alters transcription factor binding and protects from type 1 diabetes in infants

Author

Niina Sandholm, Arcadio Rubio García, Marcin L. Pekalski, Jamie R. J. Inshaw, Antony J. Cutler, John A. Todd, Research Programs Unit, Medicum, HUS Abdominal Center, University of Helsinki, CAMM - Research Program for Clinical and Molecular Metabolism, and Faculty of Medicine

Subjects
RISK, ARCHITECTURE, Multidisciplinary, Thymocytes, CHROMATIN-STATE DISCOVERY, Quantitative Trait Loci, LOCI, Infant, THEMIS, GENE, Chromatin, MECHANISMS, Diabetes Mellitus, Type 1, 3123 Gynaecology and paediatrics, Humans, Genetic Predisposition to Disease, Child, NEGATIVE SELECTION
Abstract

We recently mapped a genetic susceptibility locus on chromosome 6q22.33 for type 1 diabetes (T1D) diagnosed below the age of 7 years between the PTPRK and thymocyte-selection-associated (THEMIS) genes. As the thymus plays a central role in shaping the T cell repertoire, we aimed to identify the most likely causal genetic factors behind this association using thymocyte genomic data. In four thymocyte populations, we identified 253 DNA sequence motifs underlying histone modifications. The G insertion allele of rs138300818, associated with protection from diabetes, created thymocyte motifs for multiple histone modifications and thymocyte types. In a parallel approach to identifying variants that alter transcription factor binding motifs, the same variant disrupted a predicted motif for Rfx7, which is abundantly expressed in the thymus. Chromatin state and RNA sequencing data suggested strong transcription overlapping rs138300818 in fetal thymus, while expression quantitative trait locus and chromatin conformation data associate the insertion with lower THEMIS expression. Extending the analysis to other T1D loci further highlighted rs66733041 affecting the GATA3 transcription factor binding in the AFF3 locus. Taken together, our results support a role for thymic THEMIS gene expression and the rs138300818 variant in promoting the development of early-onset T1D.

Published
2022

8. Open Targets Genetics: systematic identification of trait-associated genes using large-scale genetics and functional genomics

Author

Asier Gonzalez-Uriarte, Paola Roncaglia, Helen Parkinson, Ellen M. McDonagh, Denise Carvalho-Silva, Jeffrey C. Barrett, Cinzia Malangone, Maya Ghoussaini, Eliseo Papa, James D. Hayhurst, Zoë May Pendlington, Andrew Hercules, Simon Jupp, Ian Dunham, Edward Mountjoy, Ellen M. Schmidt, Annalisa Buniello, Javier Ferrer, Mohd Anisul Karim, Gautier Koscielny, Olga Vrousgou, Daniel Wright, Daniel Suveges, Gareth Peat, David G. Hulcoop, Alfredo Miranda, Tony Burdett, Miguel Carmona, David Ochoa, Jeremy Schwartzentruber, Luca Fumis, John A. Todd, Jacqueline A. L. MacArthur, Jarrod Baker, and Sandra Machlitt-Northen

Subjects
Genotype, AcademicSubjects/SCI00010, Quantitative Trait Loci, Datasets as Topic, Genome-wide association study, Biology, Quantitative trait locus, Genome, 03 medical and health sciences, 0302 clinical medicine, Quantitative Trait, Heritable, Databases, Genetic, Drug Discovery, Genetics, Database Issue, Humans, Molecular Targeted Therapy, 030304 developmental biology, 0303 health sciences, Internet, Drug discovery, Genome, Human, Drug Repositioning, Inflammatory Bowel Diseases, Chromatin, Phenotype, Expression quantitative trait loci, Trait, Identification (biology), Functional genomics, 030217 neurology & neurosurgery, Software, Genome-Wide Association Study
Abstract

Open Targets Genetics (https://genetics.opentargets.org) is an open-access integrative resource that aggregates human GWAS and functional genomics data including gene expression, protein abundance, chromatin interaction and conformation data from a wide range of cell types and tissues to make robust connections between GWAS-associated loci, variants and likely causal genes. This enables systematic identification and prioritisation of likely causal variants and genes across all published trait-associated loci. In this paper, we describe the public resources we aggregate, the technology and analyses we use, and the functionality that the portal offers. Open Targets Genetics can be searched by variant, gene or study/phenotype. It offers tools that enable users to prioritise causal variants and genes at disease-associated loci and access systematic cross-disease and disease-molecular trait colocalization analysis across 92 cell types and tissues including the eQTL Catalogue. Data visualizations such as Manhattan-like plots, regional plots, credible sets overlap between studies and PheWAS plots enable users to explore GWAS signals in depth. The integrated data is made available through the web portal, for bulk download and via a GraphQL API, and the software is open source. Applications of this integrated data include identification of novel targets for drug discovery and drug repurposing.

Published
2020

9. Elevations in blood glucose before and after the appearance of islet autoantibodies in children

Author

Katharina Warncke, Andreas Weiss, Peter Achenbach, Thekla von dem Berge, Reinhard Berner, Kristina Casteels, Lidia Groele, Konstantinos Hatzikotoulas, Angela Hommel, Olga Kordonouri, Helena Elding Larsson, Markus Lundgren, Benjamin A. Marcus, Matthew D. Snape, Agnieszka Szypowska, John A. Todd, Ezio Bonifacio, and Anette-G. Ziegler

Subjects
Blood Glucose, Diabetes, Immunology, Autoimmunity, General Medicine, Islets of Langerhans, Diabetes Mellitus, Type 1, Insulin, Child, Preschool, Humans, Genetic Predisposition to Disease, Child, Autoantibodies
Abstract

The etiology of type 1 diabetes has polygenic and environmental determinants that lead to autoimmune responses against pancreatic β cells and promote β cell death. The autoimmunity is considered silent without metabolic consequences until late preclinical stages,and it remains unknown how early in the disease process the pancreatic β cell is compromised. To address this, we investigated preprandial nonfasting and postprandial blood glucose concentrations and islet autoantibody development in 1,050 children with high genetic risk of type 1 diabetes. Pre- and postprandial blood glucose decreased between 4 and 18 months of age and gradually increased until the final measurements at 3.6 years of age. Determinants of blood glucose trajectories in the first year of life included sex, body mass index, glucose-related genetic risk scores, and the type 1 diabetes-susceptible INS gene. Children who developed islet autoantibodies had early elevations in blood glucose concentrations. A sharp and sustained rise in postprandial blood glucose was observed at around 2 months prior to autoantibody seroconversion, with further increases in postprandial and, subsequently, preprandial values after seroconversion. These findings show heterogeneity in blood glucose control in infancy and early childhood and suggest that islet autoimmunity is concurrent or subsequent to insults on the pancreatic islets. ispartof: JOURNAL OF CLINICAL INVESTIGATION vol:132 issue:20 ispartof: location:United States status: published

Published
2022

10. Exponential growth, high prevalence of SARS-CoV-2, and vaccine effectiveness associated with the Delta variant

Author

Mohammad Raza, Alison E. Mather, Gilberto Betancor, Ian Merrick, Ben Taylor, Mathew A. Beale, Helen Ward, Samir Dervisevic, Michelle Cronin, Aaron R. Jeffries, Louise Smith, Steven Rudder, Mara K. N. Lawniczak, Sascha Ott, Ashok Dadrah, Luke Bedford, Gabrielle Vernet, Erik M. Volz, Rahul Batra, Johnny Debebe, Caoimhe McKerr, Samantha McGuigan, Oliver Megram, Katie Jones, Mailis Maes, Rebecca Dewar, Emma Swindells, Robert E. Johnson, Myra Hosmillo, Wen C Yew, Vineet Patel, Scott Aj Thurston, Matthew Bashton, Luke B Snell, Lynn Monaghan, David Buck, Gregory R Young, Garren Scott, Louis du Plessis, Sara Kumziene-Summerhayes, David M. Aanensen, Carl Jones, Nadine Holmes, Bernardo Gutierrez, Elizabeth Wastenge, Stavroula F Louka, Dennis Wang, Richard I. Gregory, M. Estée Török, Alistair C. Darby, Ulf Schaefer, Marc Niebel, David Robertson, E. Thomson, Carol Churcher, Patrick C McClure, Scott Elliott, Sarah Jeremiah, Katerina Galai, Matthew W. Loose, Megan Mayhew, Adhyana I K Mahanama, Angeliki Karamani, Naomi R Park, David J. Williams, Lance Turtle, Lucy R. Frost, Alicia Thornton, Jennifier Liddle, M Morgan, Tim Wyatt, Paul W Bird, Chloe Bishop, Esther Robinson, Alasdair MacLean, Inigo Martincorena, Bridget A. Knight, Emma Meader, Thomas R. Connor, Hermione J. Webster, Peter Muir, Sarah Walsh, Stephanie W. Lo, Andrew Bosworth, Hannah E Bridgewater, David Simpson, Radoslaw Poplawski, Angus I. Best, David Baker, Laura Letchford, Cassie Breen, Yann Bourgeois, Matthew Gemmell, Nikki Smith, Alison Holmes, Iliana Georgana, Christophe Fraser, Natasha Jesudason, Johnathan M Evans, Rachael Stanley, Lesley-Anne Williams, Jessica Lynch, Hannah Lowe, Eleri Wilson-Davies, Paul A. Baker, Alex Makunin, James Bonfield, Helen Adams, Christopher Fearn, Peter J. Diggle, Harry D Wilson, Carmen F. Manso, Nichola Duckworth, D Haw, Anna L. Casey, Audrey Farbos, Sam Haldenby, Vicki Chalker, Roberto Amato, Elen De Lacy, Ben Farr, Eric Witele, Buddhini Samaraweera, G MacIntyre-Cockett, Husam Osman, Jane Greenaway, Justin O'Grady, Sally Forrest, Andrew Nelson, Monika Pusok, A Lloyd, Edward Barton, James W. Harrison, Sophie Palmer, Amanda Symmonds, James Shepherd, Nazreen F. Hadjirin, Stephen L. Michell, Mohammed O Hassan-Ibrahim, Fiona Ashcroft, Daniel Mair, Richard H. Myers, Dianne Irish-Tavares, Hannah C. Howson-Wells, Jacqui Prieto, Christine Sambles, Andrew Hesketh, Alp Aydin, Sónia Gonçalves, Tabitha Mahungu, Tanzina Haque, Nicholas Ellaby, Karen Oliver, Hannah Paul, Joanne Watts, Claire McMurray, Lisa J Levett, Darren Smith, Simon Cottrell, Joanna Warwick-Dugdale, Pinglawathee Madona, Matthew J. Dorman, Lizzie Meadows, Ali R Awan, Leanne M Kermack, Jennifer Hart, Angie Lackenby, Carol Scott, Michael Spencer Chapman, Lucille Rainbow, Kyriaki Nomikou, Julianne R Brown, Juan Ledesma, Adam P Westhorpe, Giri Shankar, Karlie Fallon, Tim J Sloan, Joanne Watkins, Robert Impey, Sue Edwards, Rebecca C H Brown, Robin J Moll, Karla Spellman, Laura Gifford, Jamie Young, Adrienn Angyal, Graham Phillip Taylor, Robin Manley, Gavin Dabrera, Michelle Wantoch, Rachel Williams, David Heyburn, Mirko Menegazzo, Derrick W. Crook, Gaia Nebbia, Rachel Nelson, Elaine O'Toole, Luke Foulser, Katherine L Harper, Fatima Downing, Hassan Hartman, Nathan Moore, Gemma L. Kay, Matthew Wyles, Thanh Le-Viet, Edith Vamos, John Sillitoe, Lesley Shirley, Nicholas J. Loman, Iona Willingham, Elihu Aranday-Cortes, Ian B Vipond, Jeremy Mirza, Alberto C Cerda, Michelle L Michelsen, Steven Riley, Alison Cox, Igor Siveroni, Nadua Bayzid, Shavanthi Rajatileka, Giselda Bucca, Benjamin J Cogger, Tim Boswell, Matthew J. Bull, Stephen Carmichael, Lisa Berry, Frances Bolt, Kylie E. C. Ainslie, Martyn Guest, Sarojini Pandey, Katherine L. Bellis, Shane A. McCarthy, Christopher Ruis, Fei Sang, David Bonsall, Danni Weldon, Alex Alderton, Lee Graham, Amy Trebes, Sally Corden, Adrian W Signell, Tanya Golubchik, Huw Gulliver, Rocio Martinez Nunez, Dinesh Aggarwal, Tanya Curran, Jonathan K. Ball, Sharif Shaaban, Paul Randell, Jillian Durham, Alec Birchley, Matilde Mori, Joana Dias, Katherine A Twohig, Grant Hall, Antony D Hale, Alan McNally, Jonathan D. Edgeworth, Safiah Afifi, Andrew Rambaut, Katherine Smollett, David N. Lee, Tamyo Mbisa, Shahjahan Miah, Steven Rushton, Grace Taylor-Joyce, Hannah M Pymont, Chloe L Fisher, Cordelia Langford, Alex G. Richter, Jane A. H. Masoli, Michael Gallagher, Vicki M. Fleming, Kathleen A. Williamson, Anna Price, Holli Carden, Khalil Abudahab, Joanne D. Stockton, Meera Unnikrishnan, Jennifer Collins, Emma Moles-Garcia, Michaela John, Christine Kitchen, Tranprit Saluja, Ian Harrison, Lily Tong, Thomas G. Thompson, Thomas Helmer, Amita Patel, Siona Silveira, Deborah Ashby, Claire M Bewshea, Anita Justice, Brendan A I Payne, Alexander J. Trotter, Nikos Manesis, Katie F. Loveson, Cristina V. Ariani, Wendy Chatterton, Robert J. Munn, Julian A. Hiscox, Robert Beer, Judith Breuer, Caroline E. Walters, Liam Crawford, Ara Darzi, Will P. M. Rowe, Cariad Evans, Matthew Parker, Tammy V Merrill, Louise Aigrain, Joshua Quick, Leigh M Jackson, Samuel M. Nicholls, Jonathan W. Moore, John A Hartley, Graham P. Taylor, Cherian Koshy, Shirelle Burton-Fanning, Sheila Waugh, Catherine Moore, Danielle C. Groves, Peijun Zhang, Sahar Eldirdiri, Derek Fairley, Tim E. A. Peto, Jack Cd Lee, Sharon Glaysher, Liam Prestwood, Hannah Dent, Anita Kenyon, Stephen P. Kidd, Nick Levene, Igor Starinskij, Joseph G. Chappell, Steve Paterson, Gary Eltringham, Laia Fina, Angela Marchbank, Daniel Bradshaw, Marina Escalera Zamudio, Scott Goodwin, Andrew D Beggs, Seema Nickbakhsh, Trevor Robinson, Christina Atchison, David K. Jackson, Kathy Li, Rory Gunson, Sunando Roy, Graham S Cooke, Steven Liggett, Yasmin Chaudhry, Anoop Chauhan, Ben Temperton, Mariateresa de Cesare, Paul E Brown, Li Xu-McCrae, Martin P McHugh, Catherine Ludden, Wendy Smith, Danielle Leek, Divya K. Shah, Judith Heaney, Dominic P. Kwiatkowski, Kate M. Johnson, Robin Howe, Malorie Perry, Tetyana I. Vasylyeva, David F. Bibby, Haowei Wang, Steve Palmer, Nicholas W Machin, Charlotte A Williams, Bree Gatica-Wilcox, Angie Green, John A. Todd, Paul Elliott, Noel Craine, Jeffrey K. J. Cheng, Kate Templeton, Jonathan Hubb, Joshua Maksimovic, Christl A. Donnelly, Monique Andersson, Christopher Holmes, Dimitris Grammatopoulos, Christopher B. Williams, David G Partridge, Aminu S Jahun, Alexander Adams, Marius Cotic, Sarah Essex, Christopher J. Moore, Trudy Workman, Nicola Sheriff, Helen L Lowe, Ewan M. Harrison, Dorota Jamrozy, Rachel Jones, Ellen Higginson, Erwan Acheson, Christopher R. Jones, Oliver G. Pybus, Francesc Coll, Sian Morgan, Paul J. Parsons, Patawee Asamaphan, Veena Raviprakash, Andrew R. Bassett, Declan Bradley, Laura Atkinson, Anthony Underwood, Graciela Sluga, Sally Kay, Ellena Brooks, Oliver Eales, Andrew Whitwham, Surendra Parmar, Angela Cowell, Nicole Pacchiarini, Theocharis Tsoleridis, Jason Coombes, Robert Davies, Flavia Flaviani, Benita Percival, Jenna Nichols, Natasha M. Johnson, Salman Goudarzi, Hibo Asad, Amanda Bradley, Hannah Jones, Chrystala Constantinidou, Georgina M McManus, Minal Patel, Steven Leonard, Rebecca Williams Bmbs, Andrew J. Page, Christoph Puethe, Nicola Reynolds, Amy Ash, John Danesh, Corin Yeats, Claudia Wierzbicki, Kordo Saeed, John Boyes, Michael A. Quail, Sharon J. Peacock, Nabil-Fareed Alikhan, Jon-Paul Keatley, Claudio Fronterre, Garry Scarlett, James McKenna, Thushan I de Silva, Malte L Pinckert, Kate B. Cook, Amy Gaskin, Rajiv Shah, Matthew T. G. Holden, Sophie J Prosolek, Nathaniel Storey, Ryan P George, Lindsay Coupland, Jenifer Mason, Matthew Carlile, Thomas D Stanton, Guy Mollett, Siddharth Mookerjee, Mary Ramsay, Steven Platt, Stephen W Attwood, Susanne Stonehouse, Sophie Jones, Venkat Sivaprakasam, Amy Plimmer, Mark Whitehead, Catherine Bresner, Stefanie V Lensing, Louissa R Macfarlane-Smith, Colin P. Smith, Wendy Hogsden, Charlotte Nelson, Ian Johnston, Jeffrey C. Barrett, Joshua B Singer, Samuel Robson, Zoltán Molnár, Emma L. Wise, Sian Ellard, Kim S Smith, Alice Broos, Manjinder Khakh, Kathryn A Jackson, Claire Cormie, Rachel Tucker, Ian Goodfellow, S.E. Moses, Nicola Cumley, Meera Chand, Debra Padgett, Cassandra S Malone, James V. Price, Themoula Charalampous, Ronan A Lyons, Natalie Groves, Stefan Rooke, Rebekah E Wilson, Stephen Bonner, Richard Stark, Sharon Campbell, Michelle Lister, Carlos Balcazar, Ana da Silva Filipe, Ben Warne, Thomas N. Williams, Marta Gallis, Lauren Gilbert, Rose K Davidson, Angela Helen Beckett, Ember Hilvers, Kathryn McCluggage, Eileen Gallagher, Charlotte Beaver, Nick Cortes, Alisha Davies, Yusri Taha, Leah Ensell, Emanuela Pelosi, Elias Allara, Cressida Auckland, Eleanor Drury, Richard Eccles, Adela Alcolea-Medina, William L Hamilton, Rich Livett, Rachel Blacow, Margaret Hughes, Sarah François, Melisa Louise Fenton, Liz Ratcliffe, Verity Hill, Stephanie Hutchings, Kathryn Ann Harris, Emma Betteridge, William D. Fuller, Sophia T Girgis, Louise Berry, Gemma Clark, Nicholas M Redshaw, Richard Hopes, Leonardo de Oliveira Martins, Alexander J Keeley, Beth Blane, Wendy S. Barclay, Victoria Wright, Anita Lucaci, Luke R. Green, Fenella D. Halstead, Sarah Wyllie, Iraad F. Bronner, Áine O'Toole, Ravi Gupta, Leanne Kane, Clare M. McCann, Michael R Chapman, David W Eyre, Kelly Bicknell, Aileen G. Rowan, Sara Rey, Shazaad Ahmad, Diana Rajan, S Taylor, Sarah J. O'Brien, Alessandro M Carabelli, Amelia Joseph, Max Whiteley, Riaz Jannoo, Victoria Blakey, Martin D. Curran, David J. Studholme, Harmeet K Gill, Thomas R. A. Davis, Sushmita Sridhar, Clive Graham, Julian Tang, Clare Pearson, Mark Kristiansen, Miren Iturriza-Gomara, National Institute for Health Research, and UK Research and Innovation

Subjects
Delta, Adult, Male, 2019-20 coronavirus outbreak, COVID-19 Vaccines, Vaccination Coverage, Coronavirus disease 2019 (COVID-19), Adolescent, General Science & Technology, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Vaccine Efficacy, Biology, Young Adult, Exponential growth, Ethnicity, Prevalence, Humans, Child, Aged, Family Characteristics, Multidisciplinary, High prevalence, COVID-19 Genomics UK (COG-UK) Consortium11‡, SARS-CoV-2, Age Factors, COVID-19, Middle Aged, Virology, Hospitalization, England, Socioeconomic Factors, COVID-19 Nucleic Acid Testing, Child, Preschool, Female, Self Report
Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections were rising during early summer 2021 in many countries as a result of the Delta variant. We assessed reverse transcription polymerase chain reaction swab positivity in the Real-time Assessment of Community Transmission–1 (REACT-1) study in England. During June and July 2021, we observed sustained exponential growth with an average doubling time of 25 days, driven by complete replacement of the Alpha variant by Delta and by high prevalence at younger, less-vaccinated ages. Prevalence among unvaccinated people [1.21% (95% credible interval 1.03%, 1.41%)] was three times that among double-vaccinated people [0.40% (95% credible interval 0.34%, 0.48%)]. However, after adjusting for age and other variables, vaccine effectiveness for double-vaccinated people was estimated at between ~50% and ~60% during this period in England. Increased social mixing in the presence of Delta had the potential to generate sustained growth in infections, even at high levels of vaccination.

Published
2021

11. Plasma levels of endothelin-1 and renal function among young and healthy adults

Author

Joel Estis, John A. Todd, Matthias Bossard, Martin Risch, Stefanie Aeschbacher, David Conen, Carolin Cordewener, Peter Egli, Andreas Fischer, and Lorenz Risch

Subjects
Adult, Male, medicine.medical_specialty, Clinical Biochemistry, Population, 030232 urology & nephrology, Renal function, 610 Medicine & health, 030204 cardiovascular system & hematology, Kidney, Gastroenterology, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Internal medicine, Diabetes mellitus, medicine, Humans, education, education.field_of_study, Creatinine, Endothelin-1, biology, business.industry, Biochemistry (medical), General Medicine, medicine.disease, Healthy Volunteers, 3. Good health, Endocrinology, Quartile, Cystatin C, chemistry, biology.protein, Female, business, Body mass index, Glomerular Filtration Rate, Kidney disease
Abstract

Background: Endothelin-1 (ET-1), a vasoconstrictive and pro-inflammatory peptide, is associated with several cardiovascular risk factors and outcomes. We aimed to investigate the association of plasma ET-1 levels and renal function among young and healthy adults. Methods: Individuals aged 25–41 years were enrolled in a population-based cohort study. Main exclusion criteria were established kidney disease, cardiovascular diseases, diabetes mellitus and a body mass index>35 kg/m2. Fasting venous plasma samples were used to measure creatinine, cystatin C and ET-1. The estimated glomerular filtration rate (eGFR) was calculated using the creatinine based chronic kidney disease epidemiology collaboration (CKD-EPI) formula. Multivariable regression models were constructed to assess interrelationships of plasma ET-1 with parameters of renal function. Results: Median age of the 2139 participants was 37 years, 47% males. Median creatinine and eGFR were 67 μmol/L and 112 mL/min/1.73 m2, respectively. Using quartile one as the reference group, the β-coefficients (95% confidence intervals [CIs]) for eGFR were 0.06 (− 1.22 to 1.35),−0.66 (− 1.95 to 0.62) and−1.70 (− 3.01 to−0.39) for quartiles 2–4 (p-for-trend=0.0056), respectively and β-coefficients (95% CIs) for cystatin C were 0.002 (− 0.01 to 0.02), 0.02 (0.003–0.03) and 0.03 (0.01–0.04) for quartiles 2–4 (p-for-trend Conclusions: ET-1 levels are strongly associated with parameters of renal function among young and healthy adults, suggesting an important role of ET-1 and endothelial function in the regulation of kidney function.

Published
2021

12. Concordance of immunological events between intrarectal and intravenous SHIVAD8-EO infection when assessed by Fiebig-equivalent staging

Author

Amarendra Pegu, Giulia Fabozzi, Joana Dias, John R. Mascola, Wanwisa Promsote, Cassandra G. Almasri, Richard A. Koup, Lucio Gama, Constantinos Petrovas, John Paul Todd, Jonathan Fintzi, Yoshiaki Nishimura, Mangaiarkarasi Asokan, Kylie March, Malcolm A. Martin, and Jeffrey D. Lifson

Subjects
Male, Time Factors, T cell, Simian Acquired Immunodeficiency Syndrome, HIV Infections, Viremia, CD8-Positive T-Lymphocytes, Serology, Translational Research, Biomedical, Administration, Rectal, Follicular phase, medicine, Animals, Humans, CXCL13, Lymph node, business.industry, General Medicine, Viral Load, medicine.disease, Acquired immune system, Macaca mulatta, medicine.anatomical_structure, Immunology, Disease Progression, HIV-1, Administration, Intravenous, Female, Simian Immunodeficiency Virus, business, CD8, Research Article
Abstract

Primary HIV-1 infection can be classified into six Fiebig stages based on virological and serological laboratory testing, whereas simian-HIV (SHIV) infection in nonhuman primates (NHPs) is defined in time post-infection, making it difficult to extrapolate NHP experiments to the clinics. We identified and extensively characterized the Fiebig-equivalent stages in NHPs challenged intrarectally or intravenously with SHIV(AD8-EO). During the first month post-challenge, intrarectally challenged monkeys were up to 1 week delayed in progression through stages. However, regardless of the challenge route, stages I–II predominated before, and stages V–VI predominated after, peak viremia. Decrease in lymph node (LN) CD4(+) T cell frequency and rise in CD8(+) T cells occurred at stage V. LN virus-specific CD8(+) T cell responses, dominated by degranulation and TNF, were first detected at stage V and increased at stage VI. A similar late elevation in follicular CXCR5(+) CD8(+) T cells occurred, consistent with higher plasma CXCL13 levels at these stages. LN SHIV(AD8-EO) RNA(+) cells were present at stage II, but appeared to decline at stage VI when virions accumulated in follicles. Fiebig-equivalent staging of SHIV(AD8-EO) infection revealed concordance of immunological events between intrarectal and intravenous infection despite different infection progressions, and can inform comparisons of NHP studies with clinical data.

Published
2021

13. Supplementation with Bifidobacterium longum subspecies infantis EVC001 for mitigation of type 1 diabetes autoimmunity: the GPPAD-SINT1A randomised controlled trial protocol

Author

Matthew D Snape, Melanie Gündert, Anette-Gabriele Ziegler, Peter Achenbach, Reinhard Berner, Kristina Casteels, Thomas Danne, Joerg Hasford, Olga Kordonouri, Karin Lange, Helena Elding Larsson, Markus Lundgren, Agnieszka Szypowska, John A Todd, Ezio Bonifacio, Nicole Zubizarreta, Christiane Winkler, Åke Lernmark, Daniel Agardh, Cigdem Gezginci, Claudia Ramminger, Marlon Scholz, Katharina Warncke, Carin Andrén Aronsson, Rasmus Bennet, Lina Fransson, Zeliha Mestan, Caroline Nilsson, Anita Ramelius, Carina Törn, Sarah Hogg, Catherine Owen, Lidia Groele, Florian Haupt, Claudia Matzke, Robin Assfalg, Matthew Snape, Felix Reschke, Marcin L Pekalski, Andreas Weiss, Andrew Johnston, Manja Jolink, Loredana Marcovecchio, Mariusz Ołtarzewski, Stefanie Arnolds, Annika Kölln, Markus Pfirrmann, Corinna Barz, Karina Blasius, Nadine Friedl, Adriano Gomez-Bantel, Martin Heigermoser, Bianca Höfelschweiger, Nadine Klein, Ramona Lickert, Rebecca Niewöhner, Katharina Schütte-Borkovec, Mira Taulien, Lara Vogel, Franziska Voß, José Maria Zapardiel Gonzalo, Philipp Sifft, Heidi Kapfelsberger, Merve Vurucu, Katharina Sarcletti, Stefanie Jacobson, Yulia Grinin, John A. Todd, Anette-G. Ziegler, Marcin L. Pekalski, Anette G. Ziegler, Annre Rochtus, An Jacobs, Jasmin Paulus, Brontë Vrancken, Natalie Van den Driessche, Renka Van Heyste, Janne Houben, Veerle Vanhuyse, Sevina Dietz, Gita Gemulla, Manja Gottschalk-Schwarz, Sophie Heinke, Angela Hommel, Susann Kowal, Fabian Lander, Robert Morgenstern, Marc Weigelt, Sari Arabi, Raphael Hoffmann, Ruth Blechschmidt, Franziska Ehrlich, Anja Loff, Laura Galuschka, Ute Holtkamp, Nils Janzen, Sarah Landsberg, Erika Marquardt, Frank Roloff, Kerstin Semler, Thekla von dem Berge, Melanie Bunk, Simone Färber-Meisterjahn, Willi Grätz, Ines Greif, Melanie Herbst, Anna Hofelich, Benjamin Marcus, Annette Munzinger, Jasmin Ohli, Franziska Reinmüller, Tiziana Welzhofer, Sylwia Dybkowska, Katarzyna Dżygało, Dorota Owczarek, Katarzyna Popko, Agnieszka Skrobot, Anna Taczanowska, Beata Zduńczyk, Charlotte Brundin, Ida Jönsson, Sara Maroufkhani, Evelyn Tekum Amboh, Katarzyna Gajewska-Knapik, Elena Romero, Suzannah Twiss, Helen Gallon, Laura Gebbie, Fiona Jenkinson, Steven Pratt, Steve Robson, Claire Simmister, Evelyn Thomson, and Eileen Walton

Subjects
Diabetes & Endocrinology, Epidemiology, General Diabetes, Immunology, Paediatrics, CHILDHOOD, diabetes & endocrinology, CHILDREN, PROGRESSION, Autoimmunity, GUT MICROBIOME, Coeliac disease, law.invention, immunology, Randomized controlled trial, law, Multicenter Studies as Topic, Cumulative incidence, Family history, Child, Randomized Controlled Trials as Topic, RISK, Respiratory infection, General Medicine, ddc, Diabetes and Endocrinology, Medicine, epidemiology, Life Sciences & Biomedicine, medicine.medical_specialty, Bifidobacterium longum subspecies infantis, paediatrics, Medicine, General & Internal, General & Internal Medicine, Internal medicine, Diabetes mellitus, medicine, Humans, Type 1 diabetes, Science & Technology, business.industry, general diabetes, Autoantibody, Infant, medicine.disease, Gastrointestinal Microbiome, Diabetes Mellitus, Type 1, Dietary Supplements, BETA-CELL AUTOIMMUNITY, AUTOANTIBODIES, business
Abstract

IntroductionThe Global Platform for the Prevention of Autoimmune Diabetes-SINT1A Study is designed as a randomised, placebo-controlled, double-blind, multicentre, multinational, primary prevention study aiming to assess whether daily administration of Bifidobacterium infantis from age 7 days to 6 weeks until age 12 months to children with elevated genetic risk for type 1 diabetes reduces the cumulative incidence of beta-cell autoantibodies in childhood.Methods and analysisInfants aged 7 days to 6 weeks from Germany, Poland, Belgium, UK and Sweden are eligible for study participation if they have a >10.0% expected risk for developing multiple beta-cell autoantibodies by age 6 years as determined by genetic risk score or family history and HLA genotype. Infants are randomised 1:1 to daily administration of B. infantis EVC001 or placebo until age 12 months and followed for a maximum of 5.5 years thereafter. The primary outcome is the development of persistent confirmed multiple beta-cell autoantibodies. Secondary outcomes are (1) Any persistent confirmed beta-cell autoantibody, defined as at least one confirmed autoantibody in two consecutive samples, including insulin autoantibodies, glutamic acid decarboxylase, islet tyrosine phosphatase 2 or zinc transporter 8, (2) Diabetes, (3) Transglutaminase autoantibodies associated with coeliac disease, (4) Respiratory infection rate in first year of life during supplementation and (5) Safety. Exploratory outcomes include allergy, antibody response to vaccines, alterations of the gut microbiome or blood metabolome, stool pH and calprotectin.Ethics and disseminationThe study was approved by the local ethical committees of the Technical University Munich, Medical Faculty, the Technische Universität Dresden, the Medizinische Hochschule Hannover, the Medical University of Warsaw, EC Research UZ Leuven and the Swedish ethical review authority. The results will be disseminated through peer-reviewed journals and conference presentations and will be openly shared after completion of the study.Trial registration numberNCT04769037.

Published
2020

14. Interprotomer disulfide-stabilized variants of the human metapneumovirus fusion glycoprotein induce high titer-neutralizing responses

Author

John-Paul Todd, Antonio Lanzavecchia, Wing-Pui Kong, Yaroslav Tsybovsky, Gwo-Yu Chuang, John R. Mascola, Peter L. Collins, Lijuan Yang, Jason Gorman, M. Gordon Joyce, Davide Corti, Mallika Sastry, Raffaello Verardi, Diana G. Scorpio, Guillaume Stewart-Jones, Yongping Yang, Ursula J. Buchholz, Cheng Cheng, Kathryn E. Foulds, Adam S. Olia, Chen-Hsiang Shen, Baoshan Zhang, Li Ou, and Peter D. Kwong

Subjects
Antigenicity, viruses, Trimer, Antibodies, Viral, Epitope, Neutralization, Epitopes, Mice, Human metapneumovirus, Animals, Humans, Disulfides, Promoter Regions, Genetic, Glycoproteins, chemistry.chemical_classification, Multidisciplinary, biology, Chemistry, Immunogenicity, virus diseases, Biological Sciences, biology.organism_classification, Virology, Antibodies, Neutralizing, respiratory tract diseases, Titer, Mutation, Macaca, Immunization, Metapneumovirus, Glycoprotein
Abstract

Human metapneumovirus (HMPV) is a major cause of respiratory disease worldwide, particularly among children and the elderly. Although there is no licensed HMPV vaccine, promising candidates have been identified for related pneumoviruses based on the structure-based stabilization of the fusion (F) glycoprotein trimer, with prefusion-stabilized F glycoprotein trimers eliciting significantly higher neutralizing responses than their postfusion F counterparts. However, immunization with HMPV F trimers in either prefusion or postfusion conformations has been reported to elicit equivalent neutralization responses. Here we investigate the impact of stabilizing disulfides, especially interprotomer disulfides (IP-DSs) linking protomers of the F trimer, on the elicitation of HMPV-neutralizing responses. We designed F trimer disulfides, screened for their expression, and used electron microscopy (EM) to confirm their formation, including that of an unexpected postfusion variant. In mice, IP-DS–stabilized prefusion and postfusion HMPV F elicited significantly higher neutralizing responses than non–IP-DS–stabilized HMPV Fs. In macaques, the impact of IP-DS stabilization was more measured, although IP-DS–stabilized variants of either prefusion or postfusion HMPV F induced neutralizing responses many times the average titers observed in a healthy human cohort. Serological and absorption-based analyses of macaque responses revealed elicited HMPV-neutralizing responses to be absorbed differently by IP-DS–containing and by non–IP-DS–containing postfusion Fs, suggesting IP-DS stabilization to alter not only the immunogenicity of select epitopes but their antigenicity as well. We speculate the observed increase in immunogenicity by IP-DS trimers to be related to reduced interprotomer flexibility within the HMPV F trimer.

Published
2021

15. Recurrent emergence of SARS-CoV-2 spike deletion H69/V70 and its role in the Alpha variant B.1.1.7

Author

Bo Meng, Steven A. Kemp, Guido Papa, Rawlings Datir, Isabella A.T.M. Ferreira, Sara Marelli, William T. Harvey, Spyros Lytras, Ahmed Mohamed, Giulia Gallo, Nazia Thakur, Dami A. Collier, Petra Mlcochova, Lidia M. Duncan, Alessandro M. Carabelli, Julia C. Kenyon, Andrew M. Lever, Anna De Marco, Christian Saliba, Katja Culap, Elisabetta Cameroni, Nicholas J. Matheson, Luca Piccoli, Davide Corti, Leo C. James, David L. Robertson, Dalan Bailey, Ravindra K. Gupta, Samuel C. Robson, Nicholas J. Loman, Thomas R. Connor, Tanya Golubchik, Rocio T. Martinez Nunez, Catherine Ludden, Sally Corden, Ian Johnston, David Bonsall, Colin P. Smith, Ali R. Awan, Giselda Bucca, M. Estee Torok, Kordo Saeed, Jacqui A. Prieto, David K. Jackson, William L. Hamilton, Luke B. Snell, Catherine Moore, Ewan M. Harrison, Sonia Goncalves, Derek J. Fairley, Matthew W. Loose, Joanne Watkins, Rich Livett, Samuel Moses, Roberto Amato, Sam Nicholls, Matthew Bull, Darren L. Smith, Jeff Barrett, David M. Aanensen, Martin D. Curran, Surendra Parmar, Dinesh Aggarwal, James G. Shepherd, Matthew D. Parker, Sharon Glaysher, Matthew Bashton, Anthony P. Underwood, Nicole Pacchiarini, Katie F. Loveson, Kate E. Templeton, Cordelia F. Langford, John Sillitoe, Thushan I. de Silva, Dennis Wang, Dominic Kwiatkowski, Andrew Rambaut, Justin O’Grady, Simon Cottrell, Matthew T.G. Holden, Emma C. Thomson, Husam Osman, Monique Andersson, Anoop J. Chauhan, Mohammed O. Hassan-Ibrahim, Mara Lawniczak, Alex Alderton, Meera Chand, Chrystala Constantinidou, Meera Unnikrishnan, Alistair C. Darby, Julian A. Hiscox, Steve Paterson, Inigo Martincorena, Erik M. Volz, Andrew J. Page, Oliver G. Pybus, Andrew R. Bassett, Cristina V. Ariani, Michael H. Spencer Chapman, Kathy K. Li, Rajiv N. Shah, Natasha G. Jesudason, Yusri Taha, Martin P. McHugh, Rebecca Dewar, Aminu S. Jahun, Claire McMurray, Sarojini Pandey, James P. McKenna, Andrew Nelson, Gregory R. Young, Clare M. McCann, Scott Elliott, Hannah Lowe, Ben Temperton, Sunando Roy, Anna Price, Sara Rey, Matthew Wyles, Stefan Rooke, Sharif Shaaban, Mariateresa de Cesare, Laura Letchford, Siona Silveira, Emanuela Pelosi, Eleri Wilson-Davies, Myra Hosmillo, Áine O’Toole, Andrew R. Hesketh, Richard Stark, Louis du Plessis, Chris Ruis, Helen Adams, Yann Bourgeois, Stephen L. Michell, Dimitris Grammatopoulos, Jonathan Edgeworth, Judith Breuer, John A. Todd, Christophe Fraser, David Buck, Michaela John, Gemma L. Kay, Steve Palmer, Sharon J. Peacock, David Heyburn, Danni Weldon, Esther Robinson, Alan McNally, Peter Muir, Ian B. Vipond, John Boyes, Venkat Sivaprakasam, Tranprit Salluja, Samir Dervisevic, Emma J. Meader, Naomi R. Park, Karen Oliver, Aaron R. Jeffries, Sascha Ott, Ana da Silva Filipe, David A. Simpson, Chris Williams, Jane A.H. Masoli, Bridget A. Knight, Christopher R. Jones, Cherian Koshy, Amy Ash, Anna Casey, Andrew Bosworth, Liz Ratcliffe, Li Xu-McCrae, Hannah M. Pymont, Stephanie Hutchings, Lisa Berry, Katie Jones, Fenella Halstead, Thomas Davis, Christopher Holmes, Miren Iturriza-Gomara, Anita O. Lucaci, Paul Anthony Randell, Alison Cox, Pinglawathee Madona, Kathryn Ann Harris, Julianne Rose Brown, Tabitha W. Mahungu, Dianne Irish-Tavares, Tanzina Haque, Jennifer Hart, Eric Witele, Melisa Louise Fenton, Steven Liggett, Clive Graham, Emma Swindells, Jennifer Collins, Gary Eltringham, Sharon Campbell, Patrick C. McClure, Gemma Clark, Tim J. Sloan, Carl Jones, Jessica Lynch, Ben Warne, Steven Leonard, Jillian Durham, Thomas Williams, Sam T. Haldenby, Nathaniel Storey, Nabil-Fareed Alikhan, Nadine Holmes, Christopher Moore, Matthew Carlile, Malorie Perry, Noel Craine, Ronan A. Lyons, Angela H. Beckett, Salman Goudarzi, Christopher Fearn, Kate Cook, Hannah Dent, Hannah Paul, Robert Davies, Beth Blane, Sophia T. Girgis, Mathew A. Beale, Katherine L. Bellis, Matthew J. Dorman, Eleanor Drury, Leanne Kane, Sally Kay, Samantha McGuigan, Rachel Nelson, Liam Prestwood, Shavanthi Rajatileka, Rahul Batra, Rachel J. Williams, Mark Kristiansen, Angie Green, Anita Justice, Adhyana I.K. Mahanama, Buddhini Samaraweera, Nazreen F. Hadjirin, Joshua Quick, Radoslaw Poplawski, Leanne M. Kermack, Nicola Reynolds, Grant Hall, Yasmin Chaudhry, Malte L. Pinckert, Iliana Georgana, Robin J. Moll, Alicia Thornton, Richard Myers, Joanne Stockton, Charlotte A. Williams, Wen C. Yew, Alexander J. Trotter, Amy Trebes, George MacIntyre-Cockett, Alec Birchley, Alexander Adams, Amy Plimmer, Bree Gatica-Wilcox, Caoimhe McKerr, Ember Hilvers, Hannah Jones, Hibo Asad, Jason Coombes, Johnathan M. Evans, Laia Fina, Lauren Gilbert, Lee Graham, Michelle Cronin, Sara Kumziene-Summerhayes, Sarah Taylor, Sophie Jones, Danielle C. Groves, Peijun Zhang, Marta Gallis, Stavroula F. Louka, Igor Starinskij, Chris Jackson, Marina Gourtovaia, Gerry Tonkin-Hill, Kevin Lewis, Jaime M. Tovar-Corona, Keith James, Laura Baxter, Mohammad T. Alam, Richard J. Orton, Joseph Hughes, Sreenu Vattipally, Manon Ragonnet-Cronin, Fabricia F. Nascimento, David Jorgensen, Olivia Boyd, Lily Geidelberg, Alex E. Zarebski, Jayna Raghwani, Moritz U.G. Kraemer, Joel Southgate, Benjamin B. Lindsey, Timothy M. Freeman, Jon-Paul Keatley, Joshua B. Singer, Leonardo de Oliveira Martins, Corin A. Yeats, Khalil Abudahab, Ben E.W. Taylor, Mirko Menegazzo, John Danesh, Wendy Hogsden, Sahar Eldirdiri, Anita Kenyon, Jenifer Mason, Trevor I. Robinson, Alison Holmes, James Price, John A. Hartley, Tanya Curran, Alison E. Mather, Giri Shankar, Rachel Jones, Robin Howe, Sian Morgan, Elizabeth Wastenge, Michael R. Chapman, Siddharth Mookerjee, Rachael Stanley, Wendy Smith, Timothy Peto, David Eyre, Derrick Crook, Gabrielle Vernet, Christine Kitchen, Huw Gulliver, Ian Merrick, Martyn Guest, Robert Munn, Declan T. Bradley, Tim Wyatt, Charlotte Beaver, Luke Foulser, Sophie Palmer, Carol M. Churcher, Ellena Brooks, Kim S. Smith, Katerina Galai, Georgina M. McManus, Frances Bolt, Francesc Coll, Lizzie Meadows, Stephen W. Attwood, Alisha Davies, Elen De Lacy, Fatima Downing, Sue Edwards, Garry P. Scarlett, Sarah Jeremiah, Nikki Smith, Danielle Leek, Sushmita Sridhar, Sally Forrest, Claire Cormie, Harmeet K. Gill, Joana Dias, Ellen E. Higginson, Mailis Maes, Jamie Young, Michelle Wantoch, Dorota Jamrozy, Stephanie Lo, Minal Patel, Verity Hill, Claire M. Bewshea, Sian Ellard, Cressida Auckland, Ian Harrison, Chloe Bishop, Vicki Chalker, Alex Richter, Andrew Beggs, Angus Best, Benita Percival, Jeremy Mirza, Oliver Megram, Megan Mayhew, Liam Crawford, Fiona Ashcroft, Emma Moles-Garcia, Nicola Cumley, Richard Hopes, Patawee Asamaphan, Marc O. Niebel, Rory N. Gunson, Amanda Bradley, Alasdair Maclean, Guy Mollett, Rachel Blacow, Paul Bird, Thomas Helmer, Karlie Fallon, Julian Tang, Antony D. Hale, Louissa R. Macfarlane-Smith, Katherine L. Harper, Holli Carden, Nicholas W. Machin, Kathryn A. Jackson, Shazaad S.Y. Ahmad, Ryan P. George, Lance Turtle, Elaine O’Toole, Joanne Watts, Cassie Breen, Angela Cowell, Adela Alcolea-Medina, Themoula Charalampous, Amita Patel, Lisa J. Levett, Judith Heaney, Aileen Rowan, Graham P. Taylor, Divya Shah, Laura Atkinson, Jack C.D. Lee, Adam P. Westhorpe, Riaz Jannoo, Helen L. Lowe, Angeliki Karamani, Leah Ensell, Wendy Chatterton, Monika Pusok, Ashok Dadrah, Amanda Symmonds, Graciela Sluga, Zoltan Molnar, Paul Baker, Stephen Bonner, Sarah Essex, Edward Barton, Debra Padgett, Garren Scott, Jane Greenaway, Brendan A.I. Payne, Shirelle Burton-Fanning, Sheila Waugh, Veena Raviprakash, Nicola Sheriff, Victoria Blakey, Lesley-Anne Williams, Jonathan Moore, Susanne Stonehouse, Louise Smith, Rose K. Davidson, Luke Bedford, Lindsay Coupland, Victoria Wright, Joseph G. Chappell, Theocharis Tsoleridis, Jonathan Ball, Manjinder Khakh, Vicki M. Fleming, Michelle M. Lister, Hannah C. Howson-Wells, Louise Berry, Tim Boswell, Amelia Joseph, Iona Willingham, Nichola Duckworth, Sarah Walsh, Emma Wise, Nathan Moore, Matilde Mori, Nick Cortes, Stephen Kidd, Rebecca Williams, Laura Gifford, Kelly Bicknell, Sarah Wyllie, Allyson Lloyd, Robert Impey, Cassandra S. Malone, Benjamin J. Cogger, Nick Levene, Lynn Monaghan, Alexander J. Keeley, David G. Partridge, Mohammad Raza, Cariad Evans, Kate Johnson, Emma Betteridge, Ben W. Farr, Scott Goodwin, Michael A. Quail, Carol Scott, Lesley Shirley, Scott A.J. Thurston, Diana Rajan, Iraad F. Bronner, Louise Aigrain, Nicholas M. Redshaw, Stefanie V. Lensing, Shane McCarthy, Alex Makunin, Carlos E. Balcazar, Michael D. Gallagher, Kathleen A. Williamson, Thomas D. Stanton, Michelle L. Michelsen, Joanna Warwick-Dugdale, Robin Manley, Audrey Farbos, James W. Harrison, Christine M. Sambles, David J. Studholme, Angie Lackenby, Tamyo Mbisa, Steven Platt, Shahjahan Miah, David Bibby, Carmen Manso, Jonathan Hubb, Gavin Dabrera, Mary Ramsay, Daniel Bradshaw, Ulf Schaefer, Natalie Groves, Eileen Gallagher, David Lee, David Williams, Nicholas Ellaby, Hassan Hartman, Nikos Manesis, Vineet Patel, Juan Ledesma, Katherine A. Twohig, Elias Allara, Clare Pearson, Jeffrey K.J. Cheng, Hannah E. Bridgewater, Lucy R. Frost, Grace Taylor-Joyce, Paul E. Brown, Lily Tong, Alice Broos, Daniel Mair, Jenna Nichols, Stephen N. Carmichael, Katherine L. Smollett, Kyriaki Nomikou, Elihu Aranday-Cortes, Natasha Johnson, Seema Nickbakhsh, Edith E. Vamos, Margaret Hughes, Lucille Rainbow, Richard Eccles, Charlotte Nelson, Mark Whitehead, Richard Gregory, Matthew Gemmell, Claudia Wierzbicki, Hermione J. Webster, Chloe L. Fisher, Adrian W. Signell, Gilberto Betancor, Harry D. Wilson, Gaia Nebbia, Flavia Flaviani, Alberto C. Cerda, Tammy V. Merrill, Rebekah E. Wilson, Marius Cotic, Nadua Bayzid, Thomas Thompson, Erwan Acheson, Steven Rushton, Sarah O’Brien, David J. Baker, Steven Rudder, Alp Aydin, Fei Sang, Johnny Debebe, Sarah Francois, Tetyana I. Vasylyeva, Marina Escalera Zamudio, Bernardo Gutierrez, Angela Marchbank, Joshua Maksimovic, Karla Spellman, Kathryn McCluggage, Mari Morgan, Robert Beer, Safiah Afifi, Trudy Workman, William Fuller, Catherine Bresner, Adrienn Angyal, Luke R. Green, Paul J. Parsons, Rachel M. Tucker, Rebecca Brown, Max Whiteley, James Bonfield, Christoph Puethe, Andrew Whitwham, Jennifier Liddle, Will Rowe, Igor Siveroni, Thanh Le-Viet, Amy Gaskin, Rob Johnson, Irina Abnizova, Mozam Ali, Laura Allen, Ralph Anderson, Cristina Ariani, Siobhan Austin-Guest, Sendu Bala, Jeffrey Barrett, Andrew Bassett, Kristina Battleday, James Beal, Mathew Beale, Sam Bellany, Tristram Bellerby, Katie Bellis, Duncan Berger, Matt Berriman, Paul Bevan, Simon Binley, Jason Bishop, Kirsty Blackburn, Nick Boughton, Sam Bowker, Timothy Brendler-Spaeth, Iraad Bronner, Tanya Brooklyn, Sarah Kay Buddenborg, Robert Bush, Catarina Caetano, Alex Cagan, Nicola Carter, Joanna Cartwright, Tiago Carvalho Monteiro, Liz Chapman, Tracey-Jane Chillingworth, Peter Clapham, Richard Clark, Adrian Clarke, Catriona Clarke, Daryl Cole, Elizabeth Cook, Maria Coppola, Linda Cornell, Clare Cornwell, Craig Corton, Abby Crackett, Alison Cranage, Harriet Craven, Sarah Craw, Mark Crawford, Tim Cutts, Monika Dabrowska, Matt Davies, Joseph Dawson, Callum Day, Aiden Densem, Thomas Dibling, Cat Dockree, David Dodd, Sunil Dogga, Matthew Dorman, Gordon Dougan, Martin Dougherty, Alexander Dove, Lucy Drummond, Monika Dudek, Laura Durrant, Elizabeth Easthope, Sabine Eckert, Pete Ellis, Ben Farr, Michael Fenton, Marcella Ferrero, Neil Flack, Howerd Fordham, Grace Forsythe, Matt Francis, Audrey Fraser, Adam Freeman, Anastasia Galvin, Maria Garcia-Casado, Alex Gedny, Sophia Girgis, James Glover, Oliver Gould, Andy Gray, Emma Gray, Coline Griffiths, Yong Gu, Florence Guerin, Will Hamilton, Hannah Hanks, Ewan Harrison, Alexandria Harrott, Edward Harry, Julia Harvison, Paul Heath, Anastasia Hernandez-Koutoucheva, Rhiannon Hobbs, Dave Holland, Sarah Holmes, Gary Hornett, Nicholas Hough, Liz Huckle, Lena Hughes-Hallet, Adam Hunter, Stephen Inglis, Sameena Iqbal, Adam Jackson, David Jackson, Carlos Jimenez Verdejo, Matthew Jones, Kalyan Kallepally, Keely Kay, Jon Keatley, Alan Keith, Alison King, Lucy Kitchin, Matt Kleanthous, Martina Klimekova, Petra Korlevic, Ksenia Krasheninnkova, Greg Lane, Cordelia Langford, Adam Laverack, Katharine Law, Stefanie Lensing, Amanah Lewis-Wade, Jennifer Liddle, Quan Lin, Sarah Lindsay, Sally Linsdell, Rhona Long, Jamie Lovell, Jon Lovell, James Mack, Mark Maddison, Aleksei Makunin, Irfan Mamun, Jenny Mansfield, Neil Marriott, Matt Martin, Matthew Mayho, Jo McClintock, Sandra McHugh, Liz MapcMinn, Carl Meadows, Emily Mobley, Robin Moll, Maria Morra, Leanne Morrow, Kathryn Murie, Sian Nash, Claire Nathwani, Plamena Naydenova, Alexandra Neaverson, Ed Nerou, Jon Nicholson, Tabea Nimz, Guillaume G. Noell, Sarah O’Meara, Valeriu Ohan, Charles Olney, Doug Ormond, Agnes Oszlanczi, Yoke Fei Pang, Barbora Pardubska, Naomi Park, Aaron Parmar, Gaurang Patel, Maggie Payne, Sharon Peacock, Arabella Petersen, Deborah Plowman, Tom Preston, Michael Quail, Richard Rance, Suzannah Rawlings, Nicholas Redshaw, Joe Reynolds, Mark Reynolds, Simon Rice, Matt Richardson, Connor Roberts, Katrina Robinson, Melanie Robinson, David Robinson, Hazel Rogers, Eduardo Martin Rojo, Daljit Roopra, Mark Rose, Luke Rudd, Ramin Sadri, Nicholas Salmon, David Saul, Frank Schwach, Phil Seekings, Alison Simms, Matt Sinnott, Shanthi Sivadasan, Bart Siwek, Dale Sizer, Kenneth Skeldon, Jason Skelton, Joanna Slater-Tunstill, Lisa Sloper, Nathalie Smerdon, Chris Smith, Christen Smith, James Smith, Katie Smith, Michelle Smith, Sean Smith, Tina Smith, Leighton Sneade, Carmen Diaz Soria, Catarina Sousa, Emily Souster, Andrew Sparkes, Michael Spencer-Chapman, Janet Squares, Robert Stanley, Claire Steed, Tim Stickland, Ian Still, Mike Stratton, Michelle Strickland, Allen Swann, Agnieszka Swiatkowska, Neil Sycamore, Emma Swift, Edward Symons, Suzanne Szluha, Emma Taluy, Nunu Tao, Katy Taylor, Sam Taylor, Stacey Thompson, Mark Thompson, Mark Thomson, Nicholas Thomson, Scott Thurston, Dee Toombs, Benjamin Topping, Jaime Tovar-Corona, Daniel Ungureanu, James Uphill, Jana Urbanova, Philip Jansen Van, Valerie Vancollie, Paul Voak, Danielle Walker, Matthew Walker, Matt Waller, Gary Ward, Charlie Weatherhogg, Niki Webb, Alan Wells, Eloise Wells, Luke Westwood, Theo Whipp, Thomas Whiteley, Georgia Whitton, Sara Widaa, Mia Williams, Mark Wilson, Sean Wright, and Apollo - University of Cambridge Repository

Subjects
0301 basic medicine, Resistance, MC UU 1201412, Plasma protein binding, Antibodies, Viral, medicine.disease_cause, MR/R024758/1, 0302 clinical medicine, Recurrence, Chlorocebus aethiops, deletion, Biology (General), Receptor, Phylogeny, Infectivity, Mutation, biology, infectivity, MC_UU_12014/12, C500, C700, UKRI, MRC, Antibody Escape, Spike Glycoprotein, Coronavirus, antibody escape, Antibody, Protein Binding, QH301-705.5, Sars-cov-2, Alpha (ethology), Article, General Biochemistry, Genetics and Molecular Biology, Virus, Cell Line, resistance, Deletion, 03 medical and health sciences, spike mutation, medicine, Alpha Variant, Animals, Humans, neutralizing antibodies, B.1.1.7, Vero Cells, Pandemics, Immune Evasion, SARS-CoV-2, Biochemistry, Genetics and Molecular Biology(all), COVID-19, MR/P008801/1, Antibodies, Neutralizing, Virology, body regions, HEK293 Cells, 030104 developmental biology, Alpha variant, Spike Mutation, biology.protein, Vero cell, Neutralizing Antibodies, 030217 neurology & neurosurgery
Abstract

We report severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike ΔH69/V70 in multiple independent lineages, often occurring after acquisition of receptor binding motif replacements such as N439K and Y453F, known to increase binding affinity to the ACE2 receptor and confer antibody escape. In vitro, we show that, although ΔH69/V70 itself is not an antibody evasion mechanism, it increases infectivity associated with enhanced incorporation of cleaved spike into virions. ΔH69/V70 is able to partially rescue infectivity of spike proteins that have acquired N439K and Y453F escape mutations by increased spike incorporation. In addition, replacement of the H69 and V70 residues in the Alpha variant B.1.1.7 spike (where ΔH69/V70 occurs naturally) impairs spike incorporation and entry efficiency of the B.1.1.7 spike pseudotyped virus. Alpha variant B.1.1.7 spike mediates faster kinetics of cell-cell fusion than wild-type Wuhan-1 D614G, dependent on ΔH69/V70. Therefore, as ΔH69/V70 compensates for immune escape mutations that impair infectivity, continued surveillance for deletions with functional effects is warranted., Graphical abstract, Meng et al. report that the SARS-CoV-2 spike ΔH69/V70 has arisen multiple times. The deletion increases entry efficiency associated with increased cleaved spike in virions and can compensate for loss of infectivity. The B.1.1.7 spike requires ΔH69/V70 for efficient cell entry and cell-cell fusion activity.

Published
2021

16. Laboratory comparison between cell cytotoxicity neutralization assay and ultrasensitive single molecule counting technology for detection of Clostridioides difficile toxins A and B, PCR, enzyme immunoassays, and multistep algorithms

Author

Jeffrey J. Bishop, Niamh Nolan, Stephen Young, Salina Abusali, Johanna Sandlund, Aaron B. Wagner, Amelita Bartolome, Sheryl Biscocho, Joel Estis, Christen Griego-Fullbright, Stanley Tam, Ray Mills, John A. Todd, and Anna Almazan

Subjects
0301 basic medicine, Microbiology (medical), Bacterial Toxins, 030106 microbiology, medicine.disease_cause, Polymerase Chain Reaction, Sensitivity and Specificity, Neutralization, law.invention, Enterotoxins, Feces, 03 medical and health sciences, 0302 clinical medicine, Bacterial Proteins, Glutamate Dehydrogenase, Cell cytotoxicity, law, medicine, Humans, Nucleic Acid Amplification Tests, 030212 general & internal medicine, Enterocolitis, Pseudomembranous, Polymerase chain reaction, Immunoassay, Bacteriological Techniques, Clostridioides difficile, Chemistry, Toxin, Glutamate dehydrogenase, Diff-Quik, General Medicine, Infectious Diseases, Enzyme immunoassays, Algorithm, Algorithms
Abstract

Diagnostic tests for Clostridioides difficile infection (CDI) lack either specificity (nucleic acid amplification tests) or sensitivity (enzyme immunoassays; EIAs). The performance of the Singulex Clarity® C. diff toxins A/B assay was compared to cell cytotoxicity neutralization assay. Testing was also performed using an EIA for glutamate dehydrogenase (GDH) and C. difficile toxins A and B (C. Diff Quik Chek Complete®), polymerase chain reaction (PCR) (BD MAX™ Cdiff Assay), and 2 multistep algorithms: algorithm 1 (discordant GDH/toxin results arbitrated by PCR) and algorithm 2 (PCR-positive samples tested with toxin EIA). The Clarity assay and PCR both had 97% sensitivity, while specificity was 100% for Clarity and 79% for PCR. Algorithm 1 yielded 41% discordant results, and both toxin EIA and algorithm 2 had 58% sensitivity. Median toxin concentrations, as measured by the Clarity C. difficile toxin assay, were 3590, 11.5, 0.4, and 0 pg/mL for GDH+/toxin+, GDH+/toxin-/PCR+, GDH+/toxin-/PCR-, and GDH-/toxin- samples, respectively (P 0.001). The Clarity assay may offer a single-test solution for CDI.

Published
2019

17. A blood atlas of COVID-19 defines hallmarks of disease severity and specificity

Author

David J. Ahern, Zhichao Ai, Mark Ainsworth, Chris Allan, Alice Allcock, Brian Angus, M. Azim Ansari, Carolina V. Arancibia-Cárcamo, Dominik Aschenbrenner, Moustafa Attar, J. Kenneth Baillie, Eleanor Barnes, Rachael Bashford-Rogers, Archana Bashyal, Sally Beer, Georgina Berridge, Amy Beveridge, Sagida Bibi, Tihana Bicanic, Luke Blackwell, Paul Bowness, Andrew Brent, Andrew Brown, John Broxholme, David Buck, Katie L. Burnham, Helen Byrne, Susana Camara, Ivan Candido Ferreira, Philip Charles, Wentao Chen, Yi-Ling Chen, Amanda Chong, Elizabeth A. Clutterbuck, Mark Coles, Christopher P. Conlon, Richard Cornall, Adam P. Cribbs, Fabiola Curion, Emma E. Davenport, Neil Davidson, Simon Davis, Calliope A. Dendrou, Julie Dequaire, Lea Dib, James Docker, Christina Dold, Tao Dong, Damien Downes, Hal Drakesmith, Susanna J. Dunachie, David A. Duncan, Chris Eijsbouts, Robert Esnouf, Alexis Espinosa, Rachel Etherington, Benjamin Fairfax, Rory Fairhead, Hai Fang, Shayan Fassih, Sally Felle, Maria Fernandez Mendoza, Ricardo Ferreira, Roman Fischer, Thomas Foord, Aden Forrow, John Frater, Anastasia Fries, Veronica Gallardo Sanchez, Lucy C. Garner, Clementine Geeves, Dominique Georgiou, Leila Godfrey, Tanya Golubchik, Maria Gomez Vazquez, Angie Green, Hong Harper, Heather A. Harrington, Raphael Heilig, Svenja Hester, Jennifer Hill, Charles Hinds, Clare Hird, Ling-Pei Ho, Renee Hoekzema, Benjamin Hollis, Jim Hughes, Paula Hutton, Matthew A. Jackson-Wood, Ashwin Jainarayanan, Anna James-Bott, Kathrin Jansen, Katie Jeffery, Elizabeth Jones, Luke Jostins, Georgina Kerr, David Kim, Paul Klenerman, Julian C. Knight, Vinod Kumar, Piyush Kumar Sharma, Prathiba Kurupati, Andrew Kwok, Angela Lee, Aline Linder, Teresa Lockett, Lorne Lonie, Maria Lopopolo, Martyna Lukoseviciute, Jian Luo, Spyridoula Marinou, Brian Marsden, Jose Martinez, Philippa C. Matthews, Michalina Mazurczyk, Simon McGowan, Stuart McKechnie, Adam Mead, Alexander J. Mentzer, Yuxin Mi, Claudia Monaco, Ruddy Montadon, Giorgio Napolitani, Isar Nassiri, Alex Novak, Darragh P. O'Brien, Daniel O'Connor, Denise O'Donnell, Graham Ogg, Lauren Overend, Inhye Park, Ian Pavord, Yanchun Peng, Frank Penkava, Mariana Pereira Pinho, Elena Perez, Andrew J. Pollard, Fiona Powrie, Bethan Psaila, T. Phuong Quan, Emmanouela Repapi, Santiago Revale, Laura Silva-Reyes, Jean-Baptiste Richard, Charlotte Rich-Griffin, Thomas Ritter, Christine S. Rollier, Matthew Rowland, Fabian Ruehle, Mariolina Salio, Stephen Nicholas Sansom, Raphael Sanches Peres, Alberto Santos Delgado, Tatjana Sauka-Spengler, Ron Schwessinger, Giuseppe Scozzafava, Gavin Screaton, Anna Seigal, Malcolm G. Semple, Martin Sergeant, Christina Simoglou Karali, David Sims, Donal Skelly, Hubert Slawinski, Alberto Sobrinodiaz, Nikolaos Sousos, Lizzie Stafford, Lisa Stockdale, Marie Strickland, Otto Sumray, Bo Sun, Chelsea Taylor, Stephen Taylor, Adan Taylor, Supat Thongjuea, Hannah Thraves, John A. Todd, Adriana Tomic, Orion Tong, Amy Trebes, Dominik Trzupek, Felicia Anna Tucci, Lance Turtle, Irina Udalova, Holm Uhlig, Erinke van Grinsven, Iolanda Vendrell, Marije Verheul, Alexandru Voda, Guanlin Wang, Lihui Wang, Dapeng Wang, Peter Watkinson, Robert Watson, Michael Weinberger, Justin Whalley, Lorna Witty, Katherine Wray, Luzheng Xue, Hing Yuen Yeung, Zixi Yin, Rebecca K. Young, Jonathan Youngs, Ping Zhang, Yasemin-Xiomara Zurke, Cribbs, AP, and Consortium, COvid-19 Multi-omics Blood ATlas (COMBAT)

Subjects
Resource, Adult, Male, Myeloid, Proteome, coronavirus, Cell Cycle Proteins, Disease, Severity of Illness Index, General Biochemistry, Genetics and Molecular Biology, Monocytes, Sepsis, Machine Learning, Mitogen-Activated Protein Kinase 14, transcriptomics, Immune system, proteomics, blood, Influenza, Human, medicine, Humans, Lymphocytes, Progenitor cell, Principal Component Analysis, epigenetics, business.industry, SARS-CoV-2, Clinical study design, Acute-phase protein, COVID-19, personalized medicine, Blood Proteins, multi-omics, Middle Aged, medicine.disease, Coronavirus, Transcription Factor AP-1, medicine.anatomical_structure, Drug development, Immunology, Female, immune, business, Biomarkers
Abstract

Treatment of severe COVID-19 is currently limited by clinical heterogeneity and incomplete description of specific immune biomarkers. We present here a comprehensive multi-omic blood atlas for patients with varying COVID-19 severity in an integrated comparison with influenza and sepsis patients versus healthy volunteers. We identify immune signatures and correlates of host response. Hallmarks of disease severity involved cells, their inflammatory mediators and networks, including progenitor cells and specific myeloid and lymphocyte subsets, features of the immune repertoire, acute phase response, metabolism and coagulation. Persisting immune activation involving AP-1/p38MAPK was a specific feature of COVID-19. The plasma proteome enabled sub-phenotyping into patient clusters, predictive of severity and outcome. Systems-based integrative analyses including tensor and matrix decomposition of all modalities revealed feature groupings linked with severity and specificity compared to influenza and sepsis. Our approach and blood atlas will support future drug development, clinical trial design and personalized medicine approaches for COVID-19., Graphical Abstract, A multi-omic analysis of patient blood samples reveals both similarities and specific features of COVID-19 when compared with samples obtained from sepsis or influenza patients which could yield better targetted therapies for severe COVID-19.

Published
2021

18. Changes in symptomatology, reinfection, and transmissibility associated with the SARS-CoV-2 variant B.1.1.7: an ecological study

Author

Mark S Graham, Carole H Sudre, Anna May, Michela Antonelli, Benjamin Murray, Thomas Varsavsky, Kerstin Kläser, Liane S Canas, Erika Molteni, Marc Modat, David A Drew, Long H Nguyen, Lorenzo Polidori, Somesh Selvachandran, Christina Hu, Joan Capdevila, Alexander Hammers, Andrew T Chan, Jonathan Wolf, Tim D Spector, Claire J Steves, Sebastien Ourselin, Cherian Koshy, Amy Ash, Emma Wise, Nathan Moore, Matilde Mori, Nick Cortes, Jessica Lynch, Stephen Kidd, Derek J Fairley, Tanya Curran, James P McKenna, Helen Adams, Christophe Fraser, Tanya Golubchik, David Bonsall, Mohammed O Hassan-Ibrahim, Cassandra S Malone, Benjamin J Cogger, Michelle Wantoch, Nicola Reynolds, Ben Warne, Joshua Maksimovic, Karla Spellman, Kathryn McCluggage, Michaela John, Robert Beer, Safiah Afifi, Sian Morgan, Angela Marchbank, Anna Price, Christine Kitchen, Huw Gulliver, Ian Merrick, Joel Southgate, Martyn Guest, Robert Munn, Trudy Workman, Thomas R Connor, William Fuller, Catherine Bresner, Luke B Snell, Amita Patel, Themoula Charalampous, Gaia Nebbia, Rahul Batra, Jonathan Edgeworth, Samuel C Robson, Angela H Beckett, David M Aanensen, Anthony P Underwood, Corin A Yeats, Khalil Abudahab, Ben EW Taylor, Mirko Menegazzo, Gemma Clark, Wendy Smith, Manjinder Khakh, Vicki M Fleming, Michelle M Lister, Hannah C Howson-Wells, Louise Berry, Tim Boswell, Amelia Joseph, Iona Willingham, Carl Jones, Christopher Holmes, Paul Bird, Thomas Helmer, Karlie Fallon, Julian Tang, Veena Raviprakash, Sharon Campbell, Nicola Sheriff, Victoria Blakey, Lesley-Anne Williams, Matthew W Loose, Nadine Holmes, Christopher Moore, Matthew Carlile, Victoria Wright, Fei Sang, Johnny Debebe, Francesc Coll, Adrian W Signell, Gilberto Betancor, Harry D Wilson, Sahar Eldirdiri, Anita Kenyon, Thomas Davis, Oliver G Pybus, Louis du Plessis, Alex E Zarebski, Jayna Raghwani, Moritz UG Kraemer, Sarah Francois, Stephen W Attwood, Tetyana I Vasylyeva, Marina Escalera Zamudio, Bernardo Gutierrez, M. Estee Torok, William L Hamilton, Ian G Goodfellow, Grant Hall, Aminu S Jahun, Yasmin Chaudhry, Myra Hosmillo, Malte L Pinckert, Iliana Georgana, Samuel Moses, Hannah Lowe, Luke Bedford, Jonathan Moore, Susanne Stonehouse, Chloe L Fisher, Ali R Awan, John BoYes, Judith Breuer, Kathryn Ann Harris, Julianne Rose Brown, Divya Shah, Laura Atkinson, Jack CD Lee, Nathaniel Storey, Flavia Flaviani, Adela Alcolea-Medina, Rebecca Williams, Gabrielle Vernet, Michael R Chapman, Lisa J Levett, Judith Heaney, Wendy Chatterton, Monika Pusok, Li Xu-McCrae, Darren L Smith, Matthew Bashton, Gregory R Young, Alison Holmes, Paul Anthony Randell, Alison Cox, Pinglawathee Madona, Frances Bolt, James Price, Siddharth Mookerjee, Manon Ragonnet-Cronin, Fabricia F. Nascimento, David Jorgensen, Igor Siveroni, Rob Johnson, Olivia Boyd, Lily Geidelberg, Erik M Volz, Aileen Rowan, Graham P Taylor, Katherine L Smollett, Nicholas J Loman, Joshua Quick, Claire McMurray, Joanne Stockton, Sam Nicholls, Will Rowe, Radoslaw Poplawski, Alan McNally, Rocio T Martinez Nunez, Jenifer Mason, Trevor I Robinson, Elaine O'Toole, Joanne Watts, Cassie Breen, Angela Cowell, Graciela Sluga, Nicholas W Machin, Shazaad S Y Ahmad, Ryan P George, Fenella Halstead, Venkat Sivaprakasam, Wendy Hogsden, Chris J Illingworth, Chris Jackson, Emma C Thomson, James G Shepherd, Patawee Asamaphan, Marc O Niebel, Kathy K Li, Rajiv N Shah, Natasha G Jesudason, Lily Tong, Alice Broos, Daniel Mair, Jenna Nichols, Stephen N Carmichael, Kyriaki Nomikou, Elihu Aranday-Cortes, Natasha Johnson, Igor Starinskij, Ana da Silva Filipe, David L Robertson, Richard J Orton, Joseph Hughes, Sreenu Vattipally, Joshua B Singer, Seema Nickbakhsh, Antony D Hale, Louissa R Macfarlane-Smith, Katherine L Harper, Holli Carden, Yusri Taha, Brendan AI Payne, Shirelle Burton-Fanning, Sheila Waugh, Jennifer Collins, Gary Eltringham, Steven Rushton, Sarah O'Brien, Amanda Bradley, Alasdair Maclean, Guy Mollett, Rachel Blacow, Kate E Templeton, Martin P McHugh, Rebecca Dewar, Elizabeth Wastenge, Samir Dervisevic, Rachael Stanley, Emma J Meader, Lindsay Coupland, Louise Smith, Clive Graham, Edward Barton, Debra Padgett, Garren Scott, Emma Swindells, Jane Greenaway, Andrew Nelson, Clare M McCann, Wen C Yew, Monique Andersson, Timothy Peto, Anita Justice, David Eyre, Derrick Crook, Tim J Sloan, Nichola Duckworth, Sarah Walsh, Anoop J Chauhan, Sharon Glaysher, Kelly Bicknell, Sarah Wyllie, Scott Elliott, Allyson Lloyd, Robert Impey, Nick Levene, Lynn Monaghan, Declan T Bradley, Tim Wyatt, Elias Allara, Clare Pearson, Husam Osman, Andrew Bosworth, Esther Robinson, Peter Muir, Ian B Vipond, Richard Hopes, Hannah M Pymont, Stephanie Hutchings, Martin D Curran, Surendra Parmar, Angie Lackenby, Tamyo Mbisa, Steven Platt, Shahjahan Miah, David Bibby, Carmen Manso, Jonathan Hubb, Meera Chand, Gavin Dabrera, Mary Ramsay, Daniel Bradshaw, Alicia Thornton, Richard Myers, Ulf Schaefer, Natalie Groves, Eileen Gallagher, David Lee, David Williams, Nicholas Ellaby, Ian Harrison, Hassan Hartman, Nikos Manesis, Vineet Patel, Chloe Bishop, Vicki Chalker, Juan Ledesma, Katherine A Twohig, Matthew T.G. Holden, Sharif Shaaban, Alec Birchley, Alexander Adams, Alisha Davies, Amy Gaskin, Amy Plimmer, Bree Gatica-Wilcox, Caoimhe McKerr, Catherine Moore, Chris Williams, David Heyburn, Elen De Lacy, Ember Hilvers, Fatima Downing, Giri Shankar, Hannah Jones, Hibo Asad, Jason Coombes, Joanne Watkins, Johnathan M Evans, Laia Fina, Laura Gifford, Lauren Gilbert, Lee Graham, Malorie Perry, Mari Morgan, Matthew Bull, Michelle Cronin, Nicole Pacchiarini, Noel Craine, Rachel Jones, Robin Howe, Sally Corden, Sara Rey, Sara Kumziene-SummerhaYes, Sarah Taylor, Simon Cottrell, Sophie Jones, Sue Edwards, Justin O'Grady, Andrew J Page, Alison E Mather, David J Baker, Steven Rudder, Alp Aydin, Gemma L Kay, Alexander J Trotter, Nabil-Fareed Alikhan, Leonardo de Oliveira Martins, Thanh Le-Viet, Lizzie Meadows, Anna Casey, Liz Ratcliffe, David A Simpson, Zoltan Molnar, Thomas Thompson, Erwan Acheson, Jane AH Masoli, Bridget A Knight, Sian Ellard, Cressida Auckland, Christopher R Jones, Tabitha W Mahungu, Dianne Irish-Tavares, Tanzina Haque, Jennifer Hart, Eric Witele, Melisa Louise Fenton, Ashok Dadrah, Amanda Symmonds, Tranprit Saluja, Yann Bourgeois, Garry P Scarlett, Katie F Loveson, Salman Goudarzi, Christopher Fearn, Kate Cook, Hannah Dent, Hannah Paul, David G Partridge, Mohammad Raza, Cariad Evans, Kate Johnson, Steven Liggett, Paul Baker, Stephen Bonner, Sarah Essex, Ronan A Lyons, Kordo Saeed, Adhyana I.K Mahanama, Buddhini Samaraweera, Siona Silveira, Emanuela Pelosi, Eleri Wilson-Davies, Rachel J Williams, Mark Kristiansen, Sunando Roy, Charlotte A Williams, Marius Cotic, Nadua Bayzid, Adam P Westhorpe, John A Hartley, Riaz Jannoo, Helen L Lowe, Angeliki Karamani, Leah Ensell, Jacqui A Prieto, Sarah Jeremiah, Dimitris Grammatopoulos, Sarojini Pandey, Lisa Berry, Katie Jones, Alex Richter, Andrew Beggs, Angus Best, Benita Percival, Jeremy Mirza, Oliver Megram, Megan Mayhew, Liam Crawford, Fiona Ashcroft, Emma Moles-Garcia, Nicola Cumley, Colin P Smith, Giselda Bucca, Andrew R Hesketh, Beth Blane, Sophia T Girgis, Danielle Leek, Sushmita Sridhar, Sally Forrest, Claire Cormie, Harmeet K Gill, Joana Dias, Ellen E Higginson, Mailis Maes, Jamie Young, Leanne M Kermack, Ravi Kumar Gupta, Catherine Ludden, Sharon J Peacock, Sophie Palmer, Carol M Churcher, Nazreen F Hadjirin, Alessandro M Carabelli, Ellena Brooks, Kim S Smith, Katerina Galai, Georgina M McManus, Chris Ruis, Rose K Davidson, Andrew Rambaut, Thomas Williams, Carlos E Balcazar, Michael D Gallagher, Áine O'Toole, Stefan Rooke, Verity Hill, Kathleen A Williamson, Thomas D Stanton, Stephen L Michell, Claire M Bewshea, Ben Temperton, Michelle L Michelsen, Joanna Warwick-Dugdale, Robin Manley, Audrey Farbos, James W Harrison, Christine M Sambles, David J Studholme, Aaron R Jeffries, Alistair C Darby, Julian A Hiscox, Steve Paterson, Miren Iturriza-Gomara, Kathryn A Jackson, Anita O Lucaci, Edith E Vamos, Margaret Hughes, Lucille Rainbow, Richard Eccles, Charlotte Nelson, Mark Whitehead, Lance Turtle, Sam T Haldenby, Richard Gregory, Matthew Gemmell, Claudia Wierzbicki, Hermione J Webster, Thushan I de Silva, Nikki Smith, Adrienn Angyal, Benjamin B Lindsey, Danielle C Groves, Luke R Green, Dennis Wang, Timothy M Freeman, Matthew D Parker, Alexander J Keeley, Paul J Parsons, Rachel M Tucker, Rebecca Brown, Matthew Wyles, Max Whiteley, Peijun Zhang, Marta Gallis, Stavroula F Louka, Chrystala Constantinidou, Meera Unnikrishnan, Sascha Ott, Jeffrey K.J. Cheng, Hannah E. Bridgewater, Lucy R. Frost, Grace Taylor-Joyce, Richard Stark, Laura Baxter, Mohammad T. Alam, Paul E Brown, Dinesh Aggarwal, Alberto C Cerda, Tammy V Merrill, Rebekah E Wilson, Patrick C McClure, Joseph G Chappell, Theocharis Tsoleridis, Jonathan Ball, David Buck, John A Todd, Angie Green, Amy Trebes, George MacIntyre-Cockett, Mariateresa de Cesare, Alex Alderton, Roberto Amato, Cristina V Ariani, Mathew A Beale, Charlotte Beaver, Katherine L Bellis, Emma Betteridge, James Bonfield, John Danesh, Matthew J Dorman, Eleanor Drury, Ben W Farr, Luke Foulser, Sonia Goncalves, Scott Goodwin, Marina Gourtovaia, Ewan M Harrison, David K Jackson, Dorota Jamrozy, Ian Johnston, Leanne Kane, Sally Kay, Jon-Paul Keatley, Dominic Kwiatkowski, Cordelia F Langford, Mara Lawniczak, Laura Letchford, Rich Livett, Stephanie Lo, Inigo Martincorena, Samantha McGuigan, Rachel Nelson, Steve Palmer, Naomi R Park, Minal Patel, Liam Prestwood, Christoph Puethe, Michael A Quail, Shavanthi Rajatileka, Carol Scott, Lesley Shirley, John Sillitoe, Michael H Spencer Chapman, Scott AJ Thurston, Gerry Tonkin-Hill, Danni Weldon, Diana Rajan, Iraad F Bronner, Louise Aigrain, Nicholas M Redshaw, Stefanie V Lensing, Robert Davies, Andrew Whitwham, Jennifier Liddle, Kevin Lewis, Jaime M Tovar-Corona, Steven Leonard, Jillian Durham, Andrew R Bassett, Shane McCarthy, Robin J Moll, Keith James, Karen Oliver, Alex Makunin, Jeff Barrett, Rory N Gunson, Sudre, Carole H [0000-0001-5753-428X], Molteni, Erika [0000-0001-7773-8140], Apollo - University of Cambridge Repository, and Medical Research Council (MRC)

Subjects
Adult, Male, medicine.medical_specialty, Adolescent, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), B100, B200, 01 natural sciences, Spearman's rank correlation coefficient, 03 medical and health sciences, Young Adult, 0302 clinical medicine, COVID-19 Genomics UK (COG-UK) Consortium, Epidemiology, medicine, Humans, 030212 general & internal medicine, 0101 mathematics, Young adult, Aged, business.industry, SARS-CoV-2, Incidence (epidemiology), Public health, Comment, 010102 general mathematics, Public Health, Environmental and Occupational Health, Ecological study, COVID-19, C500, Articles, Middle Aged, C700, Transmissibility (vibration), United Kingdom, Reinfection, Female, Public aspects of medicine, RA1-1270, business, Demography
Abstract

Background: The SARS-CoV-2 variant B.1.1.7 was first identified in December, 2020, in England. We aimed to investigate whether increases in the proportion of infections with this variant are associated with differences in symptoms or disease course, reinfection rates, or transmissibility. Methods: We did an ecological study to examine the association between the regional proportion of infections with the SARS-CoV-2 B.1.1.7 variant and reported symptoms, disease course, rates of reinfection, and transmissibility. Data on types and duration of symptoms were obtained from longitudinal reports from users of the COVID Symptom Study app who reported a positive test for COVID-19 between Sept 28 and Dec 27, 2020 (during which the prevalence of B.1.1.7 increased most notably in parts of the UK). From this dataset, we also estimated the frequency of possible reinfection, defined as the presence of two reported positive tests separated by more than 90 days with a period of reporting no symptoms for more than 7 days before the second positive test. The proportion of SARS-CoV-2 infections with the B.1.1.7 variant across the UK was estimated with use of genomic data from the COVID-19 Genomics UK Consortium and data from Public Health England on spike-gene target failure (a non-specific indicator of the B.1.1.7 variant) in community cases in England. We used linear regression to examine the association between reported symptoms and proportion of B.1.1.7. We assessed the Spearman correlation between the proportion of B.1.1.7 cases and number of reinfections over time, and between the number of positive tests and reinfections. We estimated incidence for B.1.1.7 and previous variants, and compared the effective reproduction number, R t, for the two incidence estimates. Findings: From Sept 28 to Dec 27, 2020, positive COVID-19 tests were reported by 36 920 COVID Symptom Study app users whose region was known and who reported as healthy on app sign-up. We found no changes in reported symptoms or disease duration associated with B.1.1.7. For the same period, possible reinfections were identified in 249 (0·7% [95% CI 0·6–0·8]) of 36 509 app users who reported a positive swab test before Oct 1, 2020, but there was no evidence that the frequency of reinfections was higher for the B.1.1.7 variant than for pre-existing variants. Reinfection occurrences were more positively correlated with the overall regional rise in cases (Spearman correlation 0·56–0·69 for South East, London, and East of England) than with the regional increase in the proportion of infections with the B.1.1.7 variant (Spearman correlation 0·38–0·56 in the same regions), suggesting B.1.1.7 does not substantially alter the risk of reinfection. We found a multiplicative increase in the R t of B.1.1.7 by a factor of 1·35 (95% CI 1·02–1·69) relative to pre-existing variants. However, R t fell below 1 during regional and national lockdowns, even in regions with high proportions of infections with the B.1.1.7 variant. Interpretation: The lack of change in symptoms identified in this study indicates that existing testing and surveillance infrastructure do not need to change specifically for the B.1.1.7 variant. In addition, given that there was no apparent increase in the reinfection rate, vaccines are likely to remain effective against the B.1.1.7 variant. Funding: Zoe Global, Department of Health (UK), Wellcome Trust, Engineering and Physical Sciences Research Council (UK), National Institute for Health Research (UK), Medical Research Council (UK), Alzheimer's Society.

Published
2021

19. Childhood body size directly increases type 1 diabetes risk based on a lifecourse Mendelian randomization approach

Author

Tom G, Richardson, Daniel J M, Crouch, Grace M, Power, Fernanda, Morales-Berstein, Emma, Hazelwood, Si, Fang, Yoonsu, Cho, Jamie R J, Inshaw, Catherine C, Robertson, Carlo, Sidore, Francesco, Cucca, Steven S, Rich, John A, Todd, and George, Davey Smith

Subjects
Adult, Pediatric Obesity, Diabetes Mellitus, Type 1, Infant, Newborn, Body Size, Humans, Mendelian Randomization Analysis, Overweight, Child
Abstract

The rising prevalence of childhood obesity has been postulated as an explanation for the increasing rate of individuals diagnosed with type 1 diabetes (T1D). In this study, we use Mendelian randomization (MR) to provide evidence that childhood body size has an effect on T1D risk (OR = 2.05 per change in body size category, 95% CI = 1.20 to 3.50, P = 0.008), which remains after accounting for body size at birth and during adulthood using multivariable MR (OR = 2.32, 95% CI = 1.21 to 4.42, P = 0.013). We validate this direct effect of childhood body size using data from a large-scale T1D meta-analysis based on n = 15,573 cases and n = 158,408 controls (OR = 1.94, 95% CI = 1.21 to 3.12, P = 0.006). We also provide evidence that childhood body size influences risk of asthma, eczema and hypothyroidism, although multivariable MR suggested that these effects are mediated by body size in later life. Our findings support a causal role for higher childhood body size on risk of being diagnosed with T1D, whereas its influence on the other immune-associated diseases is likely explained by a long-term effect of remaining overweight for many years over the lifecourse.

Published
2021

20. Fusion peptide priming reduces immune responses to HIV-1 envelope trimer base

Author

Nicole A. Doria-Rose, Cheng Cheng, Tyler Stephens, Shuishu Wang, Steven J. Chen, Peter D. Kwong, John Paul Todd, Christopher A. Gonelli, Amarendra Pegu, Sijy O'Dell, Richard A. Koup, Vrc Production Program, Kai Xu, Baoshan Zhang, John R. Mascola, Adrian B. McDermott, Hongying Duan, Jelle van Schooten, Li Ou, Jeffrey C. Boyington, Manjula Basappa, Angela R. Corrigan, Sarah O’Connell, Sandeep Narpala, Kathryn E. Foulds, Megan E. DeMouth, Marit J. van Gils, Yaroslav Tsybovsky, Tongqing Zhou, Hui Geng, Graduate School, AII - Infectious diseases, and Medical Microbiology and Infection Prevention

Subjects
0301 basic medicine, Male, HIV vaccine, Recombinant Fusion Proteins, Priming (immunology), Trimer, Models, Biological, General Biochemistry, Genetics and Molecular Biology, Neutralization, Article, immune response, 03 medical and health sciences, Immunoglobulin Fab Fragments, SOSIP, 0302 clinical medicine, Immune system, trimer base, Animals, Humans, nanoparticle immunogen, lcsh:QH301-705.5, Chemistry, env Gene Products, Human Immunodeficiency Virus, Antibodies, Monoclonal, prefusion-stabilized trimer, neutralization, Virology, Antibodies, Neutralizing, Macaca mulatta, immunogen cocktail, 030104 developmental biology, Immunization, lcsh:Biology (General), Antibody Formation, immunization regimen, HIV-1, fusion peptide, Female, Protein Multimerization, Peptides, 030217 neurology & neurosurgery, Fusion peptide, Conjugate
Abstract

SUMMARY Soluble “SOSIP”-stabilized envelope (Env) trimers are promising HIV-vaccine immunogens. However, they induce high-titer responses against the glycan-free trimer base, which is occluded on native virions. To delineate the effect on base responses of priming with immunogens targeting the fusion peptide (FP) site of vulnerability, here, we quantify the prevalence of trimer-base antibody responses in 49 non-human primates immunized with various SOSIP-stabilized Env trimers and FP-carrier conjugates. Trimer-base responses account for ~90% of the overall trimer response in animals immunized with trimer only, ~70% in animals immunized with a cocktail of SOSIP trimer and FP conjugate, and ~30% in animals primed with FP conjugates before trimer immunization. Notably, neutralization breadth in FP-conjugate-primed animals correlates inversely with trimer-base responses. Our data provide methods to quantify the prevalence of trimer-base responses and reveal that FP-conjugate priming, either alone or as part of a cocktail, can reduce the trimer-base response and improve the neutralization outcome., In brief The exposed base region of soluble HIV-1 Env trimers elicits strong non-neutralizing antibody responses. Corrigan et al. quantify plasma anti-base responses in immunized NHPs and observe a reduction in anti-base responses with fusion-peptide priming. The percentage of anti-base responses correlates inversely with neutralization breadth, providing insights for improving vaccination strategies., Graphical Abstract

Published
2021

21. Evaluating the effects of SARS-CoV-2 Spike mutation D614G on transmissibility and pathogenicity

Author

Erik Volz, Verity Hill, John T. McCrone, Anna Price, David Jorgensen, Áine O’Toole, Joel Southgate, Robert Johnson, Ben Jackson, Fabricia F. Nascimento, Sara M. Rey, Samuel M. Nicholls, Rachel M. Colquhoun, Ana da Silva Filipe, James Shepherd, David J. Pascall, Rajiv Shah, Natasha Jesudason, Kathy Li, Ruth Jarrett, Nicole Pacchiarini, Matthew Bull, Lily Geidelberg, Igor Siveroni, Ian Goodfellow, Nicholas J. Loman, Oliver G. Pybus, David L. Robertson, Emma C. Thomson, Andrew Rambaut, Thomas R. Connor, Cherian Koshy, Emma Wise, Nick Cortes, Jessica Lynch, Stephen Kidd, Matilde Mori, Derek J. Fairley, Tanya Curran, James P. McKenna, Helen Adams, Christophe Fraser, Tanya Golubchik, David Bonsall, Catrin Moore, Sarah L. Caddy, Fahad A. Khokhar, Michelle Wantoch, Nicola Reynolds, Ben Warne, Joshua Maksimovic, Karla Spellman, Kathryn McCluggage, Michaela John, Robert Beer, Safiah Afifi, Sian Morgan, Angela Marchbank, Christine Kitchen, Huw Gulliver, Ian Merrick, Martyn Guest, Robert Munn, Trudy Workman, William Fuller, Catherine Bresner, Luke B. Snell, Themoula Charalampous, Gaia Nebbia, Rahul Batra, Jonathan Edgeworth, Samuel C. Robson, Angela Beckett, Katie F. Loveson, David M. Aanensen, Anthony P. Underwood, Corin A. Yeats, Khalil Abudahab, Ben E.W. Taylor, Mirko Menegazzo, Gemma Clark, Wendy Smith, Manjinder Khakh, Vicki M. Fleming, Michelle M. Lister, Hannah C. Howson-Wells, Louise Berry, Tim Boswell, Amelia Joseph, Iona Willingham, Paul Bird, Thomas Helmer, Karlie Fallon, Christopher Holmes, Julian Tang, Veena Raviprakash, Sharon Campbell, Nicola Sheriff, Matthew W. Loose, Nadine Holmes, Christopher Moore, Matthew Carlile, Victoria Wright, Fei Sang, Johnny Debebe, Francesc Coll, Adrian W. Signell, Gilberto Betancor, Harry D. Wilson, Theresa Feltwell, Charlotte J. Houldcroft, Sahar Eldirdiri, Anita Kenyon, Thomas Davis, Oliver Pybus, Louis du Plessis, Alex Zarebski, Jayna Raghwani, Moritz Kraemer, Sarah Francois, Stephen Attwood, Tetyana Vasylyeva, M. Estee Torok, William L. Hamilton, Ian G. Goodfellow, Grant Hall, Aminu S. Jahun, Yasmin Chaudhry, Myra Hosmillo, Malte L. Pinckert, Iliana Georgana, Anna Yakovleva, Luke W. Meredith, Samuel Moses, Hannah Lowe, Felicity Ryan, Chloe L. Fisher, Ali R. Awan, John Boyes, Judith Breuer, Kathryn Ann Harris, Julianne Rose Brown, Divya Shah, Laura Atkinson, Jack C.D. Lee, Adela Alcolea-Medina, Nathan Moore, Nicholas Cortes, Rebecca Williams, Michael R. Chapman, Lisa J. Levett, Judith Heaney, Darren L. Smith, Matthew Bashton, Gregory R. Young, John Allan, Joshua Loh, Paul A. Randell, Alison Cox, Pinglawathee Madona, Alison Holmes, Frances Bolt, James Price, Siddharth Mookerjee, Aileen Rowan, Graham P. Taylor, Manon Ragonnet-Cronin, Rob Johnson, Olivia Boyd, Erik M. Volz, Kirstyn Brunker, Katherine L. Smollett, Joshua Quick, Claire McMurray, Joanne Stockton, Sam Nicholls, Will Rowe, Radoslaw Poplawski, Rocio T. Martinez-Nunez, Jenifer Mason, Trevor I. Robinson, Elaine O'Toole, Joanne Watts, Cassie Breen, Angela Cowell, Catherine Ludden, Graciela Sluga, Nicholas W. Machin, Shazaad S.Y. Ahmad, Ryan P. George, Fenella Halstead, Venkat Sivaprakasam, James G. Shepherd, Patawee Asamaphan, Marc O. Niebel, Kathy K. Li, Rajiv N. Shah, Natasha G. Jesudason, Yasmin A. Parr, Lily Tong, Alice Broos, Daniel Mair, Jenna Nichols, Stephen N. Carmichael, Kyriaki Nomikou, Elihu Aranday-Cortes, Natasha Johnson, Igor Starinskij, Richard J. Orton, Joseph Hughes, Sreenu Vattipally, Joshua B. Singer, Antony D. Hale, Louissa R. Macfarlane-Smith, Katherine L. Harper, Yusri Taha, Brendan A.I. Payne, Shirelle Burton-Fanning, Sheila Waugh, Jennifer Collins, Gary Eltringham, Kate E. Templeton, Martin P. McHugh, Rebecca Dewar, Elizabeth Wastenge, Samir Dervisevic, Rachael Stanley, Reenesh Prakash, Claire Stuart, Ngozi Elumogo, Dheeraj K. Sethi, Emma J. Meader, Lindsay J. Coupland, Will Potter, Clive Graham, Edward Barton, Debra Padgett, Garren Scott, Emma Swindells, Jane Greenaway, Andrew Nelson, Wen C. Yew, Paola C. Resende Silva, Monique Andersson, Robert Shaw, Timothy Peto, Anita Justice, David Eyre, Derrick Crooke, Sarah Hoosdally, Tim J. Sloan, Nichola Duckworth, Sarah Walsh, Anoop J. Chauhan, Sharon Glaysher, Kelly Bicknell, Sarah Wyllie, Ethan Butcher, Scott Elliott, Allyson Lloyd, Robert Impey, Nick Levene, Lynn Monaghan, Declan T. Bradley, Elias Allara, Clare Pearson, Peter Muir, Ian B. Vipond, Richard Hopes, Hannah M. Pymont, Stephanie Hutchings, Martin D. Curran, Surendra Parmar, Angie Lackenby, Tamyo Mbisa, Steven Platt, Shahjahan Miah, David Bibby, Carmen Manso, Jonathan Hubb, Meera Chand, Gavin Dabrera, Mary Ramsay, Daniel Bradshaw, Alicia Thornton, Richard Myers, Ulf Schaefer, Natalie Groves, Eileen Gallagher, David Lee, David Williams, Nicholas Ellaby, Ian Harrison, Hassan Hartman, Nikos Manesis, Vineet Patel, Chloe Bishop, Vicki Chalker, Husam Osman, Andrew Bosworth, Esther Robinson, Matthew T.G. Holden, Sharif Shaaban, Alec Birchley, Alexander Adams, Alisha Davies, Amy Gaskin, Amy Plimmer, Bree Gatica-Wilcox, Caoimhe McKerr, Catherine Moore, Chris Williams, David Heyburn, Elen De Lacy, Ember Hilvers, Fatima Downing, Giri Shankar, Hannah Jones, Hibo Asad, Jason Coombes, Joanne Watkins, Johnathan M. Evans, Laia Fina, Laura Gifford, Lauren Gilbert, Lee Graham, Malorie Perry, Mari Morgan, Michelle Cronin, Noel Craine, Rachel Jones, Robin Howe, Sally Corden, Sara Rey, Sara Kumziene-Summerhayes, Sarah Taylor, Simon Cottrell, Sophie Jones, Sue Edwards, Justin O’Grady, Andrew J. Page, John Wain, Mark A. Webber, Alison E. Mather, David J. Baker, Steven Rudder, Muhammad Yasir, Nicholas M. Thomson, Alp Aydin, Ana P. Tedim, Gemma L. Kay, Alexander J. Trotter, Rachel A.J. Gilroy, Nabil-Fareed Alikhan, Leonardo de Oliveira Martins, Thanh Le-Viet, Lizzie Meadows, Anastasia Kolyva, Maria Diaz, Andrew Bell, Ana Victoria Gutierrez, Ian G. Charles, Evelien M. Adriaenssens, Robert A. Kingsley, Anna Casey, David A. Simpson, Zoltan Molnar, Thomas Thompson, Erwan Acheson, Jane A.H. Masoli, Bridget A. Knight, Andrew Hattersley, Sian Ellard, Cressida Auckland, Tabitha W. Mahungu, Dianne Irish-Tavares, Tanzina Haque, Yann Bourgeois, Garry P. Scarlett, David G. Partridge, Mohammad Raza, Cariad Evans, Kate Johnson, Steven Liggett, Paul Baker, Sarah Essex, Ronan A. Lyons, Laura G. Caller, Sergi Castellano, Rachel J. Williams, Mark Kristiansen, Sunando Roy, Charlotte A. Williams, Patricia L. Dyal, Helena J. Tutill, Yasmin N. Panchbhaya, Leysa M. Forrest, Paola Niola, Jacqueline Findlay, Tony T. Brooks, Artemis Gavriil, Lamia Mestek-Boukhibar, Sam Weeks, Sarojini Pandey, Lisa Berry, Katie Jones, Alex Richter, Andrew Beggs, Colin P. Smith, Giselda Bucca, Andrew R. Hesketh, Ewan M. Harrison, Sharon J. Peacock, Sophie Palmer, Carol M. Churcher, Katherine L. Bellis, Sophia T. Girgis, Plamena Naydenova, Beth Blane, Sushmita Sridhar, Chris Ruis, Sally Forrest, Claire Cormie, Harmeet K. Gill, Joana Dias, Ellen E. Higginson, Mailis Maes, Jamie Young, Leanne M. Kermack, Nazreen F. Hadjirin, Dinesh Aggarwal, Luke Griffith, Tracey Swingler, Rose K. Davidson, Thomas Williams, Carlos E. Balcazar, Michael D. Gallagher, Áine O'Toole, Stefan Rooke, Rachel Colquhoun, Jordan Ashworth, J.T. McCrone, Emily Scher, Xiaoyu Yu, Kathleen A. Williamson, Thomas D. Stanton, Stephen L. Michell, Claire M. Bewshea, Ben Temperton, Michelle L. Michelsen, Joanna Warwick-Dugdale, Robin Manley, Audrey Farbos, James W. Harrison, Christine M. Sambles, David J. Studholme, Aaron R. Jeffries, Alistair C. Darby, Julian A. Hiscox, Steve Paterson, Miren Iturriza-Gomara, Kathryn A. Jackson, Anita O. Lucaci, Edith E. Vamos, Margaret Hughes, Lucille Rainbow, Richard Eccles, Charlotte Nelson, Mark Whitehead, Lance Turtle, Sam T. Haldenby, Richard Gregory, Matthew Gemmell, Dominic Kwiatkowski, Thushan I. de Silva, Nikki Smith, Adrienn Angyal, Benjamin B. Lindsey, Danielle C. Groves, Luke R. Green, Dennis Wang, Timothy M. Freeman, Matthew D. Parker, Alexander J. Keeley, Paul J. Parsons, Rachel M. Tucker, Rebecca Brown, Matthew Wyles, Chrystala Constantinidou, Meera Unnikrishnan, Sascha Ott, Jeffrey K.J. Cheng, Hannah E. Bridgewater, Lucy R. Frost, Grace Taylor-Joyce, Richard Stark, Laura Baxter, Mohammad T. Alam, Paul E. Brown, Patrick C. McClure, Joseph G. Chappell, Theocharis Tsoleridis, Jonathan Ball, Dimitris Grammatopoulos, David Buck, John A. Todd, Angie Green, Amy Trebes, George MacIntyre-Cockett, Mariateresa de Cesare, Cordelia Langford, Alex Alderton, Roberto Amato, Sonia Goncalves, David K. Jackson, Ian Johnston, John Sillitoe, Steve Palmer, Mara Lawniczak, Matt Berriman, John Danesh, Rich Livett, Lesley Shirley, Ben Farr, Mike Quail, Scott Thurston, Naomi Park, Emma Betteridge, Danni Weldon, Scott Goodwin, Rachel Nelson, Charlotte Beaver, Laura Letchford, David A. Jackson, Luke Foulser, Liz McMinn, Liam Prestwood, Sally Kay, Leanne Kane, Matthew J. Dorman, Inigo Martincorena, Christoph Puethe, Jon-Paul Keatley, Gerry Tonkin-Hill, Christen Smith, Dorota Jamrozy, Mathew A. Beale, Minal Patel, Cristina Ariani, Michael Spencer-Chapman, Eleanor Drury, Stephanie Lo, Shavanthi Rajatileka, Carol Scott, Keith James, Sarah K. Buddenborg, Duncan J. Berger, Gaurang Patel, Maria V. Garcia-Casado, Thomas Dibling, Samantha McGuigan, Hazel A. Rogers, Adam D. Hunter, Emily Souster, Alexandra S. Neaverson, Medical Research Council (MRC), Pascall, David [0000-0002-7543-0860], and Apollo - University of Cambridge Repository

Subjects
Genome, Genetic analysis, 0302 clinical medicine, Clade, 11 Medical and Health Sciences, Genetics, 0303 health sciences, education.field_of_study, Phylogenetic tree, Virulence, C500, COG-UK Consortium, C700, Transmissibility (vibration), 3. Good health, founder effect, Spike Glycoprotein, Coronavirus, epidemiology, Viral load, Population, Glycine, B100, Genomics, Genome, Viral, Biology, Article, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, evolution, Humans, education, 030304 developmental biology, Aspartic Acid, Whole Genome Sequencing, Biochemistry, Genetics and Molecular Biology(all), SARS-CoV-2, COVID-19, spike, The COVID-19 Genomics UK Consortium, A300, 06 Biological Sciences, United Kingdom, Amino Acid Substitution, Evolutionary biology, Mutation, Biological dispersal, 030217 neurology & neurosurgery, Founder effect, Developmental Biology
Abstract

Global dispersal and increasing frequency of the SARS-CoV-2 spike protein variant D614G are suggestive of a selective advantage but may also be due to a random founder effect. We investigate the hypothesis for positive selection of spike D614G in the United Kingdom using more than 25,000 whole genome SARS-CoV-2 sequences. Despite the availability of a large dataset, well represented by both spike 614 variants, not all approaches showed a conclusive signal of positive selection. Population genetic analysis indicates that 614G increases in frequency relative to 614D in a manner consistent with a selective advantage. We do not find any indication that patients infected with the spike 614G variant have higher COVID-19 mortality or clinical severity, but 614G is associated with higher viral load and younger age of patients. Significant differences in growth and size of 614G phylogenetic clusters indicate a need for continued study of this variant., Graphical Abstract, Highlights • Increasing frequency of SARS-CoV-2 D614G is consistent with a selective advantage • Phylodynamic analyses do not show significantly different growth of D614G clusters • There is no association of D614G replacement with greater severity of infection • The D614G replacement is associated with higher viral loads and younger patient age, Analysis of the spread and frequency of SARS-CoV-2 D614G in the United Kingdom suggests a selective advantage for this strain that is associated with higher viral loads in younger patients but not higher COVID-19 clinical severity or mortality.

Published
2021

22. Fine-mapping, trans-ancestral and genomic analyses identify causal variants, cells, genes and drug targets for type 1 diabetes

Author

Patrick Concannon, Amy S. Shah, Linda S. Wicker, Suna Onengut-Gumuscu, Dana Dabelea, Chen W-M., Robert P. Kimberly, Jasmin Divers, David B. Dunger, Peter K. Gregersen, Jeffrey C. Edberg, Stephen S. Rich, Huan Yang, Santica M. Marcovina, Antony J. Cutler, S L Bridges, Marian Rewers, Carla J. Greenbaum, Flemming Pociot, Jorge R. Oksenberg, Jean M. Lawrence, Inshaw Jrj., D F Santa Cruz, Andrea K. Steck, Panagiotis Deloukas, Mark A. Atkinson, John A. Todd, Emily Farber, Crouch Djm., Jane H. Buckner, and Catherine C. Robertson

Subjects
False discovery rate, Drug, CD4-Positive T-Lymphocytes, endocrine system diseases, media_common.quotation_subject, Gene Expression, Autoimmunity, Computational biology, Quantitative trait locus, Biology, Genetic analysis, Article, 03 medical and health sciences, Immune system, 0302 clinical medicine, Genetic variation, Drug Discovery, Protein Interaction Mapping, Genetics, medicine, Humans, Genetic Predisposition to Disease, Molecular Targeted Therapy, Allele, Gene, Alleles, 030304 developmental biology, media_common, 0303 health sciences, Type 1 diabetes, Drug discovery, Chromosome Mapping, Genetic Variation, Genomics, medicine.disease, Chromatin, 3. Good health, Diabetes Mellitus, Type 1, General Economics, Econometrics and Finance, 030217 neurology & neurosurgery
Abstract

We report the largest and most ancestrally diverse genetic study of type 1 diabetes (T1D) to date (61,427 participants), yielding 152 regions associated to false discovery rate < 0.01, including 36 regions associated to genome-wide significance for the first time. Credible sets of disease-associated variants are specifically enriched in immune cell accessible chromatin, particularly in CD4+ effector T cells. Colocalization with chromatin accessibility quantitative trait loci (QTL) in CD4+ T cells identified five regions where differences in T1D risk and chromatin accessibility are potentially driven by the same causal variant. Allele-specific chromatin accessibility further refined the set of putative causal variants with functional relevance in CD4+ T cells and integration of whole blood expression QTLs identified candidate T1D genes, providing high-yield targets for mechanistic follow-up. We highlight rs72938038 in BACH2 as a candidate causal T1D variant, where the T1D risk allele leads to decreased enhancer accessibility and BACH2 expression in T cells. Finally, we prioritise potential drug targets by integrating genetic evidence, functional genomic maps, and immune protein-protein interactions, identifying 12 genes implicated in T1D that have been targeted in clinical trials for autoimmune diseases. These findings provide an expanded genomic landscape for T1D, including proposed genetic regulatory mechanisms of T1D-associated variants and genetic support for therapeutic targets for immune intervention.

Published
2021

23. An open approach to systematically prioritize causal variants and genes at all published human GWAS trait-associated loci

Author

Edward, Mountjoy, Ellen M, Schmidt, Miguel, Carmona, Jeremy, Schwartzentruber, Gareth, Peat, Alfredo, Miranda, Luca, Fumis, James, Hayhurst, Annalisa, Buniello, Mohd Anisul, Karim, Daniel, Wright, Andrew, Hercules, Eliseo, Papa, Eric B, Fauman, Jeffrey C, Barrett, John A, Todd, David, Ochoa, Ian, Dunham, and Maya, Ghoussaini

Subjects
Epigenomics, Machine Learning, Models, Genetic, Quantitative Trait Loci, Chromosome Mapping, Humans, Genomics, Polymorphism, Single Nucleotide, Genome-Wide Association Study
Abstract

Genome-wide association studies (GWASs) have identified many variants associated with complex traits, but identifying the causal gene(s) is a major challenge. In the present study, we present an open resource that provides systematic fine mapping and gene prioritization across 133,441 published human GWAS loci. We integrate genetics (GWAS Catalog and UK Biobank) with transcriptomic, proteomic and epigenomic data, including systematic disease-disease and disease-molecular trait colocalization results across 92 cell types and tissues. We identify 729 loci fine mapped to a single-coding causal variant and colocalized with a single gene. We trained a machine-learning model using the fine-mapped genetics and functional genomics data and 445 gold-standard curated GWAS loci to distinguish causal genes from neighboring genes, outperforming a naive distance-based model. Our prioritized genes were enriched for known approved drug targets (odds ratio = 8.1, 95% confidence interval = 5.7, 11.5). These results are publicly available through a web portal ( http://genetics.opentargets.org ), enabling users to easily prioritize genes at disease-associated loci and assess their potential as drug targets.

Published
2020

24. Fc-mediated effector function contributes to the in vivo antiviral effect of an HIV neutralizing antibody

Author

Sung Hee Ko, Wei Shi, Anna Maximova, Wanwisa Promsote, Laura E. Liao, Richard A. Koup, Eli Boritz, John R. Mascola, Katharine Best, Jeffrey D. Lifson, Keenan Ernste, Mangaiarkarasi Asokan, Daniel C. Douek, Alan S. Perelson, Andrew R. Crowley, Joana Dias, Krisha McKee, Amarendra Pegu, Jianfei Hu, Xuejun Chen, Rafick Pierre Sekaly, Cuiping Liu, Slim Fourati, John-Paul Todd, David R. Ambrozak, Cassandra G Almasri, Lucio Gama, Margaret E. Ackerman, and Divya Kilam

Subjects
medicine.drug_class, Simian Acquired Immunodeficiency Syndrome, HIV Infections, HIV Antibodies, Monoclonal antibody, Virus, Viral entry, In vivo, Medicine, Animals, Humans, Neutralizing antibody, Cells, Cultured, Antibody-dependent cell-mediated cytotoxicity, Multidisciplinary, biology, business.industry, Effector, Receptors, IgG, Antibody-Dependent Cell Cytotoxicity, virus diseases, Biological Sciences, Virology, Antibodies, Neutralizing, Macaca mulatta, Disease Models, Animal, biology.protein, HIV-1, Leukocytes, Mononuclear, Fc-Gamma Receptor, Simian Immunodeficiency Virus, business
Abstract

Treatment of HIV infection with either antiretroviral (ARV) therapy or neutralizing monoclonal antibodies (NAbs) leads to a reduction in HIV plasma virus. Both ARVs and NAbs prevent new rounds of viral infection, but NAbs may have the additional capacity to accelerate the loss of virus-infected cells through Fc gamma receptor (FcγR)-mediated effector functions, which should affect the kinetics of plasma-virus decline. Here, we formally test the role of effector function in vivo by comparing the rate and timing of plasma-virus clearance in response to a single-dose treatment with either unmodified NAb or those with either reduced or augmented Fc function. When infused into viremic simian HIV (SHIV)-infected rhesus macaques, there was a 21% difference in slope of plasma-virus decline between NAb and NAb with reduced Fc function. NAb engineered to increase FcγRIII binding and improve antibody-dependent cellular cytotoxicity (ADCC) in vitro resulted in arming of effector cells in vivo, yet led to viral-decay kinetics similar to NAbs with reduced Fc function. These studies show that the predominant mechanism of antiviral activity of HIV NAbs is through inhibition of viral entry, but that Fc function can contribute to the overall antiviral activity, making them distinct from standard ARVs.

Published
2020

25. CD70 expression determines the therapeutic efficacy of expanded human regulatory T cells

Author

Kathryn J. Wood, John A. Todd, Waseem Qasim, Joanna Hester, Dominik Trzupek, Ricardo C. Ferreira, Fadi Issa, Peng Hua, He L-Z., Christos Georgiadis, and R Arroyo Hornero

Subjects
0301 basic medicine, Translational immunology, Medicine (miscellaneous), High resolution, chemical and pharmacologic phenomena, Biology, T-Lymphocytes, Regulatory, Article, General Biochemistry, Genetics and Molecular Biology, In vitro stimulation, Gene Knockout Techniques, 03 medical and health sciences, 0302 clinical medicine, CRISPR-Associated Protein 9, Animals, Humans, Immune homeostasis, lcsh:QH301-705.5, Lymphocyte activation, CD70, Gene Editing, Mice, Inbred BALB C, Sequence Analysis, RNA, RNA, Forkhead Transcription Factors, hemic and immune systems, Regulatory T cells, Flow Cytometry, Peripheral blood, Tumor Necrosis Factor Receptor Superfamily, Member 7, Blockade, 030104 developmental biology, lcsh:Biology (General), 030220 oncology & carcinogenesis, Cancer research, Female, CRISPR-Cas Systems, Transcriptome, General Agricultural and Biological Sciences, Function (biology), CD27 Ligand
Abstract

Regulatory T cells (Tregs) are critical mediators of immune homeostasis. The co-stimulatory molecule CD27 is a marker of highly suppressive Tregs, although the role of the CD27-CD70 receptor-ligand interaction in Tregs is not clear. Here we show that after prolonged in vitro stimulation, a significant proportion of human Tregs gain stable CD70 expression while losing CD27. The expression of CD70 in expanded Tregs is associated with a profound loss of regulatory function and an unusual ability to provide CD70-directed co-stimulation to TCR-activated conventional T cells. Genetic deletion of CD70 or its blockade prevents Tregs from delivering this co-stimulatory signal, thus maintaining their regulatory activity. High resolution targeted single-cell RNA sequencing of human peripheral blood confirms the presence of CD27−CD70+ Treg cells. These findings have important implications for Treg-based clinical studies where cells are expanded over extended periods in order to achieve sufficient treatment doses., Regulatory T cells maintain immune homeostasis and help control development of autoimmunity and allergy. Arroyo-Hornero et al show that upon prolonged stimulation, regulatory T cells may switch to an immunostimulatory phenotype by upregulating the expression of the co-stimulatory molecule CD70.

Published
2020

26. Discovery of CD80 and CD86 as recent activation markers on regulatory T cells by protein-RNA single-cell analysis

Author

Mercede Lee, Daniel B. Rainbow, Joanne L. Jones, Leila Godfrey, Dominik Trzupek, Antony J. Cutler, John A. Todd, Lorna B. Jarvis, Dominik Aschenbrenner, Linda S. Wicker, H Uhlig, Ricardo C. Ferreira, Melanie L. Dunstan, Ferreira, Ricardo C [0000-0001-5733-3285], Apollo - University of Cambridge Repository, and Ferreira, Ricardo C. [0000-0001-5733-3285]

Subjects
Male, Proteome, lcsh:Medicine, T-Lymphocytes, Regulatory, Transcriptome, 0302 clinical medicine, Single-cell analysis, CD80, CD86, AbSeq, RNA-Seq, Genetics (clinical), 0303 health sciences, Multi-omics, Regulatory T cells (Tregs), Forkhead Transcription Factors, Cell biology, medicine.anatomical_structure, B7-1 Antigen, Molecular Medicine, Female, Antibody, Single-Cell Analysis, Adult, lcsh:QH426-470, Adolescent, Regulatory T cell, T cell, Biology, Immunophenotyping, 03 medical and health sciences, Immune system, Genetics, medicine, Humans, Molecular Biology, 030304 developmental biology, Single-cell RNA sequencing (scRNA-seq), Research, lcsh:R, CD4+ T cells, lcsh:Genetics, biology.protein, RNA, B7-2 Antigen, 030215 immunology, C-C chemokine receptor type 9 (CCR9)
Abstract

Background Traditionally, the transcriptomic and proteomic characterisation of CD4+ T cells at the single-cell level has been performed by two largely exclusive types of technologies: single-cell RNA sequencing (scRNA-seq) and antibody-based cytometry. Here, we present a multi-omics approach allowing the simultaneous targeted quantification of mRNA and protein expression in single cells and investigate its performance to dissect the heterogeneity of human immune cell populations. Methods We have quantified the single-cell expression of 397 genes at the mRNA level and up to 68 proteins using oligo-conjugated antibodies (AbSeq) in 43,656 primary CD4+ T cells isolated from the blood and 31,907 CD45+ cells isolated from the blood and matched duodenal biopsies. We explored the sensitivity of this targeted scRNA-seq approach to dissect the heterogeneity of human immune cell populations and identify trajectories of functional T cell differentiation. Results We provide a high-resolution map of human primary CD4+ T cells and identify precise trajectories of Th1, Th17 and regulatory T cell (Treg) differentiation in the blood and tissue. The sensitivity provided by this multi-omics approach identified the expression of the B7 molecules CD80 and CD86 on the surface of CD4+ Tregs, and we further demonstrated that B7 expression has the potential to identify recently activated T cells in circulation. Moreover, we identified a rare subset of CCR9+ T cells in the blood with tissue-homing properties and expression of several immune checkpoint molecules, suggestive of a regulatory function. Conclusions The transcriptomic and proteomic hybrid technology described in this study provides a cost-effective solution to dissect the heterogeneity of immune cell populations at extremely high resolution. Unexpectedly, CD80 and CD86, normally expressed on antigen-presenting cells, were detected on a subset of activated Tregs, indicating a role for these co-stimulatory molecules in regulating the dynamics of CD4+ T cell responses.

Published
2020

27. Assessing the effect of closed-loop insulin delivery from onset of type 1 diabetes in youth on residual beta-cell function compared to standard insulin therapy (CLOuD study): a randomised parallel study protocol

Author

Korey K. Hood, Nicola Trevelyan, Roman Hovorka, Fiona Margaret Campbell, John A. Todd, Daniela Elleri, Judy Sibayan, Janet M Allen, Sara Hartnell, Malgorzata E Wilinska, Atrayee Ghatak, Martin Tauschmann, Julia Lawton, Charlotte K. Boughton, Tabitha Randell, Gianluca Musolino, Elizabeth Northam, Carlo L. Acerini, Nate Cohen, David B. Dunger, Rachel E J Besser, Craig Kollman, Stephane Roze, Eleanor M. Scott, Boughton, Charlotte [0000-0003-3272-9544], Dunger, Professor David [0000-0002-2566-9304], and Apollo - University of Cambridge Repository

Subjects
medicine.medical_specialty, Adolescent, type 1 diabetes, medicine.medical_treatment, 030209 endocrinology & metabolism, Artificial pancreas, 03 medical and health sciences, 0302 clinical medicine, Insulin Infusion Systems, Internal medicine, Insulin-Secreting Cells, medicine, Humans, Hypoglycemic Agents, Insulin, Multicenter Studies as Topic, 030212 general & internal medicine, Child, Randomized Controlled Trials as Topic, Protocol (science), Glycated Hemoglobin, Type 1 diabetes, closed-loop, business.industry, Standard treatment, Blood Glucose Self-Monitoring, artificial pancreas, Parallel study, General Medicine, medicine.disease, 3. Good health, Diabetes and Endocrinology, Diabetes Mellitus, Type 1, Treatment Outcome, Basal (medicine), Metabolic control analysis, Medicine, business
Abstract

IntroductionManagement of newly diagnosed type 1 diabetes (T1D) in children and adolescents is challenging for patients, families and healthcare professionals. The objective of this study is to determine whether continued intensive metabolic control using hybrid closed-loop (CL) insulin delivery following diagnosis of T1D can preserve C-peptide secretion, a marker of residual beta-cell function, compared with standard multiple daily injections (MDI) therapy.Methods and analysisThe study adopts an open-label, multicentre, randomised, parallel design, and aims to randomise 96 participants aged 10–16.9 years, recruited within 21 days of diagnosis with T1D. Following a baseline mixed meal tolerance test (MMTT), participants will be randomised to receive 24 months treatment with conventional MDI therapy or with CL insulin delivery. A further 24-month optional extension phase will be offered to all participants to continue with the allocated treatment. The primary outcome is the between group difference in area under the stimulated C-peptide curve (AUC) of the MMTT at 12 months post diagnosis. Analyses will be conducted on an intention-to-treat basis. Key secondary outcomes are between group differences in time spent in target glucose range (3.9–10 mmol/L), glycated haemoglobin (HbA1c) and time spent in hypoglycaemia (Ethics and disseminationEthics approval has been obtained from Cambridge East Research Ethics Committee. The results will be disseminated by peer-reviewed publications and conference presentations.Trial registration numberNCT02871089; Pre-results.

Published
2020

28. Potent anti-viral activity of a trispecific HIV neutralizing antibody in SHIV-infected monkeys

Author

Amarendra Pegu, Ling Xu, Megan E. DeMouth, Giulia Fabozzi, Kylie March, Cassandra G. Almasri, Michelle D. Cully, Keyun Wang, Eun Sung Yang, Joana Dias, Christine M. Fennessey, Jason Hataye, Ronnie R. Wei, Ercole Rao, Joseph P. Casazza, Wanwisa Promsote, Mangaiarkarasi Asokan, Krisha McKee, Stephen D. Schmidt, Xuejun Chen, Cuiping Liu, Wei Shi, Hui Geng, Kathryn E. Foulds, Shing-Fen Kao, Amy Noe, Hui Li, George M. Shaw, Tongqing Zhou, Constantinos Petrovas, John-Paul Todd, Brandon F. Keele, Jeffrey D. Lifson, Nicole A. Doria-Rose, Richard A. Koup, Zhi-yong Yang, Gary J. Nabel, and John R. Mascola

Subjects
THP-1 Cells, Simian Acquired Immunodeficiency Syndrome, virus diseases, CD8-Positive T-Lymphocytes, HIV Antibodies, Antiviral Agents, Macaca mulatta, Article, General Biochemistry, Genetics and Molecular Biology, Cell Line, Tumor, HIV-1, Animals, Humans, Simian Immunodeficiency Virus, Immunotherapy, Viremia, Broadly Neutralizing Antibodies, Immune Evasion
Abstract

Broadly neutralizing antibodies (bNAbs) represent an alternative to drug therapy for the treatment of HIV-1 infection. Immunotherapy with single bNAbs often leads to emergence of escape variants, suggesting a potential benefit of combination bNAb therapy. Here, a trispecific bNAb reduces viremia 100- to 1000-fold in viremic SHIV-infected macaques. After treatment discontinuation, viremia rebounds transiently and returns to low levels, through CD8-mediated immune control. These viruses remain sensitive to the trispecific antibody, despite loss of sensitivity to one of the parental bNAbs. Similarly, the trispecific bNAb suppresses the emergence of resistance in viruses derived from HIV-1-infected subjects, in contrast to parental bNAbs. Trispecific HIV-1 neutralizing antibodies, therefore, mediate potent antiviral activity in vivo and may minimize the potential for immune escape.

Published
2022

29. Surface-Matrix Screening Identifies Semi-specific Interactions that Improve Potency of a Near Pan-reactive HIV-1-Neutralizing Antibody

Author

Ivelin S. Georgiev, Diana G. Scorpio, Peter D. Kwong, Robert T. Bailer, John R. Mascola, Nicole A. Doria-Rose, Mangaiarkarasi Asokan, Young Do Kwon, Slobodanka D. Manceva, Kshitij Wagh, Baoshan Zhang, Krisha McKee, Vivian Jin, Mikyung Kim, Xuejun Chen, Misook Choe, Lisa A. Kueltzo, John-Paul Todd, Marie Pancera, Mark K. Louder, Sijy O'Dell, Reda Rawi, Tatyana Gindin, Ellis L. Reinherz, Rajoshi Chaudhuri, Stephen D. Schmidt, Lawrence Shapiro, Gwo-Yu Chuang, Bette Korber, Keyun Wang, Bob C. Lin, Amarendra Pegu, and Mark Connors

Subjects
0301 basic medicine, Arginine, Mutant, HIV Antibodies, surface-matrix screening, Article, General Biochemistry, Genetics and Molecular Biology, Neutralization, broadly neutralizing antibody, 03 medical and health sciences, Antigen, Neutralization Tests, Polysaccharides, Humans, Potency, Neutralizing antibody, lcsh:QH301-705.5, membrane-proximal external region, biology, Chemistry, antibody improvement, Cell Membrane, Viral membrane, Antibodies, Neutralizing, HIV Envelope Protein gp41, MPER, 030104 developmental biology, lcsh:Biology (General), Biochemistry, HIV-1, biology.protein, Antibody, Half-Life, Protein Binding
Abstract

SUMMARY Highly effective HIV-1-neutralizing antibodies could have utility in the prevention or treatment of HIV-1 infection. To improve the potency of 10E8, an antibody capable of near pan-HIV-1 neutralization, we engineered 10E8-surface mutants and screened for improved neutralization. Variants with the largest functional enhancements involved the addition of hydrophobic or positively charged residues, which were positioned to interact with viral membrane lipids or viral glycan-sialic acids, respectively. In both cases, the site of improvement was spatially separated from the region of antibody mediating molecular contact with the protein component of the antigen, thereby improving peripheral semi-specific interactions while maintaining unmodified dominant contacts responsible for broad recognition. The optimized 10E8 antibody, with mutations to phenylalanine and arginine, retained the extraordinary breadth of 10E8 but with ~10-fold increased potency. We propose surface-matrix screening as a general method to improve antibodies, with improved semi-specific interactions between antibody and antigen enabling increased potency without compromising breadth., In Brief Antibodies could impact the treatment and prevention of HIV-1 if they were sufficiently potent to allow cost-effective delivery. Kwon et al. used a surface-matrix screening approach to improve the potency of antibody 10E8 by ~10-fold. The improved antibody, 10E8v4-5R+100cF, has among the best breadth and potency of current HIV-1-neutralizing antibodies.

Published
2018

30. Using de novo assembly to identify structural variation of eight complex immune system gene regions

Author

John A. Todd, Justin P. Whalley, Julian C. Knight, Andrew Brown, Hannah E. Roberts, Emma Betteridge, David S. C. Flores, Jia-Yuan Zhang, Antony J. Cutler, Karen Oliver, Barbara Xella, Gavin Band, Olga Mielczarek, Craig Corton, Rachael Bashford-Rogers, Helen Lockstone, and David Buck

Subjects
Heredity, Physiology, Gene Expression, Sequence assembly, Immune Receptors, Biochemistry, Database and Informatics Methods, 0302 clinical medicine, Receptors, KIR, HLA Antigens, Heterochromatin, Immune Physiology, Medicine and Health Sciences, Immunogenetic Phenomena, Biology (General), Segmental duplication, 0303 health sciences, Immune System Proteins, Heterozygosity, Ecology, Chromosome Biology, High-Throughput Nucleotide Sequencing, Genomics, Chromatin, Genetic Mapping, Computational Theory and Mathematics, Modeling and Simulation, Epigenetics, Sequence Analysis, Algorithms, Research Article, Signal Transduction, DNA Copy Number Variations, Bioinformatics, QH301-705.5, Immunology, Receptors, Antigen, T-Cell, Immunoglobulins, Sequence alignment, Computational biology, Human leukocyte antigen, Biology, Research and Analysis Methods, Antibodies, Structural variation, 03 medical and health sciences, Cellular and Molecular Neuroscience, Genetics, Humans, Molecular Biology, Ecology, Evolution, Behavior and Systematics, 030304 developmental biology, Genome, Human, Haplotype, Biology and Life Sciences, Proteins, Computational Biology, Genetic Variation, Cell Biology, Sequence Analysis, DNA, T Cell Receptors, Haplotypes, Immune System, Nanopore sequencing, Sequence Alignment, 030217 neurology & neurosurgery
Abstract

Driven by the necessity to survive environmental pathogens, the human immune system has evolved exceptional diversity and plasticity, to which several factors contribute including inheritable structural polymorphism of the underlying genes. Characterizing this variation is challenging due to the complexity of these loci, which contain extensive regions of paralogy, segmental duplication and high copy-number repeats, but recent progress in long-read sequencing and optical mapping techniques suggests this problem may now be tractable. Here we assess this by using long-read sequencing platforms from PacBio and Oxford Nanopore, supplemented with short-read sequencing and Bionano optical mapping, to sequence DNA extracted from CD14+ monocytes and peripheral blood mononuclear cells from a single European individual identified as HV31. We use this data to build a de novo assembly of eight genomic regions encoding four key components of the immune system, namely the human leukocyte antigen, immunoglobulins, T cell receptors, and killer-cell immunoglobulin-like receptors. Validation of our assembly using k-mer based and alignment approaches suggests that it has high accuracy, with estimated base-level error rates below 1 in 10 kb, although we identify a small number of remaining structural errors. We use the assembly to identify heterozygous and homozygous structural variation in comparison to GRCh38. Despite analyzing only a single individual, we find multiple large structural variants affecting core genes at all three immunoglobulin regions and at two of the three T cell receptor regions. Several of these variants are not accurately callable using current algorithms, implying that further methodological improvements are needed. Our results demonstrate that assessing haplotype variation in these regions is possible given sufficiently accurate long-read and associated data. Continued reductions in the cost of these technologies will enable application of these methods to larger samples and provide a broader catalogue of germline structural variation at these loci, an important step toward making these regions accessible to large-scale genetic association studies., Author summary The human immune system is incredibly versatile underlying its capacity to defend the body against thousands of pathogens. At a molecular level, it recognizes pathogens using large libraries of antibodies and related protein receptors. These molecules are encoded by gene families that are particularly difficult to analyze due to their unusually complex patterns of similarities and differences between genes and individuals. To overcome this, we applied several sequencing methods to DNA from a single individual and developed methods to reconstruct the underlying sequence at eight of the immune-associated regions. Importantly, we used DNA extracted from monocytes to avoid capturing the further rearrangements that occur in active immune cells. We generated accurate assemblies by integrating multiple complementary data types, although we noted a small subset of locations that remain challenging. Moreover, we found that this individual contains multiple structural differences between the two inherited chromosomes and compared to previously analyzed genomes, affecting the copy number of immune system genes. Application of these methods in larger numbers of individuals will clearly uncover much more variation than is currently known, and might lead to new understanding of the effect of genetic variation on the broad range of human diseases determined by the immune response.

Published
2021

31. Trispecific broadly neutralizing HIV antibodies mediate potent SHIV protection in macaques

Author

Zachary Mankoff, Ronnie Wei, Dennis R. Burton, Krisha McKee, Dana M. Lord, Richard A. Koup, Christian Lange, Wulf Dirk Leuschner, Keyun Wang, Mario Roederer, Stephen D. Schmidt, Tongqing Zhou, Dan H. Barouch, Rebecca Sendak, Lawrence J. Tartaglia, Sijy O'Dell, Zhi Yong Yang, Misook Choe, Robert T. Bailer, Lan Wu, John R. Mascola, Mangaiarkarasi Asokan, Young Do Kwon, Amarendra Pegu, Ercole Rao, Ling Xu, Mark Connors, Peter D. Kwong, Jochen Kruip, Xuejun Chen, John-Paul Todd, Gejing Deng, Mark K. Louder, Gary J. Nabel, Nicole A. Doria-Rose, Christian Beil, and Jochen Beninga

Subjects
0301 basic medicine, Glycan, CD4 antigen, Simian Acquired Immunodeficiency Syndrome, HIV Antibodies, Crystallography, X-Ray, Protein Engineering, medicine.disease_cause, Autoimmunity, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Immunity, medicine, Animals, Humans, Binding site, AIDS Vaccines, Multidisciplinary, biology, Protein engineering, Antibodies, Neutralizing, Macaca mulatta, Virology, 030104 developmental biology, chemistry, 030220 oncology & carcinogenesis, CD4 Antigens, Immunology, HIV-1, biology.protein, Antibody
Abstract

A triple threat for HIV The HIV virus continually evolves tricks to evade elimination by the host. Prevention and a cure will likely rely on broadly neutralizing antibodies that can recognize and conquer multiple viral strains or subtypes. Xu et al. engineered a single antibody molecule to recognize three highly conserved proteins needed for HIV infection (see the Perspective by Cohen and Corey). This “trispecific” antibody uses two sites (V1V2 and MPER) to bind HIV-infected cells, while the third site (CD4bs) recruits killer T lymphocytes that can eliminate the virus. When tested against >200 different HIV strains, trispecific antibodies were highly potent and broadly neutralized ∼99% of HIV viruses. This approach could potentially simplify HIV treatment regimens and improve therapy response. Science , this issue p. 85 ; see also p. 46

Published
2017

32. The chromosome 6q22.33 region is associated with age at diagnosis of type 1 diabetes and disease risk in those diagnosed under 5 years of age

Author

Neil Walker, Jamie Inshaw, Chris Wallace, John A. Todd, Leonardo Bottolo, Wallace, Chris [0000-0001-9755-1703], Bottolo, Leonardo [0000-0002-6381-2327], and Apollo - University of Cambridge Repository

Subjects
Adult, Male, 0301 basic medicine, medicine.medical_specialty, Pathology, type 1 diabetes, Endocrinology, Diabetes and Metabolism, Age at diagnosis, Disease, genetic risk, medicine.disease_cause, Polymorphism, Single Nucleotide, Article, Chromosomes, Autoimmunity, 03 medical and health sciences, Immune system, Internal medicine, Internal Medicine, medicine, Humans, SNP, Genetic Predisposition to Disease, Gene, Type 1 diabetes, business.industry, Chromosome, Middle Aged, medicine.disease, 3. Good health, Diabetes Mellitus, Type 1, 030104 developmental biology, Haplotypes, age at diagnosis, Female, business, early diagnosis
Abstract

Aims/hypothesis The genetic risk of type 1 diabetes has been extensively studied. However, the genetic determinants of age at diagnosis (AAD) of type 1 diabetes remain relatively unexplained. Identification of AAD genes and pathways could provide insight into the earliest events in the disease process. Methods Using ImmunoChip data from 15,696 cases, we aimed to identify regions in the genome associated with AAD. Results Two regions were convincingly associated with AAD (p 0.001), the SNP most associated with AAD, rs72975913, was associated with susceptibility to type 1 diabetes in those individuals diagnosed at less than 5 years old (p = 2.3 × 10−9). Conclusion/interpretation PTPRK and its neighbour THEMIS are required for early development of the thymus, which we can assume influences the initiation of autoimmunity. Non-HLA genes may only be detectable as risk factors for the disease in individuals diagnosed under the age 5 years because, after that period of immune development, their role in disease susceptibility has become redundant. Electronic supplementary material The online version of this article (10.1007/s00125-017-4440-y) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

Published
2017

33. Quantification of the Impact of the HIV-1-Glycan Shield on Antibody Elicitation

Author

Michael Chambers, Chen-Hsiang Shen, Adrian B. McDermott, Barton F. Haynes, Leonidas Stamatatos, Marie Pancera, Yaroslav Tsybovsky, Diana G. Scorpio, Mark K. Louder, M. Gordon Joyce, Cinque Soto, Timothy G. Wanninger, Nicole A. Doria-Rose, Tongqing Zhou, Ivelin S. Georgiev, Baoshan Zhang, Lei Chen, Mallika Sastry, Stephen D. Schmidt, Guillaume Stewart-Jones, Rita E. Chen, Lawrence Shapiro, Peng Zhao, Reda Rawi, Kai Xu, Thomas Lemmin, Sandeep Narpala, Young Do Kwon, Sijy O'Dell, Anqi Zheng, John-Paul Todd, John R. Mascola, Krisha McKee, Peter D. Kwong, Cheng Cheng, Aliaksandr Druz, Kathryn E. Foulds, Hui Geng, Lance Wells, Yongping Yang, Gwo-Yu Chuang, Michael Tiemeyer, and S. Katie Farney

Subjects
immunogen design, 0301 basic medicine, crystal structure, Glycan, Glycosylation, glycan shield, Guinea Pigs, envelope glycoprotein, Heterologous, HIV Antibodies, Molecular Dynamics Simulation, immunogenicity, Crystallography, X-Ray, General Biochemistry, Genetics and Molecular Biology, Neutralization, Epitope, glycomics, Glycomics, Epitopes, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Antibody Specificity, Polysaccharides, Animals, Humans, CD4-binding site, Protein Structure, Quaternary, lcsh:QH301-705.5, Binding Sites, biology, Immunogenicity, env Gene Products, Human Immunodeficiency Virus, targeted deglycosylation, Antibodies, Neutralizing, Macaca mulatta, Virology, carbohydrates (lipids), 030104 developmental biology, lcsh:Biology (General), chemistry, CD4 Antigens, HIV-1, vaccine design, biology.protein, Immunization, Antibody, 030217 neurology & neurosurgery
Abstract

While the HIV-1-glycan shield is known to shelter Env from the humoral immune response, its quantitative impact on antibody elicitation has been unclear. Here, we use targeted deglycosylation to measure the impact of the glycan shield on elicitation of antibodies against the CD4 supersite. We engineered diverse Env trimers with select glycans removed proximal to the CD4 supersite, characterized their structures and glycosylation, and immunized guinea pigs and rhesus macaques. Immunizations yielded little neutralization against wild-type viruses but potent CD4-supersite neutralization (titers 1: >1,000,000 against four-glycan-deleted autologous viruses with over 90% breadth against four-glycan-deleted heterologous strains exhibiting tier 2 neutralization character). To a first approximation, the immunogenicity of the glycan-shielded protein surface was negligible, with Env-elicited neutralization (ID50) proportional to the exponential of the protein-surface area accessible to antibody. Based on these high titers and exponential relationship, we propose site-selective deglycosylated trimers as priming immunogens to increase the frequency of site-targeting antibodies.

Published
2017

34. Extensive brain masses and cavitary lung lesions associated with toxoplasmosis and acquired immunodeficiency syndrome

Author

Firas Al-Delfi, Folusakin Ayoade, John R. Todd, and John King

Subjects
Male, Pathology, medicine.medical_specialty, Pyridones, Toxoplasma encephalitis, Antiprotozoal Agents, Leucovorin, Antibodies, Protozoan, Dermatology, Polymerase Chain Reaction, Piperazines, 03 medical and health sciences, 0302 clinical medicine, Anti-Infective Agents, Acquired immunodeficiency syndrome (AIDS), Oxazines, medicine, Humans, Pharmacology (medical), In patient, 030212 general & internal medicine, Cd4 cell count, Acquired Immunodeficiency Syndrome, Lung, AIDS-Related Opportunistic Infections, business.industry, Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination, Public Health, Environmental and Occupational Health, Brain, Middle Aged, medicine.disease, Magnetic Resonance Imaging, Toxoplasmosis, CD4 Lymphocyte Count, Treatment Outcome, Infectious Diseases, medicine.anatomical_structure, Toxoplasmosis, Cerebral, Immunology, Brain lesions, business, Heterocyclic Compounds, 3-Ring, Toxoplasma, 030217 neurology & neurosurgery
Abstract

Toxoplasmosis is an important cause of enhancing brain lesions in patients with acquired immunodeficiency syndrome (AIDS), and it is typically associated with low CD4-lymphocyte counts. Extensive toxoplasma encephalitis when the CD4-lymphocyte count is above 100 cells/µl is unusual. Cavitary lung lesions are also not typically associated with toxoplasmosis. Here, we present a case of toxoplasmosis associated with extensive brain masses and cavitary lung lesions, both of which improved with directed toxoplasmosis therapy, in an AIDS patient with a CD4 cell count of 120 cells/µl.

Published
2017

35. Beta-Cell Fragility As a Common Underlying Risk Factor in Type 1 and Type 2 Diabetes

Author

Vasiliki Lagou, Adrian Liston, and John A. Todd

Subjects
0301 basic medicine, medicine.medical_specialty, Type 2 diabetes, Biology, medicine.disease_cause, Autoimmunity, 03 medical and health sciences, Fragility, Risk Factors, Insulin-Secreting Cells, Internal medicine, Diabetes mellitus, medicine, Animals, Humans, Metabolic Stress, Risk factor, Beta (finance), Molecular Biology, medicine.disease, Diabetes Mellitus, Type 1, Glucose, 030104 developmental biology, Endocrinology, Diabetes Mellitus, Type 2, Immunology, Molecular Medicine, Beta cell
Abstract

Type 1 and type 2 diabetes are distinct clinical entities primarily driven by autoimmunity and metabolic dysfunction, respectively. However, there is a growing appreciation that they may share an etiopathological factor, namely the role of variation in beta-cell sensitivity to stress factors. Increased sensitivity increases the risk of beta-cell death or insulin secretion dysfunction. The beta-cell fragility model proposes that this variation contributes to the risk of developing either type 1 or type 2 diabetes, in the presence of immunological and/or metabolic stress factors. Therapeutics that increase the resistance of beta cells to these factors and decreasing fragility may constitute a new class of anti-diabetogenics, with potential use across both diseases.

Published
2017

36. Genetic Variants Predisposing Most Strongly to Type 1 Diabetes Diagnosed Under Age 7 Years Lie Near Candidate Genes That Function in the Immune System and in Pancreatic β-Cells

Author

Linda S. Wicker, Antony J. Cutler, John A. Todd, Jamie Inshaw, and Crouch Djm.

Subjects
Adult, Male, Candidate gene, Adolescent, Genotype, Endocrinology, Diabetes and Metabolism, 030209 endocrinology & metabolism, Human leukocyte antigen, 03 medical and health sciences, Islets of Langerhans, Young Adult, 0302 clinical medicine, Immune system, Diabetes mellitus, Insulin-Secreting Cells, Commentaries, Internal Medicine, Medicine, Humans, Genetic Predisposition to Disease, 030212 general & internal medicine, Allele, Age of Onset, Child, Alleles, Autoantibodies, Advanced and Specialized Nursing, Type 1 diabetes, Polymorphism, Genetic, business.industry, Infant, Newborn, Infant, Middle Aged, medicine.disease, IKZF3, Interleukin 10, Diabetes Mellitus, Type 1, Haplotypes, Case-Control Studies, Child, Preschool, Immune System, Immunology, Female, business
Abstract

OBJECTIVE Immunohistological analyses of pancreata from patients with type 1 diabetes suggest distinct autoimmune islet β-cell pathology between those diagnosed at RESEARCH DESIGN AND METHODS Using multinomial logistic regression models, we tested if known type 1 diabetes loci (17 within the HLA and 55 non-HLA loci) had significantly stronger effect sizes in the RESULTS Six HLA haplotypes/classical alleles and six non-HLA regions, one of which functions specifically in β-cells (GLIS3) and the other five likely affecting key T-cell (IL2RA, IL10, IKZF3, and THEMIS), thymus (THEMIS), and B-cell development/functions (IKZF3 and IL10) or in both immune and β-cells (CTSH), showed evidence for stronger effects in the CONCLUSIONS A subset of type 1 diabetes–associated variants are more prevalent in children diagnosed under the age of 7 years and are near candidate genes that act in both pancreatic β- and immune cells.

Published
2019

37. Type 1 Diabetes Prevention: A Goal Dependent on Accepting a Diagnosis of an Asymptomatic Disease

Author

Alvin C. Powers, John A. Todd, Ezio Bonifacio, Anette-G. Ziegler, Leonard C. Harrison, Mark A. Atkinson, and Apollo - University of Cambridge Repository

Subjects
Blood Glucose, medicine.medical_specialty, Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, Population, 030209 endocrinology & metabolism, Disease, 03 medical and health sciences, 0302 clinical medicine, Diabetes mellitus, Internal Medicine, medicine, Humans, Insulin, 030212 general & internal medicine, Disease management (health), education, Intensive care medicine, Asymptomatic Diseases, Type 1 diabetes, education.field_of_study, business.industry, Blood Glucose Self-Monitoring, medicine.disease, 3. Good health, Surgery, Natural history, Diabetes Mellitus, Type 1, Perspectives in Diabetes, business
Abstract

Type 1 diabetes, a disease defined by absolute insulin deficiency, is considered a chronic autoimmune disorder resulting from the destruction of insulin-producing pancreatic β-cells. The incidence of childhood-onset type 1 diabetes has been increasing at a rate of 3%–5% per year globally. Despite the introduction of an impressive array of therapies aimed at improving disease management, no means for a practical “cure” exist. This said, hope remains high that any of a number of emerging technologies (e.g., continuous glucose monitoring, insulin pumps, smart algorithms), alongside advances in stem cell biology, cell encapsulation methodologies, and immunotherapy, will eventually impact the lives of those with recently diagnosed or established type 1 diabetes. However, efforts aimed at reversing insulin dependence do not address the obvious benefits of disease prevention. Hence, key “stretch goals” for type 1 diabetes research include identifying improved and increasingly practical means for diagnosing the disease at earlier stages in its natural history (i.e., early, presymptomatic diagnosis), undertaking such efforts in the population at large to optimally identify those with presymptomatic type 1 diabetes, and introducing safe and effective therapeutic options for prevention.

Published
2016

38. A Method to Exploit the Structure of Genetic Ancestry Space to Enhance Case-Control Studies

Author

Corneliu A. Bodea, Benjamin M. Neale, Stephan Ripke, Mark J. Daly, Bernie Devlin, Kathryn Roeder, Murray Barclay, Laurent Peyrin-Biroulet, Mathias Chamaillard, Jean-Frederick Colombel, Mario Cottone, Anthony Croft, Renata D’Incà, Jonas Halfvarson, Katherine Hanigan, Paul Henderson, Jean-Pierre Hugot, Amir Karban, Nicholas A. Kennedy, Mohammed Azam Khan, Marc Lémann, Arie Levine, Dunecan Massey, Monica Milla, Grant W. Montgomery, Sok Meng Evelyn Ng, Ioannis Oikonomou, Harald Peeters, Deborah D. Proctor, Jean-Francois Rahier, Rebecca Roberts, Paul Rutgeerts, Frank Seibold, Laura Stronati, Kirstin M. Taylor, Leif Törkvist, Kullak Ublick, Johan Van Limbergen, Andre Van Gossum, Morten H. Vatn, Hu Zhang, Wei Zhang, Jane M. Andrews, Peter A. Bampton, Timothy H. Florin, Richard Gearry, Krupa Krishnaprasad, Ian C. Lawrance, Gillian Mahy, Graham Radford-Smith, Rebecca L. Roberts, Lisa A. Simms, Leila Amininijad, Isabelle Cleynen, Olivier Dewit, Denis Franchimont, Michel Georges, Debby Laukens, Emilie Theatre, André Van Gossum, Severine Vermeire, Guy Aumais, Leonard Baidoo, Arthur M. Barrie, Karen Beck, Edmond-Jean Bernard, David G. Binion, Alain Bitton, Steve R. Brant, Judy H. Cho, Albert Cohen, Kenneth Croitoru, Lisa W. Datta, Colette Deslandres, Richard H. Duerr, Debra Dutridge, John Ferguson, Joann Fultz, Philippe Goyette, Gordon R. Greenberg, Talin Haritunians, Gilles Jobin, Seymour Katz, Raymond G. Lahaie, Dermot P. McGovern, Linda Nelson, Sok Meng Ng, Kaida Ning, Pierre Paré, Miguel D. Regueiro, John D. Rioux, Elizabeth Ruggiero, L. Philip Schumm, Marc Schwartz, Regan Scott, Yashoda Sharma, Mark S. Silverberg, Denise Spears, A. Hillary Steinhart, Joanne M. Stempak, Jason M. Swoger, Constantina Tsagarelis, Clarence Zhang, Hongyu Zhao, Jan Aerts, Tariq Ahmad, Hazel Arbury, Anthony Attwood, Adam Auton, Stephen G. Ball, Anthony J. Balmforth, Chris Barnes, Jeffrey C. Barrett, Inês Barroso, Anne Barton, Amanda J. Bennett, Sanjeev Bhaskar, Katarzyna Blaszczyk, John Bowes, Oliver J. Brand, Peter S. Braund, Francesca Bredin, Gerome Breen, Morris J. Brown, Ian N. Bruce, Jaswinder Bull, Oliver S. Burren, John Burton, Jake Byrnes, Sian Caesar, Niall Cardin, Chris M. Clee, Alison J. Coffey, John M.C. Connell, Donald F. Conrad, Jason D. Cooper, Anna F. Dominiczak, Kate Downes, Hazel E. Drummond, Darshna Dudakia, Andrew Dunham, Bernadette Ebbs, Diana Eccles, Sarah Edkins, Cathryn Edwards, Anna Elliot, Paul Emery, David M. Evans, Gareth Evans, Steve Eyre, Anne Farmer, Nicol Ferrier, Edward Flynn, Alistair Forbes, Liz Forty, Jayne A. Franklyn, Timothy M. Frayling, Rachel M. Freathy, Eleni Giannoulatou, Polly Gibbs, Paul Gilbert, Katherine Gordon-Smith, Emma Gray, Elaine Green, Chris J. Groves, Detelina Grozeva, Rhian Gwilliam, Anita Hall, Naomi Hammond, Matt Hardy, Pile Harrison, Neelam Hassanali, Husam Hebaishi, Sarah Hines, Anne Hinks, Graham A. Hitman, Lynne Hocking, Chris Holmes, Eleanor Howard, Philip Howard, Joanna M.M. Howson, Debbie Hughes, Sarah Hunt, John D. Isaacs, Mahim Jain, Derek P. Jewell, Toby Johnson, Jennifer D. Jolley, Ian R. Jones, Lisa A. Jones, George Kirov, Cordelia F. Langford, Hana Lango-Allen, G. Mark Lathrop, James Lee, Kate L. Lee, Charlie Lees, Kevin Lewis, Cecilia M. Lindgren, Meeta Maisuria-Armer, Julian Maller, John Mansfield, Jonathan L. Marchini, Paul Martin, Dunecan C.O. Massey, Wendy L. McArdle, Peter McGuffin, Kirsten E. McLay, Gil McVean, Alex Mentzer, Michael L. Mimmack, Ann E. Morgan, Andrew P. Morris, Craig Mowat, Patricia B. Munroe, Simon Myers, William Newman, Elaine R. Nimmo, Michael C. O’Donovan, Abiodun Onipinla, Nigel R. Ovington, Michael J. Owen, Kimmo Palin, Aarno Palotie, Kirstie Parnell, Richard Pearson, David Pernet, John R.B. Perry, Anne Phillips, Vincent Plagnol, Natalie J. Prescott, Inga Prokopenko, Michael A. Quail, Suzanne Rafelt, Nigel W. Rayner, David M. Reid, Anthony Renwick, Susan M. Ring, Neil Robertson, Samuel Robson, Ellie Russell, David St Clair, Jennifer G. Sambrook, Jeremy D. Sanderson, Stephen J. Sawcer, Helen Schuilenburg, Carol E. Scott, Richard Scott, Sheila Seal, Sue Shaw-Hawkins, Beverley M. Shields, Matthew J. Simmonds, Debbie J. Smyth, Elilan Somaskantharajah, Katarina Spanova, Sophia Steer, Jonathan Stephens, Helen E. Stevens, Kathy Stirrups, Millicent A. Stone, David P. Strachan, Zhan Su, Deborah P.M. Symmons, John R. Thompson, Wendy Thomson, Martin D. Tobin, Mary E. Travers, Clare Turnbull, Damjan Vukcevic, Louise V. Wain, Mark Walker, Neil M. Walker, Chris Wallace, Margaret Warren-Perry, Nicholas A. Watkins, John Webster, Michael N. Weedon, Anthony G. Wilson, Matthew Woodburn, B. Paul Wordsworth, Chris Yau, Allan H. Young, Eleftheria Zeggini, Matthew A. Brown, Paul R. Burton, Mark J. Caulfield, Alastair Compston, Martin Farrall, Stephen C.L. Gough, Alistair S. Hall, Andrew T. Hattersley, Adrian V.S. Hill, Christopher G. Mathew, Marcus Pembrey, Jack Satsangi, Michael R. Stratton, Jane Worthington, Matthew E. Hurles, Audrey Duncanson, Willem H. Ouwehand, Miles Parkes, Nazneen Rahman, John A. Todd, Nilesh J. Samani, Dominic P. Kwiatkowski, Mark I. McCarthy, Nick Craddock, Panos Deloukas, Peter Donnelly, Jenefer M. Blackwell, Elvira Bramon, Juan P. Casas, Aiden Corvin, Janusz Jankowski, Hugh S. Markus, Colin N.A. Palmer, Robert Plomin, Anna Rautanen, Richard C. Trembath, Ananth C. Viswanathan, Nicholas W. Wood, Chris C.A. Spencer, Gavin Band, Céline Bellenguez, Colin Freeman, Garrett Hellenthal, Matti Pirinen, Amy Strange, Hannah Blackburn, Suzannah J. Bumpstead, Serge Dronov, Matthew Gillman, Alagurevathi Jayakumar, Owen T. McCann, Jennifer Liddle, Simon C. Potter, Radhi Ravindrarajah, Michelle Ricketts, Matthew Waller, Paul Weston, Sara Widaa, Pamela Whittaker, UCL - SSS/IREC/GAEN - Pôle d'Hépato-gastro-entérologie, UCL - (MGD) Service de gastro-entérologie, Institute for Molecular Medicine Finland, Aarno Palotie / Principal Investigator, and Genomics of Neurological and Neuropsychiatric Disorders

Subjects
0301 basic medicine, Heredity, Genetics, Genetics (clinical), Computer science, Genetic Linkage, Genome-wide association study, VARIANTS, 030105 genetics & heredity, computer.software_genre, Bayes' theorem, Gene Frequency, HISTORY, IMPUTATION, False positive paradox, Genetics(clinical), Disease, 0303 health sciences, education.field_of_study, 030305 genetics & heredity, Inheritance (genetic algorithm), Genotype, DATABASE, Genetic genealogy, POWER, Population, Genomics, POPULATION STRATIFICATION, Biology, INHERITANCE, Population stratification, Machine learning, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, Humans, Genetic Predisposition to Disease, GENOME-WIDE ASSOCIATION, education, Allele frequency, FAMILY-BASED ASSOCIATION, 030304 developmental biology, Genetic association, business.industry, Bayes Theorem, DISEASE ASSOCIATION, Human genetics, Hierarchical clustering, Genetics, Population, 030104 developmental biology, Case-Control Studies, 3111 Biomedicine, Artificial intelligence, business, computer, Software, Imputation (genetics)
Abstract

A. Palotie on työryhmän Int IBD Genetics Consortium jäsen. One goal of human genetics is to understand the genetic basis of disease, a challenge for diseases of complex inheritance because risk alleles are few relative to the vast set of benign variants. Risk variants are often sought by association studies in which allele frequencies in case subjects are contrasted with those from population-based samples used as control subjects. In an ideal world we would know population-level allele frequencies, releasing researchers to focus on case subjects. We argue this ideal is possible, at least theoretically, and we outline a path to achieving it in reality. If such a resource were to exist, it would yield ample savings and would facilitate the effective use of data repositories by removing administrative and technical barriers. We call this concept the Universal Control Repository Network (UNICORN), a means to perform association analyses without necessitating direct access to individual-level control data. Our approach to UNICORN uses existing genetic resources and various statistical tools to analyze these data, including hierarchical clustering with spectral analysis of ancestry; and empirical Bayesian analysis along with Gaussian spatial processes to estimate ancestry-specific allele frequencies. We demonstrate our approach using tens of thousands of control subjects from studies of Crohn disease, showing how it controls false positives, provides power similar to that achieved when all control data are directly accessible, and enhances power when control data are limiting or even imperfectly matched ancestrally. These results highlight how UNICORN can enable reliable, powerful, and convenient genetic association analyses without access to the individual-level data.

Published
2016

39. Structure-based design of a quadrivalent fusion glycoprotein vaccine for human parainfluenza virus types 1-4

Author

Baoshan Zhang, Bridget Carragher, Yongping Yang, Paul V. Thomas, Kai Xu, Ulrich Baxa, Peter D. Kwong, Li Ou, Andres M. Salazar, Yaroslav Tsybovsky, Guillaume Stewart-Jones, Diana G. Scorpio, Clinton S. Potter, Gwo-Yu Chuang, Tongqing Zhou, Wing-Pui Kong, Kathryn E. Foulds, Martina Beltramello, Chiara Silacci-Fregni, Valentina Gilardi, Antonio Lanzavecchia, John-Paul Todd, Davide Corti, Blanca Fernandez-Rodriguez, Hui Wei, John R. Mascola, Priyamvada Acharya, and Aliaksandr Druz

Subjects
0301 basic medicine, Male, Immunogen, Respiratory Syncytial Virus Infections, Antibodies, Viral, Respirovirus Infections, Virus, Neutralization, 03 medical and health sciences, Mice, 0302 clinical medicine, Animals, Humans, 030212 general & internal medicine, chemistry.chemical_classification, Multidisciplinary, biology, Cryoelectron Microscopy, Viral Vaccines, Biological Sciences, Virology, Antibodies, Neutralizing, Macaca mulatta, 3. Good health, Parainfluenza Virus 1, Human, Parainfluenza Virus 2, Human, Parainfluenza Virus 3, Human, Parainfluenza Virus 4, Human, Titer, Human Parainfluenza Virus, 030104 developmental biology, chemistry, Immunization, biology.protein, Female, Antibody, Glycoprotein, Viral Fusion Proteins
Abstract

Parainfluenza virus types 1–4 (PIV1–4) are highly infectious human pathogens, of which PIV3 is most commonly responsible for severe respiratory illness in newborns, elderly, and immunocompromised individuals. To obtain a vaccine effective against all four PIV types, we engineered mutations in each of the four PIV fusion (F) glycoproteins to stabilize their metastable prefusion states, as such stabilization had previously enabled the elicitation of high-titer neutralizing antibodies against the related respiratory syncytial virus. A cryoelectron microscopy structure of an engineered PIV3 F prefusion-stabilized trimer, bound to the prefusion-specific antibody PIA174, revealed atomic-level details for how introduced mutations improved stability as well as how a single PIA174 antibody recognized the trimeric apex of prefusion PIV3 F. Nine combinations of six newly identified disulfides and two cavity-filling mutations stabilized the prefusion PIV3 F immunogens and induced 200- to 500-fold higher neutralizing titers in mice than were elicited by PIV3 F in the postfusion conformation. For PIV1, PIV2, and PIV4, we also obtained stabilized prefusion Fs, for which prefusion versus postfusion titers were 2- to 20-fold higher. Elicited murine responses were PIV type-specific, with little cross-neutralization of other PIVs. In nonhuman primates (NHPs), quadrivalent immunization with prefusion-stabilized Fs from PIV1–4 consistently induced potent neutralizing responses against all four PIVs. For PIV3, the average elicited NHP titer from the quadrivalent immunization was more than fivefold higher than any titer observed in a cohort of over 100 human adults, highlighting the ability of a prefusion-stabilized immunogen to elicit especially potent neutralization.

Published
2018

40. The DILfrequency study is an adaptive trial to identify optimal IL-2 dosing in patients with type 1 diabetes

Author

Eleonora Seelig, Emma L Arbon, Marcin L. Pekalski, James Howlett, Linda S. Wicker, Adrian Mander, Neil Walker, Mark L. Evans, Linsey Porter, James Heywood, Simon Bond, Ravinder Atkar, Ed Rytina, John A. Todd, Katerina Anselmiova, Lucy Truman, Jane Kennet, Frank Waldron-Lynch, Howlett, James [0000-0001-9274-5170], Evans, Mark [0000-0001-8122-8987], Mander, Adrian [0000-0002-0742-9040], Bond, Simon [0000-0003-2528-1040], Waldron-Lynch, Frank [0000-0002-0597-4328], and Apollo - University of Cambridge Repository

Subjects
0301 basic medicine, Oncology, Adult, Male, medicine.medical_specialty, Adolescent, Autoimmune diseases, T cells, Autoimmunity, Lymphocyte Activation, T-Lymphocytes, Regulatory, Drug Administration Schedule, law.invention, 03 medical and health sciences, Young Adult, Randomized controlled trial, law, Aldesleukin, Internal medicine, Injection site reaction, Medicine, Humans, Clinical Trials, Dosing, Lymphocyte Count, Adverse effect, Aged, Type 1 diabetes, Dose-Response Relationship, Drug, business.industry, Diabetes, Interleukin-2 Receptor alpha Subunit, General Medicine, Middle Aged, medicine.disease, Recombinant Proteins, Clinical trial, Regimen, 030104 developmental biology, Diabetes Mellitus, Type 1, Treatment Outcome, Feasibility Studies, Interleukin-2, Female, Clinical Medicine, business
Abstract

BACKGROUND. Type 1 diabetes (T1D) results from loss of immune regulation, leading to the development of autoimmunity to pancreatic β cells, involving autoreactive T effector cells (Teffs). Tregs, which prevent autoimmunity, require IL-2 for maintenance of immunosuppressive functions. Using a response-adaptive design, we aimed to determine the optimal regimen of aldesleukin (recombinant human IL-2) to physiologically enhance Tregs while limiting expansion of Teffs. METHODS. DILfrequency is a nonrandomized, open-label, response-adaptive study of participants, aged 18–70 years, with T1D. The initial learning phase allocated 12 participants to 6 different predefined regimens. Then, 3 cohorts of 8 participants were sequentially allocated dose frequencies, based on repeated interim analyses of all accumulated trial data. The coprimary endpoints were percentage change in Tregs and Teffs and CD25 (α subunit of the IL-2 receptor) expression by Tregs, from baseline to steady state. RESULTS. Thirty-eight participants were enrolled, with thirty-six completing treatment. The optimal regimen to maintain a steady-state increase in Tregs of 30% and CD25 expression of 25% without Teff expansion is 0.26 × 106 IU/m2 (95% CI –0.007 to 0.485) every 3 days. Tregs and CD25 were dose-frequency responsive, Teffs were not. The commonest adverse event was injection site reaction (464 of 694 events). CONCLUSIONS. Using a response-adaptive design, aldesleukin treatment can be optimized. Our methodology can generally be employed to immediately access proof of mechanism, thereby leading to more efficient and safe drug development. TRIAL REGISTRATION. International Standard Randomised Controlled Trial Number Register, ISRCTN40319192; ClinicalTrials.gov, {"type":"clinical-trial","attrs":{"text":"NCT02265809","term_id":"NCT02265809"}}NCT02265809. FUNDING. Sir Jules Thorn Trust, the Swiss National Science Foundation, Wellcome, JDRF, and NIHR Cambridge Biomedical Research Centre.

Published
2018

41. Genomic atlas of the human plasma proteome

Author

Mihir A Kamat, Robert M. Plenge, An Chi, Nicholas W. Morrell, Adam S. Butterworth, James E. Peters, Heiko Runz, Joseph C. Maranville, James A. Blackshaw, James R Staley, Caroline S. Fox, Clare Oliver-Williams, Ellie Paige, Benjamin B. Sun, Tao Jiang, Angela M. Wood, John Danesh, John A. Todd, Stephen Burgess, John Bradley, David Stacey, Sheri K. Wilcox, Nebojsa Janjic, Narinder Bansal, Bram P. Prins, Sarah L. Spain, Willem H. Ouwehand, Praveen Surendran, Erik S Zimmerman, Nicole Soranzo, David J. Roberts, Dirk S. Paul, Karsten Suhre, Sun, Ben [0000-0001-6347-2281], Blackshaw, James [0000-0002-0343-0319], Burgess, Stephen [0000-0001-5365-8760], Surendran, Praveen [0000-0002-4911-6077], Oliver-Williams, Clare [0000-0002-3573-2426], Bansal, Narinder [0000-0002-6925-1719], Wood, Angela [0000-0002-7937-304X], Morrell, Nicholas [0000-0001-5700-9792], Bradley, John [0000-0002-7774-8805], Ouwehand, Willem [0000-0002-7744-1790], Soranzo, Nicole [0000-0003-1095-3852], Paul, Dirk [0000-0002-8230-0116], Danesh, John [0000-0003-1158-6791], Butterworth, Adam [0000-0002-6915-9015], Apollo - University of Cambridge Repository, and United Kingdom Research and Innovation

Subjects
0301 basic medicine, Male, Vasculitis, Proteome, General Science & Technology, Myeloblastin, Quantitative Trait Loci, Mutation, Missense, Genomics, Disease, Computational biology, Quantitative trait locus, Biology, medicine.disease_cause, Article, 03 medical and health sciences, 0302 clinical medicine, Proto-Oncogene Proteins, Genetic variation, medicine, Humans, Mutation, Multidisciplinary, Hepatocyte Growth Factor, Mendelian Randomization Analysis, Blood Proteins, Inflammatory Bowel Diseases, Genetic architecture, 030104 developmental biology, alpha 1-Antitrypsin, Female, Positive Regulatory Domain I-Binding Factor 1, 030217 neurology & neurosurgery
Abstract

Although plasma proteins have important roles in biological processes and are the direct targets of many drugs, the genetic factors that control inter-individual variation in plasma protein levels are not well understood. Here we characterize the genetic architecture of the human plasma proteome in healthy blood donors from the INTERVAL study. We identify 1,927 genetic associations with 1,478 proteins, a fourfold increase on existing knowledge, including trans associations for 1,104 proteins. To understand the consequences of perturbations in plasma protein levels, we apply an integrated approach that links genetic variation with biological pathway, disease, and drug databases. We show that protein quantitative trait loci overlap with gene expression quantitative trait loci, as well as with disease-associated loci, and find evidence that protein biomarkers have causal roles in disease using Mendelian randomization analysis. By linking genetic factors to diseases via specific proteins, our analyses highlight potential therapeutic targets, opportunities for matching existing drugs with new disease indications, and potential safety concerns for drugs under development.

Published
2018

42. Allele-specific methylation of type 1 diabetes susceptibility genes

Author

Eva-Maria Sedlmeier, Simone Wahl, Jan Knoop, John A. Todd, Alida S.D. Kindt, Ezio Bonifacio, Jan Krumsiek, Rory P. Wilson, Angela Hommel, Michael Laimighofer, Rainer W. Fuerst, Anette-G. Ziegler, Tanja Telieps, Markus Hippich, and Maria A. Woerheide

Subjects
0301 basic medicine, Adult, Male, Risk, musculoskeletal diseases, Autoimmunity, Epigenetics, Hla, Insulin Autoantibodies, Insulin Gene, Lactate Dehydrogenase C, Genotype, Immunology, Human leukocyte antigen, Major histocompatibility complex, Epigenesis, Genetic, 03 medical and health sciences, HLA-DQ Antigens, medicine, Immunology and Allergy, Humans, Insulin, Genetic Predisposition to Disease, skin and connective tissue diseases, Alleles, Genetic Association Studies, Aged, Autoantibodies, Genetics, Type 1 diabetes, Polymorphism, Genetic, biology, L-Lactate Dehydrogenase, Haplotype, Infant, Newborn, Infant, nutritional and metabolic diseases, Methylation, DNA Methylation, Middle Aged, medicine.disease, 030104 developmental biology, Diabetes Mellitus, Type 1, CpG site, Child, Preschool, biology.protein, Female, HLA-DRB1 Chains
Abstract

The susceptibility to autoimmune diseases is influenced by genes encoding major histocompatibility complex (MHC) proteins. By examining the epigenetic methylation maps of cord blood samples, we found marked differences in the methylation status of CpG sites within the MHC genes (cis-metQTLs) between carriers of the type 1 diabetes risk haplotypes HLA-DRB1*03-DQA1*0501-DQB1*0201 (DR3-DQ2) and HLA-DRB1*04-DQA1*0301-DQB1*0302 (DR4-DQ8). These differences were found in children and adults, and were accompanied by reduced HLA-DR protein expression in immune cells with the HLA-DR3-DQ2 haplotype. Extensive cis-metQTLs were identified in all 45 immune and non-immune type 1 diabetes susceptibility genes analyzed in this study. We observed and validated a novel association between the methylation status of CpG sites within the LDHC gene and the development of insulin autoantibodies in early childhood in children who are carriers of the highest type 1 diabetes risk genotype. Functionally relevant epigenetic changes in susceptibility genes may represent therapeutic targets for type 1 diabetes.

Published
2018

43. The plasma biomarker soluble SIGLEC-1 is associated with the type I interferon transcriptional signature, ethnic background and renal disease in systemic lupus erythematosus

Author

João J, Oliveira, Sarah, Karrar, Daniel B, Rainbow, Christopher L, Pinder, Pamela, Clarke, Arcadio, Rubio García, Osama, Al-Assar, Keith, Burling, Sian, Morris, Richard, Stratton, Tim J, Vyse, Linda S, Wicker, John A, Todd, and Ricardo C, Ferreira

Subjects
Adult, Immunoassay, Male, Interferonopathy, Sialic Acid Binding Ig-like Lectin 1, Interferon-alpha, Autoimmunity, Biomarker, Middle Aged, Soluble SIGLEC-1, Lupus Nephritis, Young Adult, Humans, Lupus Erythematosus, Systemic, Female, Transcriptome, Type I interferon, Biomarkers, Aged, Research Article
Abstract

Background The molecular heterogeneity of autoimmune and inflammatory diseases has been one of the main obstacles to the development of safe and specific therapeutic options. Here, we evaluated the diagnostic and clinical value of a robust, inexpensive, immunoassay detecting the circulating soluble form of the monocyte-specific surface receptor sialic acid binding Ig-like lectin 1 (sSIGLEC-1). Methods We developed an immunoassay to measure sSIGLEC-1 in small volumes of plasma/serum from systemic lupus erythematosus (SLE) patients (n = 75) and healthy donors (n = 504). Samples from systemic sclerosis patients (n = 99) were studied as an autoimmune control. We investigated the correlation between sSIGLEC-1 and both monocyte surface SIGLEC-1 and type I interferon-regulated gene (IRG) expression. Associations of sSIGLEC-1 with clinical features were evaluated in an independent cohort of SLE patients (n = 656). Results Plasma concentrations of sSIGLEC-1 strongly correlated with expression of SIGLEC-1 on the surface of blood monocytes and with IRG expression in SLE patients. We found ancestry-related differences in sSIGLEC-1 concentrations in SLE patients, with patients of non-European ancestry showing higher levels compared to patients of European ancestry. Higher sSIGLEC-1 concentrations were associated with lower serum complement component 3 and increased frequency of renal complications in European patients, but not with the SLE Disease Activity Index clinical score. Conclusions Our sSIGLEC-1 immunoassay provides a specific and easily assayed marker for monocyte–macrophage activation, and interferonopathy in SLE and other diseases. Further studies can extend its clinical associations and its potential use to stratify patients and as a secondary endpoint in clinical trials. Electronic supplementary material The online version of this article (10.1186/s13075-018-1649-1) contains supplementary material, which is available to authorized users.

Published
2018

44. Approaches and advances in the genetic causes of autoimmune disease and their implications

Author

M. Irina Stefana, John A. Todd, Antony J. Cutler, Jamie Inshaw, Oliver S. Burren, Burren, Oliver [0000-0002-3388-5760], and Apollo - University of Cambridge Repository

Subjects
0301 basic medicine, Autoimmune disease, Clinical study design, Microbiota, Immunology, Chromosome Mapping, Genetic Variation, Computational biology, Human physiology, Biology, medicine.disease, Infections, 3. Good health, Autoimmune Diseases, 03 medical and health sciences, Random Allocation, 030104 developmental biology, Sample Size, medicine, Disease risk, Immunology and Allergy, Humans, In patient, Genetic association, Genome-Wide Association Study
Abstract

Genome-wide association studies are transformative in revealing the polygenetic basis of common diseases, with autoimmune diseases leading the charge. Although the field is just over 10 years old, advances in understanding the underlying mechanistic pathways of these conditions, which result from a dense multifactorial blend of genetic, developmental and environmental factors, have already been informative, including insights into therapeutic possibilities. Nevertheless, the challenge of identifying the actual causal genes and pathways and their biological effects on altering disease risk remains for many identified susceptibility regions. It is this fundamental knowledge that will underpin the revolution in patient stratification, the discovery of therapeutic targets and clinical trial design in the next 20 years. Here we outline recent advances in analytical and phenotyping approaches and the emergence of large cohorts with standardized gene-expression data and other phenotypic data that are fueling a bounty of discovery and improved understanding of human physiology.

Published
2017

45. Additive and interaction effects at three amino acid positions in HLA-DQ and HLA-DR molecules drive type 1 diabetes risk

Author

John A. Todd, Tobias L. Lenz, Soumya Raychaudhuri, Joanna M. M. Howson, Xinli Hu, Aaron J. Deutsch, Buhm Han, Paul I.W. de Bakker, Wei-Min Chen, Stephen S. Rich, Suna Onengut-Gumuscu, Howson, Joanna [0000-0001-7618-0050], and Apollo - University of Cambridge Repository

Subjects
Male, Linkage disequilibrium, Genotype, Locus (genetics), Human leukocyte antigen, Biology, Research Support, Major histocompatibility complex, Polymorphism, Single Nucleotide, Article, HLA-DQ alpha-Chains, N.I.H, Genetic, Research Support, N.I.H., Extramural, Models, Risk Factors, HLA-DQ, Diabetes Mellitus, Journal Article, Genetics, HLA-DR, HLA-DQ beta-Chains, Humans, Polymorphism, Amino Acids, Non-U.S. Gov't, chemistry.chemical_classification, Models, Genetic, Research Support, Non-U.S. Gov't, Extramural, Epistasis, Genetic, Single Nucleotide, Explained variation, Amino acid, Diabetes Mellitus, Type 1, Logistic Models, Phenotype, Haplotypes, chemistry, Case-Control Studies, Epistasis, biology.protein, Female, Algorithms, Type 1, HLA-DRB1 Chains
Abstract

Variation in the human leukocyte antigen (HLA) genes accounts for one-half of the genetic risk in type 1 diabetes (T1D). Amino acid changes in the HLA-DR and HLA-DQ molecules mediate most of the risk, but extensive linkage disequilibrium complicates the localization of independent effects. Using 18,832 case-control samples, we localized the signal to 3 amino acid positions in HLA-DQ and HLA-DR. HLA-DQβ1 position 57 (previously known; P = 1 × 10(-1,355)) by itself explained 15.2% of the total phenotypic variance. Independent effects at HLA-DRβ1 positions 13 (P = 1 × 10(-721)) and 71 (P = 1 × 10(-95)) increased the proportion of variance explained to 26.9%. The three positions together explained 90% of the phenotypic variance in the HLA-DRB1-HLA-DQA1-HLA-DQB1 locus. Additionally, we observed significant interactions for 11 of 21 pairs of common HLA-DRB1-HLA-DQA1-HLA-DQB1 haplotypes (P = 1.6 × 10(-64)). HLA-DRβ1 positions 13 and 71 implicate the P4 pocket in the antigen-binding groove, thus pointing to another critical protein structure for T1D risk, in addition to the HLA-DQ P9 pocket.

Published
2015

46. Plasma endothelin-1 and cardiovascular risk among young and healthy adults

Author

Joel Estis, Stéphanie van der Lely, John A. Todd, Tobias Schoen, Martin Risch, Lorenz Risch, Stefanie Aeschbacher, David Conen, Matthias Bossard, Tschuenschen Lam, Katrin Pumpol, and Philipp Krisai

Subjects
Adult, Male, medicine.medical_specialty, Systole, Population, Renal function, Cohort Studies, Young Adult, Risk Factors, Surveys and Questionnaires, Diabetes mellitus, Internal medicine, medicine, Humans, education, Inflammation, 2. Zero hunger, education.field_of_study, Endothelin-1, business.industry, Smoking, Odds ratio, medicine.disease, Healthy Volunteers, Confidence interval, 3. Good health, Phenotype, Endocrinology, Blood pressure, Quartile, Cardiovascular Diseases, Multivariate Analysis, Female, Cardiology and Cardiovascular Medicine, business, Liechtenstein, Body mass index, Glomerular Filtration Rate
Abstract

OBJECTIVES Endothelial dysfunction is a major precursor of atherosclerosis. The aim of this study was to assess the interrelationships between plasma endothelin 1 (ET 1) levels and cardiovascular risk among young and healthy individuals. METHODS We performed a population based study among 2160 healthy adults aged between 25 and 41 years in the Principality of Liechtenstein. Individuals with prevalent cardiovascular disease diabetes or a body mass index >35 kg/m(2) were excluded. Plasma ET 1 was measured using a novel high sensitive single molecule counting technology. The relationships between plasma levels of ET 1 and various cardiovascular risk factors were assessed by multivariable regression analyses. RESULTS Median age of our population was 37 years. Median ET 1 levels across ET 1 quartiles were 1.86 2.33 2.76 and 3.48 pg/mL. After multivariable adjustment there were significant correlations of ET 1 with systolic blood pressure (ß per 1 unit increase in log transformed ET 1 2.30 (95 confidence interval (CI) 1.03; 3.58 p = 0.0004) C reactive protein (ß 0.19 (95 CI 0.03; 0.34 p = 0.021) glomerular filtration rate (ß 1.73 (95 CI 3.17; 0.29 p = 0.019) and current smoking (Odds ratio 1.94 (95 CI 1.39; 2.71 p

Published
2015

47. Relationships of kidney injury molecule-1 with renal function and cardiovascular risk factors in the general population

Author

Lorenz Risch, Martin Risch, Matthias Bossard, Pascal Meyre, Laura Bargetzi, Joel Estis, Lucien Eggimann, David Conen, Peter Egli, Steffen Blum, John A. Todd, and Stefanie Aeschbacher

Subjects
Adult, Male, medicine.medical_specialty, Clinical Biochemistry, Population, 030232 urology & nephrology, Renal function, 030204 cardiovascular system & hematology, Biochemistry, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Interquartile range, Risk Factors, Internal medicine, medicine, Humans, Hepatitis A Virus Cellular Receptor 1, education, Creatinine, Kidney, education.field_of_study, biology, business.industry, Biochemistry (medical), General Medicine, medicine.disease, Confidence interval, Healthy Volunteers, medicine.anatomical_structure, chemistry, Cystatin C, Cardiovascular Diseases, biology.protein, Regression Analysis, Female, Kidney Diseases, business, Kidney disease, Glomerular Filtration Rate
Abstract

Background Kidney injury molecule-1 (KIM-1) has been associated with kidney damage in patients with preexisting renal disease. However, little is known about the relationships of KIM-1 with renal function and cardiovascular risk factors in healthy individuals from the general population. Methods Healthy individuals aged 25–41 years were enrolled in a population-based study. Main exclusion criteria were a BMI > 35 kg/m2, preexisting kidney disease or established cardiovascular disease. KIM-1 was measured from frozen plasma samples using a high-sensitivity assay. Multivariable linear regression models were constructed to assess the relationships of KIM-1 with renal function and various cardiovascular risk factors. Results We included 2060 individuals (47% men, median (interquartile range) age: 37 (31–40) years) in this analysis. Median KIM-1 levels were 82.5 (IQR 59.4–112.7) pg/ml. We found no significant relationship of KIM-1 with creatinine (adjusted β-coefficient (95% confidence interval) 0.0005 (− 0.002; 0.003), p = 0.61) and cystatin C (− 0.02 (− 0.21; 0.17), p = 0.84). There were significant linear relationships of log-transformed KIM-1 with systolic blood pressure (adjusted β-coefficient (95% confidence interval) 0.07 (0.04; 0.09), p Conclusion Among healthy adults from the general population, plasma levels of KIM-1 were not associated with renal function but were independently related to multiple cardiovascular risk factors.

Published
2017

48. Cells with Treg-specific FOXP3 demethylation but low CD25 are prevalent in autoimmunity

Author

Xin Yang, Xaquin Castro Dopico, Henry Z. Simons, Whitney S. Thompson, Linda S. Wicker, Natalia Savinykh, Antony J. Cutler, João J. Oliveira, Ricardo C. Ferreira, Helen Baxendale, Deborah J. Smyth, David B. Dunger, Meghavi Mashar, John A. Todd, Timothy J. Vyse, Marcin L. Pekalski, Chris Wallace, Daniel B. Rainbow, Anita Chandra, Dunger, David [0000-0002-2566-9304], Chandra, Anita [0000-0002-9061-879X], Wallace, Chris [0000-0001-9755-1703], and Apollo - University of Cambridge Repository

Subjects
Adult, Male, Adolescent, FOXP3, Autoimmunity, chemical and pharmacologic phenomena, treg-specific demethylated region (TSDR), Biology, Epigenetic Repression, T-Lymphocytes, Regulatory, Article, Interleukin 21, Ikaros Transcription Factor, Young Adult, Immune system, T-Lymphocyte Subsets, TheoryofComputation_ANALYSISOFALGORITHMSANDPROBLEMCOMPLEXITY, Cytotoxic T cell, Humans, Lupus Erythematosus, Systemic, IL-2 receptor, Child, CD25, Cells, Cultured, Aged, Regulatory T cells (Tregs), Treg-specific demethylated region (TSDR), ZAP70, autoimmunity, Interleukin-2 Receptor alpha Subunit, High-Throughput Nucleotide Sequencing, Forkhead Transcription Factors, hemic and immune systems, Middle Aged, Natural killer T cell, Demethylation, regulatory T cells (tregs), Immunology, Interleukin 12, Female
Abstract

Identification of alterations in the cellular composition of the human immune system is key to understanding the autoimmune process. Recently, a subset of FOXP3+ cells with low CD25 expression was found to be increased in peripheral blood from systemic lupus erythematosus (SLE) patients, although its functional significance remains controversial. Here we find in comparisons with healthy donors that the frequency of FOXP3+ cells within CD127lowCD25low CD4+ T cells (here defined as CD25lowFOXP3+ T cells) is increased in patients affected by autoimmune disease of varying severity, from combined immunodeficiency with active autoimmunity, SLE to type 1 diabetes. We show that CD25lowFOXP3+ T cells share phenotypic features resembling conventional CD127lowCD25highFOXP3+ Tregs, including demethylation of the Treg-specific epigenetic control region in FOXP3, HELIOS expression, and lack of IL-2 production. As compared to conventional Tregs, more CD25lowFOXP3+HELIOS+ T cells are in cell cycle (33.0% vs 20.7% Ki-67+; P = 1.3 × 10−9) and express the late-stage inhibitory receptor PD-1 (67.2% vs 35.5%; P = 4.0 × 10−18), while having reduced expression of the early-stage inhibitory receptor CTLA-4, as well as other Treg markers, such as FOXP3 and CD15s. The number of CD25lowFOXP3+ T cells is correlated (P = 3.1 × 10−7) with the proportion of CD25highFOXP3+ T cells in cell cycle (Ki-67+). These findings suggest that CD25lowFOXP3+ T cells represent a subset of Tregs that are derived from CD25highFOXP3+ T cells, and are a peripheral marker of recent Treg expansion in response to an autoimmune reaction in tissues., Highlights • FOXP3+ compartment within CD127lowCD25low T cells is expanded in autoimmune patients. • Increased numbers of CD25lowFOXP3+ T cells are a circulating marker of autoimmunity. • CD25lowFOXP3+ HELIOS+ T cells are fully demethylated at the FOXP3 TSDR. • CD25lowFOXP3+ T cells could represent a terminal differentiation stage of regulatory T cells.

Published
2017

49. Fine-mapping and functional studies highlight potential causal variants for rheumatoid arthritis and type 1 diabetes

Author

Javier Martin, John A. Todd, Wei-Min Chen, Marta Martinez Bonet, Stephen S. Rich, Yang Luo, Aaron R. Quinlan, Lars Klareskog, Solbritt Rantapää-Dahlqvist, Annette Lee, Harm-Jan Westra, Peter A. Nigrovic, Soumya Raychaudhuri, Suna Onengut-Gumuscu, Jane Worthington, Nikola Teslovich, Steve Eyre, Tom W J Huizinga, and Peter K. Gregersen

Subjects
0301 basic medicine, medicine.medical_specialty, Lydia Becker Institute, SUSCEPTIBILITY LOCI, Quantitative Trait Loci, Arthritis, Genome-wide association study, Biology, Bioinformatics, GENOTYPE IMPUTATION, Polymorphism, Single Nucleotide, Article, Arthritis, Rheumatoid, 03 medical and health sciences, Jurkat Cells, CD28 Antigens, Gene Frequency, BURROWS-WHEELER TRANSFORM, ResearchInstitutes_Networks_Beacons/lydia_becker_institute_of_immunology_and_inflammation, Diabetes mellitus, Genetics, medicine, Humans, CTLA-4 Antigen, Genetic Predisposition to Disease, GENOME-WIDE ASSOCIATION, SYSTEMIC-LUPUS-ERYTHEMATOSUS, CELL-TYPES, Alleles, Tumor Necrosis Factor alpha-Induced Protein 3, Autoimmune disease, Type 1 diabetes, Case-control study, Chromosome Mapping, COMPLEX TRAIT, TYROSINE-PHOSPHATASE, medicine.disease, RISK LOCI, 030104 developmental biology, Diabetes Mellitus, Type 1, Genetic Loci, Rheumatoid arthritis, Case-Control Studies, Mutation, Medical genetics, RNA, Long Noncoding, INFLAMMATORY-BOWEL-DISEASE, Genome-Wide Association Study
Abstract

To define potentially causal variants for autoimmune disease, we fine-mapped1,2 76 rheumatoid arthritis (11,475 cases, 15,870 controls)3 and type 1 diabetes loci (9,334 cases, 11,111 controls)4. After sequencing 799 1-kilobase regulatory (H3K4me3) regions within these loci in 568 individuals, we observed accurate imputation for 89% of common variants. We defined credible sets of ≤5 causal variants at 5 rheumatoid arthritis and 10 type 1 diabetes loci. We identified potentially causal missense variants at DNASE1L3, PTPN22, SH2B3, and TYK2, and noncoding variants at MEG3, CD28–CTLA4, and IL2RA. We also identified potential candidate causal variants at SIRPG and TNFAIP3. Using functional assays, we confirmed allele-specific protein binding and differential enhancer activity for three variants: the CD28–CTLA4 rs117701653 SNP, MEG3 rs34552516 indel, and TNFAIP3 rs35926684 indel.

Published
2017

50. Medical phycology 2017

Author

Ryohei Ueno, Allan Britten, John R. Todd, Uwe Roesler, Christoph Weise, Tadahiko Matsumoto, Arnold Oberle, Jayaseelan Murugaiyan, John W. King, R. Scott Pore, and Yoshinobu Odaka

Subjects
0301 basic medicine, Protothecosis, medicine.medical_specialty, Phycology, biology, Genotype, 030106 microbiology, General Medicine, Prototheca, Chlorella, biology.organism_classification, medicine.disease, Infections, Molecular Typing, 03 medical and health sciences, Molecular typing, Infectious Diseases, Geography, Family medicine, medicine, Animals, Humans
Abstract

In 2014, ISHAM formed a new working group: "Medical Phycology: Protothecosis and Chlorellosis." The purpose of this working group is to help facilitate collaboration and communication among people interested in the pathogenic algae, to share ideas and work together. Here we present reports on recent work we have done in five areas. 1. The history of medical phycology as a branch of science. 2. Aspects of the genetics of Prototheca. 3. Aspects of the proteins of Prototheca. 4. Human infections caused by Prototheca. 5. Dairy cow mastitis caused by Prototheca.

Published
2017

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