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1. HLA-DQA1*05 Carriage Associated With Development of Anti-Drug Antibodies to Infliximab and Adalimumab in Patients With Crohn's Disease

Author

Timothy R. Orchard, Rosemary H Phillips, Stephen M. Evans, Arvind Ramadas, Paul R. Banim, Guy Chung-Faye, Subramaniam Ramakrishnan, Simon Panter, Leonie Grellier, Hasnain Jafferbhoy, Nigel Trudgill, Thankam Paul, Sian Kirkham, Anna J Pigott, M J Carter, Juan De La Revella Negro, Lisa Gervais, Zia Mazhar, Suranga Dharmisari, Richard A. Miller, Cathryn Preston, Alison Simmons, Rachel Cooney, Natalie C. Direkze, Deb Ghosh, Christian P. Selinger, Andrew A. Fagbemi, Rakesh Chaudhary, J R Fraser Cummings, Stephen Gore, James O. Lindsay, Tony C.K. Tham, David Hobday, Charles Murray, David Watts, Anne Willmott, Gill Watts, Sandip Sen, Mark Reppell, Amer Azaz, Shaji Sebastian, Neil Chanchlani, R B Johnston, Ben Hope, Salil Singh, Stephen Foley, Sunil Sonwalkar, Jonathon Snook, Lawrence Armstrong, Amanda Beale, Andy Li, Tariq Mahmood, Stephen Lewis, Kevin J. Monahan, Timothy J. McDonald, Gareth T. Jones, John N. Gordon, Nicholas A Kennedy, Sheldon C. Cooper, Gareth J. Walker, James W Hart, Sarah Langlands, Carl A. Anderson, Marcus Harbord, Alistair McNair, Achuth Shenoy, Graham A. Heap, Radhakrishnan Hariraj, Mandy H Perry, Charlie Lees, Shanika de Silva, Christopher J. Hawkey, Loukas Moutsianas, Matthew J Brookes, Christos Tzivinikos, Veena Zamvar, Cathryn Edwards, Claire Bell, Rebecca Saich, Peter M. Irving, Mark S. Smith, Phillip Mayhead, Christopher Macdonald, Dharamveer Basude, Andrew T. Cole, Ailsa Hart, Daniel R. Gaya, Kasamu Dawa Kabiru, Assad Butt, John C Mansfield, John Beckly, Anton V J Gunasekera, Simon Lal, Charles Pj Charlton, Astor Rodrigues, Craig Mowat, Joel Mawdsley, Palani Sathish Babu, John C. Mansfield, Mary-Anne Morris, Senthil V. Murugesan, Dermot P.B. McGovern, Richard Pollok, Franco Torrente, Jeffrey C. Barrett, Aleksejs Sazonovs, Aminda De Silva, George MacFaul, Paul Dunckley, Neeraj Prasad, Zahid Mahmood, Neil P. Shah, Richard Shenderey, Tariq Iqbal, Anjan Dhar, Bruce McLain, James R Goodhand, Anita Modi, Daniel L. Rice, Patrick Goggin, Alka Thakur, Vinod B. Patel, Vishal Kaushik, Scott Levison, Sonia Bouri, Fraser Cummings, Emma Wesley, Anurag Agrawal, Deven Vani, Jimmy K. Limdi, Miles Parkes, David A Elphick, Mark Tighe, Nicholas M. Croft, Charlie W. Lees, Helen Matthews, B K Baburajan, Andrew Bell, Melissa A. Smith, Tariq Ahmad, Stephen Bridger, Mark Tremelling, Matthew W. Johnson, John Fell, Claire Bewshea, Bim Bhaduri, Julie Doherty, Sean Weaver, Ben Colleypriest, Chuka U. Nwokolo, John de Caestecker, Richard K. Russell, Stuart Bloom, Rice, Daniel L [0000-0002-2972-0365], Chanchlani, Neil [0000-0003-0207-6706], McDonald, Timothy J [0000-0003-3559-6660], Anderson, Carl A [0000-0003-1719-7009], and Apollo - University of Cambridge Repository

Subjects
0301 basic medicine, Male, Inflammatory bowel disease, Gastroenterology, Infliximab/immunology, 0302 clinical medicine, Crohn Disease, GWAS, Crohn's disease, Immunogenicity, Hazard ratio, PANTS, Crohn Disease/blood, Middle Aged, Ulcerative colitis, Loss Of Response, 030211 gastroenterology & hepatology, Female, medicine.drug, Adult, medicine.medical_specialty, Heterozygote, Combination therapy, Drug Persistence, HLA-DQ alpha-Chains, 03 medical and health sciences, Young Adult, Adalimumab/immunology, Internal medicine, HLA-DQ alpha-Chains/genetics, medicine, Adalimumab, Humans, Alleles, Gastroenterology & Hepatology, Hepatology, Tumor Necrosis Factor-alpha, business.industry, Tumor Necrosis Factor-alpha/antagonists & inhibitors, Patient Selection, 1103 Clinical Sciences, medicine.disease, Infliximab, 030104 developmental biology, 1114 Paediatrics and Reproductive Medicine, 1109 Neurosciences, business, Genome-Wide Association Study
Abstract

BACKGROUND & AIMS: Anti-tumor necrosis factor (anti-TNF) therapies are the most widely used biologic drugs for treating immune-mediated diseases, but repeated administration can induce the formation of anti-drug antibodies. The ability to identify patients at increased risk for development of anti-drug antibodies would facilitate selection of therapy and use of preventative strategies.METHODS: We performed a genome-wide association study to identify variants associated with time to development of anti-drug antibodies in a discovery cohort of 1240 biologic-naïve patients with Crohn's disease starting infliximab or adalimumab therapy. Immunogenicity was defined as an anti-drug antibody titer ≥10 AU/mL using a drug-tolerant enzyme-linked immunosorbent assay. Significant association signals were confirmed in a replication cohort of 178 patients with inflammatory bowel disease.RESULTS: The HLA-DQA1*05 allele, carried by approximately 40% of Europeans, significantly increased the rate of immunogenicity (hazard ratio [HR], 1.90; 95% confidence interval [CI], 1.60-2.25; P = 5.88 × 10-13). The highest rates of immunogenicity, 92% at 1 year, were observed in patients treated with infliximab monotherapy who carried HLA-DQA1*05; conversely the lowest rates of immunogenicity, 10% at 1 year, were observed in patients treated with adalimumab combination therapy who did not carry HLA-DQA1*05. We confirmed this finding in the replication cohort (HR, 2.00; 95% CI, 1.35-2.98; P = 6.60 × 10-4). This association was consistent for patients treated with adalimumab (HR, 1.89; 95% CI, 1.32-2.70) or infliximab (HR, 1.92; 95% CI, 1.57-2.33), and for patients treated with anti-TNF therapy alone (HR, 1.75; 95% CI, 1.37-2.22) or in combination with an immunomodulator (HR, 2.01; 95% CI, 1.57-2.58).CONCLUSIONS: In an observational study, we found a genome-wide significant association between HLA-DQA1*05 and the development of antibodies against anti-TNF agents. A randomized controlled biomarker trial is required to determine whether pretreatment testing for HLA-DQA1*05 improves patient outcomes by helping physicians select anti-TNF and combination therapies. ClinicalTrials.gov ID: NCT03088449.

Published
2020
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2. HLA-DQA1*05 is associated with the development of antibodies to anti-TNF therapy

Author

Daniel L. Rice, Graham A. Heap, Tariq Ahmad, Gareth J. Walker, Miles Parkes, Charlie W. Lees, Carl A. Anderson, Dermot P.B. McGovern, John C. Mansfield, Nicholas A Kennedy, Jeffrey C. Barrett, Mandy H Perry, Timothy J. McDonald, James R Goodhand, Loukas Moutsianas, Aleksejs Sazonovs, Mark Reppell, Fraser Cummings, and Claire Bewshea

Subjects
Oncology, medicine.medical_specialty, Combination therapy, biology, business.industry, Hazard ratio, Human leukocyte antigen, Disease, Infliximab, Internal medicine, Cohort, medicine, biology.protein, Adalimumab, Antibody, business, medicine.drug
Abstract

SummaryBackgroundAnti-tumour necrosis factor (anti-TNF) therapies are the most widely used biologic therapies for treating immune-mediated diseases. Their efficacy is significantly reduced by the development of anti-drug antibodies which can lead to treatment failure and adverse reactions. The biological mechanisms underlying antibody development are unknown but the ability to identify subjects at higher risk would have significant clinical benefits.MethodsThe PANTS cohort consists of Crohn’s disease patients recruited prior to first administration of anti-TNF, with serial measurements of anti-drug antibody titres. We performed a genome-wide association study across 1240 individuals from this cohort to identify genetic variants associated with anti-drug antibody development.FindingsThe Human Leukocyte Antigen allele, HLA-DQA1*05, carried by approximately 40% of Europeans, significantly increased the rate of anti-drug antibody development (hazard ratio [HR], 1.90; 95% confidence interval [CI], 1.60 to 2.25; P=5.88×10-13). This association was consistent for patients treated with adalimumab (HR, 1.89; 95% CI, 1.32 to 2.70) and infliximab (HR, 1.92; 95% CI, 1.57 to 2.33), and for patients treated with mono-(HR, 1.75; 95% CI, 1.37 to 2.22) or combination therapy with immunomodulators (HR, 2.0; 95% CI, 1.57 to 2.58).InterpretationHLA-DQA1*05 is significantly associated with an increased rate of anti-drug antibody formation in patients with Crohn’s disease treated with infliximab and adalimumab. Pre-treatment HLA-DQA1*05 genetic testing may help personalise the choice of anti-TNF therapy and allow the targeted use of immunomodulator therapy to minimise risk and maximise response.

Published
2018
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3. Genome-wide association study implicates immune activation of multiple integrin genes in inflammatory bowel disease

Author

Natalie J. Prescott, Holm H. Uhlig, Alison Simmons, William G. Newman, Loukas Moutsianas, David C. Wilson, Sun-Gou Ji, John C. Mansfield, Christopher J. Hawkey, Graham A. Heap, Cathryn Edwards, Charlie W. Lees, Javier Gutierrez-Achury, James Lee, Nicholas A. Kennedy, Christopher A. Lamb, Jeffrey C. Barrett, Craig Mowat, Christopher G. Mathew, Jack Satsangi, Yang Luo, Daniel L. Rice, Carl A. Anderson, Paul Henderson, Ailsa Hart, Jeremy D. Sanderson, Tariq Ahmad, Elaine R. Nimmo, Mark Tremelling, Luke Jostins, Miles Parkes, and Katrina M. de Lange

Subjects
0301 basic medicine, Integrins, Quantitative Trait Loci, Genome-wide association study, Biology, Polymorphism, Single Nucleotide, Inflammatory bowel disease, Article, 03 medical and health sciences, 0302 clinical medicine, Immune system, Genetics, medicine, Humans, Missense mutation, Genetic Predisposition to Disease, Allele, ITGB8, Gene, Alleles, Genetic association, Inflammation, Inflammatory Bowel Diseases, medicine.disease, 3. Good health, 030104 developmental biology, 030211 gastroenterology & hepatology, Genome-Wide Association Study
Abstract

Genetic association studies have identified 215 risk loci for inflammatory bowel disease, thereby uncovering fundamental aspects of its molecular biology. We performed a genome-wide association study of 25,305 individuals and conducted a meta-analysis with published summary statistics, yielding a total sample size of 59,957 subjects. We identified 25 new susceptibility loci, 3 of which contain integrin genes that encode proteins in pathways that have been identified as important therapeutic targets in inflammatory bowel disease. The associated variants are correlated with expression changes in response to immune stimulus at two of these genes (ITGA4 and ITGB8) and at previously implicated loci (ITGAL and ICAM1). In all four cases, the expression-increasing allele also increases disease risk. We also identified likely causal missense variants in a gene implicated in primary immune deficiency, PLCG2, and a negative regulator of inflammation, SLAMF8. Our results demonstrate that new associations at common variants continue to identify genes relevant to therapeutic target identification and prioritization.

Published
2017
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4. A protein-truncating R179X variant in RNF186 confers protection against ulcerative colitis

Author

Richard H. Duerr, Dalin Li, Ming-Hsi Wang, Tariq Ahmad, John D. Rioux, Patrick Sulem, Daniel B. Graham, Steven R. Brant, Severine Vermeire, Mark Tremelling, James Lee, Leena Halme, K. de Lane, Miguel Regueiro, M Parkes, David C. Wilson, Alain Bitton, R. Milgrom, Daniel G. MacArthur, Marijn C. Visschedijk, Sören Mucha, Kenneth Croitoru, Alison Simmons, Mark S. Silverberg, Rinse K. Weersma, Jonas Halfvarson, Daniel L. Rice, J. M. Stempak, Christopher J. Hawkey, Mauro D'Amato, Christopher G. Mathew, Philippe Goyette, Frauke Degenhardt, Daniel F. Gudbjartsson, Mark J. Daly, Kari Stefansson, Beryl B. Cummings, Maarit Lappalainen, Päivi Saavalainen, Paulina Paavola-Sakki, P. Fleshner, Talin Haritunians, Joshua C. Randall, Elaine R. Nimmo, Taru Tukiainen, Christine Stevens, Subra Kugathasan, Monkol Lek, Andre Franke, Kimmo Kontula, Unnur Thorsteinsdottir, Andrew Hart, Martin O. Pollard, Gabrielle Boucher, Natalie J. Prescott, Benjamin M. Neale, Holm H. Uhlig, Carl A. Anderson, Ashwin N. Ananthakrishnan, Luke Jostins, C. Mowatt, Judy H. Cho, B. Newman, A. Nicole Desch, Yang Luo, Dermot P.B. McGovern, Clara Abraham, Ingileif Jonsdottir, Jeffrey C. Barrett, John C. Mansfield, Jean-Paul Achkar, Charlie W. Lees, Martti Färkkilä, Ramnik J. Xavier, S. R. Targan, Manuel A. Rivas, Deborah D. Proctor, Johan Van Limbergen, Nicholas A. Kennedy, Christopher A. Lamb, Jürgen Glas, Vito Annese, Yashoda Sharma, Phil Schumm, Graham A. Heap, Cathryn Edwards, Lotta L. E. Koskinen, Jack Satsangi, Mitja I. Kurki, Aarno Palotie, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA Analytic and Translational Genetics Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA deCODE Genetics, Amgen Inc., 101 Reykjavik, Iceland Research Center, Montreal Heart Institute, Montréal, Québec, Canada H1T1C8 School of Engineering and Natural Sciences, University of Iceland, 101 Reykjavik, Iceland Department of Immunology, Landspitali, the National University Hospital of Iceland, 101 Reykjavik, Iceland Faculty of Medicine, University of Iceland, 101 Reykjavik, Iceland Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, 24118 Kiel, Germany F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California 90048, USA Inflammatory Bowel Disease Center, Cedars-Sinai Medical Center, Los Angeles, California 90048 USA Department of Biosciences and Nutrition, Karolinska Institutet, 14183 Stockholm, Sweden BioCruces Health Research Institute and IKERBASQUE, Basque Foundation for Science, 48903 Bilbao, Spain Unit of Gastroenterology, Istituto di Ricovero e Cura a Carattere Scientifico-Casa Sollievo della Sofferenza (IRCCS-CSS) Hospital, 71013 San Giovanni Rotondo, Italy Strutture Organizzative Dipartimentali (SOD) Gastroenterologia 2, Azienda Ospedaliero Universitaria (AOU) Careggi, 50134 Florence, Italy Department of Clinical and Experimental Medicine, Translational Research in GastroIntestinal Disorders (TARGID), Katholieke Universiteit (KU) Leuven, Leuven 3000, Belgium Division of Gastroenterology, University Hospital Gasthuisberg, BE-3000 Leuven, Belgium Department of Gastroenterology and Hepatology, University of Groningen and University Medical Center Groningen, 9713 GZ Groningen, The Netherlands Department of Gastroenterology, Faculty of Medicine and Health, Örebro University, SE 701 82 Örebro, Sweden Department of Medicine, University of Helsinki, 00100 Helsinki, Finland Helsinki University Hospital, 00100 Helsinki, Finland Clinic of Gastroenterology, Helsinki University Hospital, 00100 Helsinki, Finland Research Programs Unit, Immunobiology, and Department of Medical and Clinical Genetics, University of Helsinki, 00014 Helsinki, Finland Department of Transplantation and Liver Surgery, University of Helsinki, 00100 Helsinki, Finland Department of Medical Genetics, Biomedicum Helsinki, University of Helsinki, 00100 Helsinki, Finland Gastroenterology Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA Division of Medical Sciences, Harvard Medical School, Boston, Massachusetts 02114, USA Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton CB10 1SA, UK IBD Pharmacogenetics, Royal Devon and Exeter NHS Trust, Exeter EX2 5DW, UK Graham A. Heap Peninsula College of Medicine and Dentistry, Exeter PL6 8BU, UK Meyerhoff Inflammatory Bowel Disease Center, Department of Medicine, School of Medicine, Johns Hopkins University, Baltimore, Maryland, 21205, USA Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, 21205, USA Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA Department of Human Genetics, University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania 15261, USA Department of Medicine, Inflammatory Bowel Disease Centre, Mount Sinai Hospital, Toronto, Ontario, Canada M5G 1X5 Department of Genetics, Yale School of Medicine, New Haven, Connecticut 06510, USA Institute for Molecular Medicine Finland, University of Helsinki, 00100 Helsinki, Finland Massachusetts General Hospital, Center for Human Genetic Research, Psychiatric and Neurodevelopmental Genetics Unit, Boston, Massachusetts 02114, USA Research Programs Unit, Immunobiology, University of Helsinki, 00100 Helsinki, Finland Faculté de Médecine, Université de Montréal, Montréal, Québec, Canada H3T 1J4 Department of Gastroenterology, Torbay Hospital, Devon, UK Department of Medicine, St. Mark’s Hospital, Middlesex, UK Nottingham Digestive Disease Centre, Queens Medical Centre, Nottingham, UK Wellcome Trust Centre for Human Genetics, University of Oxford, Headington, UK Christ Church, University of Oxford, Oxford, UK Gastrointestinal Unit, Wester General Hospital, University of Edinburgh, Edinburgh, UK Newcastle University, Newcastle upon Tyne, UK Inflammatory Bowel Disease Research Group, Addenbrooke’s Hospital, Cambridge, UK Department of Medical and Molecular Genetics, Guy’s Hospital, London, UK Department of Medical and Molecular Genetics, King’s College London School of Medicine, Guy’s Hospital, London, UK Department of Medicine, Ninewells Hospital and Medical School, Dundee, UK Genetic Medicine, Manchester Academic Health Science Centre, Manchester, UK The Manchester Centre for Genomic Medicine, University of Manchester, Manchester, UK Centre for Genomic and Experimental Medicine, University of Edinburgh, Edinburgh, UK Translational Gastroenterology Unit, John Radcliffe Hospital, University of Oxford, Oxford, UK Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK Gastroenterology & General Medicine, Norfolk and Norwich University Hospital, Norwich, UK Translational Gastroenterology Unit and the Department of Pediatrics, University of Oxford, Oxford, UK Pediatric Gastroenterology and Nutrition, Royal Hospital for Sick Children, Edinburgh, UK Child Life and Health, University of Edinburgh, Edinburgh, UK Section of Digestive Diseases, Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut, USA Department of Gastroenterology and Hepatology, Digestive Disease Institute, Cleveland Clinic, Cleveland, Ohio, USA Department of Pathobiology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA Division of Gastroenterology, Royal Victoria Hospital, Montréal, Québec, Canada Inflammatory Bowel Disease Group, Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia, USA Division of Pediatric Gastroenterology, Hepatology and Nutrition, Hospital for Sick Children, Toronto, Ontario, Canada Department of Public Health Sciences, University of Chicago, Chicago, Illinois, USA Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA, Department of Medicine, Clinicum, Gastroenterologian yksikkö, Immunobiology Research Program, Research Programs Unit, Department of Medical and Clinical Genetics, Medicum, II kirurgian klinikka, Department of Surgery, Institute for Molecular Medicine Finland, Aarno Palotie / Principal Investigator, Immunomics, Kimmo Kontula Research Group, and Genomics of Neurological and Neuropsychiatric Disorders

Subjects
0301 basic medicine, AAI12, Chemistry(all), SUSCEPTIBILITY LOCI, Science, Population, General Physics and Astronomy, Physics and Astronomy(all), OF-FUNCTION VARIANTS, Inflammatory bowel disease, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, NUMBER, medicine, Ring finger, IMPUTATION, Allele, education, POPULATION, RISK, education.field_of_study, Multidisciplinary, biology, Biochemistry, Genetics and Molecular Biology(all), MUTATIONS, General Chemistry, ASSOCIATION, medicine.disease, Inflammatory Bowel Diseases, Ulcerative colitis, digestive system diseases, 3. Good health, Ubiquitin ligase, Transport protein, Transmembrane domain, 030104 developmental biology, medicine.anatomical_structure, RARE VARIANTS, Immunology, biology.protein, Cancer research, 3111 Biomedicine, INFLAMMATORY-BOWEL-DISEASE
Abstract

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked Files. This article is open access. Protein-truncating variants protective against human disease provide in vivo validation of therapeutic targets. Here we used targeted sequencing to conduct a search for protein-truncating variants conferring protection against inflammatory bowel disease exploiting knowledge of common variants associated with the same disease. Through replication genotyping and imputation we found that a predicted protein-truncating variant (rs36095412, p.R179X, genotyped in 11,148 ulcerative colitis patients and 295,446 controls, MAF=up to 0.78%) in RNF186, a single-exon ring finger E3 ligase with strong colonic expression, protects against ulcerative colitis (overall P=6.89 × 10(-7), odds ratio=0.30). We further demonstrate that the truncated protein exhibits reduced expression and altered subcellular localization, suggesting the protective mechanism may reside in the loss of an interaction or function via mislocalization and/or loss of an essential transmembrane domain. National Institute of Diabetes and Digestive and Kidney Disease (NIDDK) DK064869 DK062432 National Human Genome Research Institute (NHGRI) DK064869 DK043351 HG005923 Crohns and Colitis Foundation 3765 Leona M. & Harry B. Helmsley Charitable Trust 2015PG-IBD001 Amgen 2013583217 CCFA 3765 Cedars-Sinai F. Widjaja Foundation, info:eu-repo/grantAgreement/EC/FP7/305479, European Union DK062413 AI067068 U54DE023789-01 Leona M. and Harry B. Helmsley Charitable Trust Crohn's and Colitis Foundation of America NIH DK062431 U01 DK062429 U01 DK062422 R01 DK092235 U01 DK062420 Medical Research Council, UK MR/J00314X/1 Wellcome Trust WT091310 098051 Inflammatory Bowel Disease Genetic Research Chair at the University of Pittsburgh PO1DK046763

Published
2016
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