Lars Henrik Fugger

Resolving TYK2 locus genotype-to-phenotype differences in autoimmunity

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

  • Calliope A Dendrou, Oxford Centre for Neuroinflammation, Nuffield Department of Clinical Neurosciences, Division of Clinical Neurology, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK.
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  • Adrian Cortes, Oxford Centre for Neuroinflammation, Nuffield Department of Clinical Neurosciences, Division of Clinical Neurology, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK.
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  • Lydia Shipman, Oxford Centre for Neuroinflammation, Nuffield Department of Clinical Neurosciences, Division of Clinical Neurology, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK.
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  • Hayley G Evans, Oxford Centre for Neuroinflammation, Nuffield Department of Clinical Neurosciences, Division of Clinical Neurology, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK.
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  • Kathrine E Attfield, Medical Research Council Human Immunology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK.
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  • Luke Jostins, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
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  • Thomas Barber, Oxford Centre for Neuroinflammation, Nuffield Department of Clinical Neurosciences, Division of Clinical Neurology, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK.
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  • Gurman Kaur, Medical Research Council Human Immunology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK.
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  • Subita Balaram Kuttikkatte, Medical Research Council Human Immunology Unit, Weatherall Institute of Molecular Medicine, Oxford University, John Radcliffe Hospital, Headley Way, Oxford OX3 9DS, UK.
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  • Oliver A Leach, Oxford Centre for Neuroinflammation, Nuffield Department of Clinical Neurosciences, Division of Clinical Neurology, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK.
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  • Christiane Desel, Oxford Centre for Neuroinflammation, Nuffield Department of Clinical Neurosciences, Division of Clinical Neurology, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK.
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  • Soren L Faergeman, Oxford Centre for Neuroinflammation, Nuffield Department of Clinical Neurosciences, Division of Clinical Neurology, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK.
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  • Jane Cheeseman, Oxford Centre for Diabetes, Endocrinology, and Metabolism, University of Oxford, Oxford OX3 7LE, UK.
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  • Matt J Neville, Oxford Centre for Diabetes, Endocrinology, and Metabolism, University of Oxford, Oxford OX3 7LE, UK.
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  • Stephen Sawcer, University of Cambridge
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  • Alastair Compston, University of Cambridge
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  • Adam R Johnson, Structural Biology and Biochemical Pharmacology, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
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  • Christine Everett, Structural Biology and Biochemical Pharmacology, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
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  • John I Bell, University of Oxford, Richard Doll Building, Roosevelt Drive, Oxford OX3 7DG, UK.
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  • Fredrik Karpe, Oxford Centre for Diabetes, Endocrinology, and Metabolism, University of Oxford, Oxford OX3 7LE, UK.
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  • Mark Ultsch, Structural Biology and Biochemical Pharmacology, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
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  • Charles Eigenbrot, Structural Biology and Biochemical Pharmacology, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
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  • Gil McVean, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
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  • Lars Fugger

Thousands of genetic variants have been identified, which contribute to the development of complex diseases, but determining how to elucidate their biological consequences for translation into clinical benefit is challenging. Conflicting evidence regarding the functional impact of genetic variants in the tyrosine kinase 2 (TYK2) gene, which is differentially associated with common autoimmune diseases, currently obscures the potential of TYK2 as a therapeutic target. We aimed to resolve this conflict by performing genetic meta-analysis across disorders; subsequent molecular, cellular, in vivo, and structural functional follow-up; and epidemiological studies. Our data revealed a protective homozygous effect that defined a signaling optimum between autoimmunity and immunodeficiency and identified TYK2 as a potential drug target for certain common autoimmune disorders.

Original languageEnglish
JournalScience Translational Medicine
Volume8
Issue363
Pages (from-to)363ra149
ISSN1946-6234
DOIs
Publication statusPublished - 2 Nov 2016

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