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Resolving TYK2 locus genotype-to-phenotype differences in autoimmunity.
Dendrou, Calliope A; Cortes, Adrian; Shipman, Lydia; Evans, Hayley G; Attfield, Kathrine E; Jostins, Luke; Barber, Thomas; Kaur, Gurman; Kuttikkatte, Subita Balaram; Leach, Oliver A; Desel, Christiane; Faergeman, Soren L; Cheeseman, Jane; Neville, Matt J; Sawcer, Stephen; Compston, Alastair; Johnson, Adam R; Everett, Christine; Bell, John I; Karpe, Fredrik; Ultsch, Mark; Eigenbrot, Charles; McVean, Gil; Fugger, Lars.
Afiliação
  • Dendrou CA; Oxford Centre for Neuroinflammation, Nuffield Department of Clinical Neurosciences, Division of Clinical Neurology, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK.
  • Cortes A; Oxford Centre for Neuroinflammation, Nuffield Department of Clinical Neurosciences, Division of Clinical Neurology, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK.
  • Shipman L; Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
  • Evans HG; Oxford Centre for Neuroinflammation, Nuffield Department of Clinical Neurosciences, Division of Clinical Neurology, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK.
  • Attfield KE; Oxford Centre for Neuroinflammation, Nuffield Department of Clinical Neurosciences, Division of Clinical Neurology, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK.
  • Jostins L; Medical Research Council Human Immunology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK.
  • Barber T; Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
  • Kaur G; Oxford Centre for Neuroinflammation, Nuffield Department of Clinical Neurosciences, Division of Clinical Neurology, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK.
  • Kuttikkatte SB; Medical Research Council Human Immunology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK.
  • Leach OA; Medical Research Council Human Immunology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK.
  • Desel C; Oxford Centre for Neuroinflammation, Nuffield Department of Clinical Neurosciences, Division of Clinical Neurology, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK.
  • Faergeman SL; Oxford Centre for Neuroinflammation, Nuffield Department of Clinical Neurosciences, Division of Clinical Neurology, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK.
  • Cheeseman J; Oxford Centre for Neuroinflammation, Nuffield Department of Clinical Neurosciences, Division of Clinical Neurology, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK.
  • Neville MJ; Department of Clinical Medicine, Aarhus University Hospital, 8200 Aarhus N, Denmark.
  • Sawcer S; Oxford Centre for Diabetes, Endocrinology, and Metabolism, University of Oxford, Oxford OX3 7LE, UK.
  • Compston A; Oxford Centre for Diabetes, Endocrinology, and Metabolism, University of Oxford, Oxford OX3 7LE, UK.
  • Johnson AR; National Institute for Health Research Oxford Biomedical Research Centre, Oxford University Hospitals Trust, Churchill Hospital, Oxford OX3 7LE, UK.
  • Everett C; Department of Clinical Neurosciences, University of Cambridge, Cambridge CB2 0QQ, UK.
  • Bell JI; Department of Clinical Neurosciences, University of Cambridge, Cambridge CB2 0QQ, UK.
  • Karpe F; Structural Biology and Biochemical Pharmacology, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
  • Ultsch M; Structural Biology and Biochemical Pharmacology, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
  • Eigenbrot C; University of Oxford, Richard Doll Building, Roosevelt Drive, Oxford OX3 7DG, UK.
  • McVean G; Oxford Centre for Diabetes, Endocrinology, and Metabolism, University of Oxford, Oxford OX3 7LE, UK.
  • Fugger L; National Institute for Health Research Oxford Biomedical Research Centre, Oxford University Hospitals Trust, Churchill Hospital, Oxford OX3 7LE, UK.
Sci Transl Med ; 8(363): 363ra149, 2016 11 02.
Article em En | MEDLINE | ID: mdl-27807284
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.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Doenças Autoimunes / TYK2 Quinase / Estudos de Associação Genética Tipo de estudo: Prognostic_studies / Systematic_reviews Limite: Animals / Female / Humans / Male Idioma: En Ano de publicação: 2016 Tipo de documento: Article
Texto completo
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Doenças Autoimunes / TYK2 Quinase / Estudos de Associação Genética Tipo de estudo: Prognostic_studies / Systematic_reviews Limite: Animals / Female / Humans / Male Idioma: En Ano de publicação: 2016 Tipo de documento: Article