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Sci Transl Med. 2016 Nov 2;8(363):363ra149.

Resolving TYK2 locus genotype-to-phenotype differences in autoimmunity.

Author information

1
Oxford Centre for Neuroinflammation, Nuffield Department of Clinical Neurosciences, Division of Clinical Neurology, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK.
2
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
3
Medical Research Council Human Immunology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK.
4
Department of Clinical Medicine, Aarhus University Hospital, 8200 Aarhus N, Denmark.
5
Oxford Centre for Diabetes, Endocrinology, and Metabolism, University of Oxford, Oxford OX3 7LE, UK.
6
National Institute for Health Research Oxford Biomedical Research Centre, Oxford University Hospitals Trust, Churchill Hospital, Oxford OX3 7LE, UK.
7
Department of Clinical Neurosciences, University of Cambridge, Cambridge CB2 0QQ, UK.
8
Structural Biology and Biochemical Pharmacology, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
9
University of Oxford, Richard Doll Building, Roosevelt Drive, Oxford OX3 7DG, UK.
10
Oxford Centre for Neuroinflammation, Nuffield Department of Clinical Neurosciences, Division of Clinical Neurology, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK. lars.fugger@imm.ox.ac.uk.

Abstract

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.

PMID:
27807284
PMCID:
PMC5737835
DOI:
10.1126/scitranslmed.aag1974
[Indexed for MEDLINE]
Free PMC Article

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