Resolving TYK2 locus genotype-to-phenotype differences in autoimmunity

Calliope A Dendrou; Adrian Cortes; Lydia Shipman; Hayley G Evans; Kathrine E Attfield; Luke Jostins; Thomas Barber; Gurman Kaur; Subita Balaram Kuttikkatte; Oliver A Leach; Christiane Desel; Soren L Faergeman; Jane Cheeseman; Matt J Neville; Stephen Sawcer; Alastair Compston; Adam R Johnson; Christine Everett; John I Bell; Fredrik Karpe; Mark Ultsch; Charles Eigenbrot; Gil McVean; Lars Fugger

doi:10.1126/scitranslmed.aag1974

Resolving TYK2 locus genotype-to-phenotype differences in autoimmunity

Sci Transl Med. 2016 Nov 2;8(363):363ra149. doi: 10.1126/scitranslmed.aag1974.

Authors

Calliope A Dendrou¹, Adrian Cortes^{1

2}, Lydia Shipman¹, Hayley G Evans¹, Kathrine E Attfield³, Luke Jostins², Thomas Barber¹, Gurman Kaur³, Subita Balaram Kuttikkatte³, Oliver A Leach¹, Christiane Desel¹, Soren L Faergeman^{1

4}, Jane Cheeseman⁵, Matt J Neville^{5

6}, Stephen Sawcer⁷, Alastair Compston⁷, Adam R Johnson⁸, Christine Everett⁸, John I Bell⁹, Fredrik Karpe^{5

6}, Mark Ultsch⁸, Charles Eigenbrot⁸, Gil McVean², Lars Fugger^{10

3

4}

Affiliations

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Autoimmune Diseases / genetics*
Autoimmunity
CD4-Positive T-Lymphocytes / cytology
Cytokines / metabolism
Epigenesis, Genetic
Female
Genetic Association Studies*
Genetic Variation
Genomics
Genotype
HEK293 Cells
Homozygote
Humans
Immune System
Janus Kinase 2 / chemistry
Leukocytes, Mononuclear / cytology
Male
Mice
Mutation, Missense
Phenotype
Polymorphism, Single Nucleotide
Protein Conformation
Quantitative Trait Loci
Recombination, Genetic
Sequence Analysis, RNA
Signal Transduction
TYK2 Kinase / genetics*
Transcriptome

Substances

Cytokines
JAK2 protein, human
Janus Kinase 2
TYK2 Kinase
TYK2 protein, human

Abstract

Publication types

MeSH terms

Substances

Grants and funding