Resolving TYK2 locus genotype-to-phenotype differences in autoimmunity.
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.
Oxford Centre for Neuroinflammation, Nuffield Department of Clinical Neurosciences, Division of Clinical Neurology, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK.
Calliope A
CA
Dendrou
Oxford Centre for Neuroinflammation, Nuffield Department of Clinical Neurosciences, Division of Clinical Neurology, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK.|Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
Adrian
A
Cortes
Oxford Centre for Neuroinflammation, Nuffield Department of Clinical Neurosciences, Division of Clinical Neurology, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK.
Lydia
L
Shipman
Oxford Centre for Neuroinflammation, Nuffield Department of Clinical Neurosciences, Division of Clinical Neurology, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK.
Hayley G
HG
Evans
Medical Research Council Human Immunology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK.
Kathrine E
KE
Attfield
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
Luke
L
Jostins
Oxford Centre for Neuroinflammation, Nuffield Department of Clinical Neurosciences, Division of Clinical Neurology, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK.
Thomas
T
Barber
Medical Research Council Human Immunology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK.
Gurman
G
Kaur
Medical Research Council Human Immunology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK.
Subita Balaram
SB
Kuttikkatte
Oxford Centre for Neuroinflammation, Nuffield Department of Clinical Neurosciences, Division of Clinical Neurology, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK.
Oliver A
OA
Leach
Oxford Centre for Neuroinflammation, Nuffield Department of Clinical Neurosciences, Division of Clinical Neurology, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK.
Christiane
C
Desel
Oxford Centre for Neuroinflammation, Nuffield Department of Clinical Neurosciences, Division of Clinical Neurology, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK.|Department of Clinical Medicine, Aarhus University Hospital, 8200 Aarhus N, Denmark.
Soren L
SL
Faergeman
Oxford Centre for Diabetes, Endocrinology, and Metabolism, University of Oxford, Oxford OX3 7LE, UK.
Jane
J
Cheeseman
Oxford Centre for Diabetes, Endocrinology, and Metabolism, University of Oxford, Oxford OX3 7LE, UK.|National Institute for Health Research Oxford Biomedical Research Centre, Oxford University Hospitals Trust, Churchill Hospital, Oxford OX3 7LE, UK.
Matt J
MJ
Neville
Department of Clinical Neurosciences, University of Cambridge, Cambridge CB2 0QQ, UK.
Stephen
S
Sawcer
Department of Clinical Neurosciences, University of Cambridge, Cambridge CB2 0QQ, UK.
Alastair
A
Compston
Structural Biology and Biochemical Pharmacology, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
Adam R
AR
Johnson
Structural Biology and Biochemical Pharmacology, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
Christine
C
Everett
University of Oxford, Richard Doll Building, Roosevelt Drive, Oxford OX3 7DG, UK.
John I
JI
Bell
Oxford Centre for Diabetes, Endocrinology, and Metabolism, University of Oxford, Oxford OX3 7LE, UK.|National Institute for Health Research Oxford Biomedical Research Centre, Oxford University Hospitals Trust, Churchill Hospital, Oxford OX3 7LE, UK.
Fredrik
F
Karpe
Structural Biology and Biochemical Pharmacology, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
Mark
M
Ultsch
Structural Biology and Biochemical Pharmacology, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
Charles
C
Eigenbrot
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
Gil
G
McVean
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.|Medical Research Council Human Immunology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK.|Department of Clinical Medicine, Aarhus University Hospital, 8200 Aarhus N, Denmark.
Lars
L
Fugger
D000818:Animals; D001327:Autoimmune Diseases / Q000235:genetics*; D015551:Autoimmunity; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology; D016207:Cytokines / Q000378:metabolism; D044127:Epigenesis, Genetic; D005260:Female; D056726:Genetic Association Studies; D014644:Genetic Variation; D023281:Genomics; D005838:Genotype; D057809:HEK293 Cells; D006720:Homozygote; D006801:Humans; D007107:Immune System; D053614:Janus Kinase 2 / Q000737:chemistry; D007963:Leukocytes, Mononuclear / Q000166:cytology; D008297:Male; D051379:Mice; D020125:Mutation, Missense; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011487:Protein Conformation; D040641:Quantitative Trait Loci; D011995:Recombination, Genetic; D017423:Sequence Analysis, RNA; D015398:Signal Transduction; D053634:TYK2 Kinase / Q000235:genetics*; D059467:Transcriptome
D016207:Cytokines; C507924:JAK2 protein, human; D053614:Janus Kinase 2; D053634:TYK2 Kinase; C070139:TYK2 protein, human