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 publication

DOI

10.1126/scitranslmed.aag1974

Type

Journal article

Journal

Science translational medicine

Publication Date

11/2016

Volume

8

Addresses

Oxford Centre for Neuroinflammation, Nuffield Department of Clinical Neurosciences, Division of Clinical Neurology, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK.

Keywords

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