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Resolving $\textit{TYK2}$ locus genotype-to-phenotype differences in autoimmunity

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Dendrou, CA 
Cortes, A 
Shipman, L 
Evans, HG 
Attfield, KE 


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.



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

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Science Translational Medicine

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American Association for the Advancement of Science
European Commission (282510)
Medical Research Council (MC_PC_12009)
Work in the authors’ laboratories is supported by the U.K. and Danish MRCs, the Alan and Babette Sainsbury Charitable Fund, the Naomi Bramson Trust, the Clinical Neuroimmunology Fund, the Oxford BRC, the Oak Foundation (L.F.), the Rosetrees Trust (L.F. and C.A.D.), and the Wellcome Trust (100308/Z/12/Z and 106130/Z/14/Z to L.F. and 100956/Z/13/Z to G.M.). L.S. was supported by a Christopher Welch Scholarship.