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Resolving TYK2 locus genotype-to-phenotype differences in autoimmunity

Authors :: Oliver A. Leach
Adam R. Johnson
Jane Cheeseman
Fredrik Karpe
Thomas R Barber
Gurman Kaur
Hayley G. Evans
Charles Eigenbrot
Adrian Cortes
Stephen Sawcer
Lars Fugger
Luke Jostins
Lydia Shipman
John Bell
Soren L. Faergeman
Calliope A. Dendrou
Kathrine E. Attfield
Christine Everett
Mark Ultsch
Alastair Compston
Gil McVean
Christiane Desel
Subita Balaram Kuttikkatte
Matt J. Neville
Source :: Dendrou, C A, Cortes, A, Shipman, L, Evans, H G, Attfield, K E, Jostins, L, Barber, T, Kaur, G, Kuttikkatte, S B, Leach, O A, Desel, C, Faergeman, S L, Cheeseman, J, Neville, M J, Sawcer, S, Compston, A, Johnson, A R, Everett, C, Bell, J I, Karpe, F, Ultsch, M, Eigenbrot, C, McVean, G & Fugger, L 2016, ' Resolving TYK2 locus genotype-to-phenotype differences in autoimmunity ', Science Translational Medicine, vol. 8, no. 363, pp. 363ra149 . https://doi.org/10.1126/scitranslmed.aag1974
Publication Year :: 2016
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.