Research ArticleAutoimmunity

Resolving TYK2 locus genotype-to-phenotype differences in autoimmunity

Science Translational Medicine  02 Nov 2016:
Vol. 8, Issue 363, pp. 363ra149
DOI: 10.1126/scitranslmed.aag1974

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TYK2’s balancing act

Determining the biological consequences of the thousands of genetic variants that contribute to common diseases for the purpose of improving health care is challenging. Genetic variants that influence autoimmune diseases have been identified in the tyrosine kinase 2 (TYK2) gene, but conflicting evidence regarding their biological impact obscures the therapeutic potential of TYK2. By resolving this conflict, Dendrou et al. have revealed a genetic effect that drives an optimal degree of immune signaling: low enough to be protective against autoimmunity but high enough to prevent immunodeficiency. These findings indicate that TYK2 may be a potential drug target in a number of autoimmune conditions.

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.

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