Abstract

Tyrosine kinase 2 (TYK2) belongs to the Janus kinase (JAK) family of tyrosine kinases, which transmit signals from activated cytokine receptors. GWAS have consistently implicated TYK2 in psoriasis susceptibility. We performed an in-depth association analysis of TYK2 using GWAS and resequencing data. Strong genetic association of three nonsynonymous variants in the exonic regions of the TYK2 gene (rs34536443, rs12720356, and rs2304256) were found. rs12720356 encoding I684S is predicted to be deleterious based on its location in the pseudokinase domain. We analyzed PBMCs from 29 individuals representing the haplotypes containing each of the significantly associated signals. STAT4 phosphorylation was evaluated by phospho-flow cytometry after CD3/CD28 activation of cells followed by IL-12 stimulation. Individuals carrying the protective I684S variant manifested significantly reduced p-STAT4 levels in CD4 + CD25 + CD45RO+ (mean Stimulation Index (S.I.) 48.08, n = 10) and CD8 + CD25 + CD45RO + cells (S.I. 55.71, n = 10), compared to controls homozygous for the ancestral haplotype (S.I. 68.19, n = 10 (p = 0.002) and 76.76 n = 10 (p = 0.0008) respectively). Reduced p-STAT4 levels were also observed in skin-homing, cutaneous lymphocyte associated antigen (CLA)-positive CD4 and CD8 cells from I684S carriers. No significant changes in p-STAT4 for the psoriasis-associated variant rs34536443 was found. These data establish the functional significance of the TYK2 I684S variant in psoriasis susceptibility.

Details

Title
The psoriasis-protective TYK2 I684S variant impairs IL-12 stimulated pSTAT4 response in skin-homing CD4+ and CD8+ memory T-cells
Author
Enerbäck, C 1   VIAFID ORCID Logo  ; Sandin, C 2 ; Lambert, S 3 ; Zawistowski, M 4 ; Stuart, P E 3 ; Verma, D 2 ; Tsoi, L C 5 ; Nair, R P 3 ; Johnston, A 3   VIAFID ORCID Logo  ; Elder, J T 6   VIAFID ORCID Logo 

1  Department of Dermatology, University of Michigan, Ann Arbor, MI, USA; Ingrid Asp Psoriasis Research Center, Department of Dermatology, Linköping University, Linköping, Sweden 
2  Ingrid Asp Psoriasis Research Center, Department of Dermatology, Linköping University, Linköping, Sweden 
3  Department of Dermatology, University of Michigan, Ann Arbor, MI, USA 
4  Department of Biostatistics, University of Michigan, Ann Arbor, MI, USA 
5  Department of Dermatology, University of Michigan, Ann Arbor, MI, USA; Department of Biostatistics, University of Michigan, Ann Arbor, MI, USA 
6  Department of Dermatology, University of Michigan, Ann Arbor, MI, USA; Ann Arbor Veterans Affairs Health System, Ann Arbor, MI, USA 
Pages
1-6
Publication year
2018
Publication date
May 2018
Publisher
Nature Publishing Group
e-ISSN
20452322
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41598-018-25282-2
ProQuest document ID
2034682819
Copyright
© 2018. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.