Cargando…
The psoriasis-protective TYK2 I684S variant impairs IL-12 stimulated pSTAT4 response in skin-homing CD4+ and CD8+ memory T-cells
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....
Autores principales: | , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2018
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5935702/ https://www.ncbi.nlm.nih.gov/pubmed/29728633 http://dx.doi.org/10.1038/s41598-018-25282-2 |
_version_ | 1783320311966466048 |
---|---|
author | Enerbäck, C. Sandin, C. Lambert, S. Zawistowski, M. Stuart, P. E. Verma, D. Tsoi, L. C. Nair, R. P. Johnston, A. Elder, J. T. |
author_facet | Enerbäck, C. Sandin, C. Lambert, S. Zawistowski, M. Stuart, P. E. Verma, D. Tsoi, L. C. Nair, R. P. Johnston, A. Elder, J. T. |
author_sort | Enerbäck, C. |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-5935702 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-59357022018-05-10 The psoriasis-protective TYK2 I684S variant impairs IL-12 stimulated pSTAT4 response in skin-homing CD4+ and CD8+ memory T-cells Enerbäck, C. Sandin, C. Lambert, S. Zawistowski, M. Stuart, P. E. Verma, D. Tsoi, L. C. Nair, R. P. Johnston, A. Elder, J. T. Sci Rep Article 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. Nature Publishing Group UK 2018-05-04 /pmc/articles/PMC5935702/ /pubmed/29728633 http://dx.doi.org/10.1038/s41598-018-25282-2 Text en © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Enerbäck, C. Sandin, C. Lambert, S. Zawistowski, M. Stuart, P. E. Verma, D. Tsoi, L. C. Nair, R. P. Johnston, A. Elder, J. T. The psoriasis-protective TYK2 I684S variant impairs IL-12 stimulated pSTAT4 response in skin-homing CD4+ and CD8+ memory T-cells |
title | The psoriasis-protective TYK2 I684S variant impairs IL-12 stimulated pSTAT4 response in skin-homing CD4+ and CD8+ memory T-cells |
title_full | The psoriasis-protective TYK2 I684S variant impairs IL-12 stimulated pSTAT4 response in skin-homing CD4+ and CD8+ memory T-cells |
title_fullStr | The psoriasis-protective TYK2 I684S variant impairs IL-12 stimulated pSTAT4 response in skin-homing CD4+ and CD8+ memory T-cells |
title_full_unstemmed | The psoriasis-protective TYK2 I684S variant impairs IL-12 stimulated pSTAT4 response in skin-homing CD4+ and CD8+ memory T-cells |
title_short | The psoriasis-protective TYK2 I684S variant impairs IL-12 stimulated pSTAT4 response in skin-homing CD4+ and CD8+ memory T-cells |
title_sort | psoriasis-protective tyk2 i684s variant impairs il-12 stimulated pstat4 response in skin-homing cd4+ and cd8+ memory t-cells |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5935702/ https://www.ncbi.nlm.nih.gov/pubmed/29728633 http://dx.doi.org/10.1038/s41598-018-25282-2 |
work_keys_str_mv | AT enerbackc thepsoriasisprotectivetyk2i684svariantimpairsil12stimulatedpstat4responseinskinhomingcd4andcd8memorytcells AT sandinc thepsoriasisprotectivetyk2i684svariantimpairsil12stimulatedpstat4responseinskinhomingcd4andcd8memorytcells AT lamberts thepsoriasisprotectivetyk2i684svariantimpairsil12stimulatedpstat4responseinskinhomingcd4andcd8memorytcells AT zawistowskim thepsoriasisprotectivetyk2i684svariantimpairsil12stimulatedpstat4responseinskinhomingcd4andcd8memorytcells AT stuartpe thepsoriasisprotectivetyk2i684svariantimpairsil12stimulatedpstat4responseinskinhomingcd4andcd8memorytcells AT vermad thepsoriasisprotectivetyk2i684svariantimpairsil12stimulatedpstat4responseinskinhomingcd4andcd8memorytcells AT tsoilc thepsoriasisprotectivetyk2i684svariantimpairsil12stimulatedpstat4responseinskinhomingcd4andcd8memorytcells AT nairrp thepsoriasisprotectivetyk2i684svariantimpairsil12stimulatedpstat4responseinskinhomingcd4andcd8memorytcells AT johnstona thepsoriasisprotectivetyk2i684svariantimpairsil12stimulatedpstat4responseinskinhomingcd4andcd8memorytcells AT elderjt thepsoriasisprotectivetyk2i684svariantimpairsil12stimulatedpstat4responseinskinhomingcd4andcd8memorytcells AT enerbackc psoriasisprotectivetyk2i684svariantimpairsil12stimulatedpstat4responseinskinhomingcd4andcd8memorytcells AT sandinc psoriasisprotectivetyk2i684svariantimpairsil12stimulatedpstat4responseinskinhomingcd4andcd8memorytcells AT lamberts psoriasisprotectivetyk2i684svariantimpairsil12stimulatedpstat4responseinskinhomingcd4andcd8memorytcells AT zawistowskim psoriasisprotectivetyk2i684svariantimpairsil12stimulatedpstat4responseinskinhomingcd4andcd8memorytcells AT stuartpe psoriasisprotectivetyk2i684svariantimpairsil12stimulatedpstat4responseinskinhomingcd4andcd8memorytcells AT vermad psoriasisprotectivetyk2i684svariantimpairsil12stimulatedpstat4responseinskinhomingcd4andcd8memorytcells AT tsoilc psoriasisprotectivetyk2i684svariantimpairsil12stimulatedpstat4responseinskinhomingcd4andcd8memorytcells AT nairrp psoriasisprotectivetyk2i684svariantimpairsil12stimulatedpstat4responseinskinhomingcd4andcd8memorytcells AT johnstona psoriasisprotectivetyk2i684svariantimpairsil12stimulatedpstat4responseinskinhomingcd4andcd8memorytcells AT elderjt psoriasisprotectivetyk2i684svariantimpairsil12stimulatedpstat4responseinskinhomingcd4andcd8memorytcells |