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- W2337299322 abstract "Tyrosine kinase 2 (TYK2) belongs to the Janus kinase (JAK) family of tyrosine kinases, which transmit signals from activated cytokine receptors. Genome-wide association studies have consistently implicated TYK2 in psoriasis susceptibility. In an in-depth analysis of the TYK2 genomic region using GWAS and resequencing data, we found a strong genetic association of three nonsynonymous variants in the exonic regions of the TYK2 gene (rs34536443, rs12720356, and rs2304256). One of them, rs12720356 encoding I684S, was not previously shown to be psoriasis-associated. In a recent study using selective TYK2 inhibitors (J Immunol 191:2205, 2013), IL-12 was shown to act specifically through TYK2 to phosphorylate STAT4, without the contribution of other JAK kinases, and was therefore selected for the evaluation of functional effects of genetic variation in TYK2. We analyzed CD3/CD28-activated PBMCs from 23 individuals representing the haplotypes containing each of the significantly associated signals. After 72h of CD3/CD28 stimulation, cells were activated for 1h with 50ng/ml of IL-12 and evaluated for STAT4 phosphorylation by phospho-flow cytometry. We found that individuals carrying the protective I684S variant had 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 with controls homozygous for the ancestral haplotype (S.I. 69.41, n=8 (p=0.0099) and 77.11 n=8 (p=0.0165) respectively). Similar reductions in p-STAT4 were also observed in skin-homing, cutaneous lymphocyte-associated antigen (CLA)-positive CD4 and CD8 cells from I684S carriers. In contrast, we found no significant changes in p-STAT4 for the previously-reported psoriasis-associated variant rs34536443 encoding P1104A in the kinase domain. These data establish the functional significance of the TYK2 I684S variant in psoriasis susceptibility." @default.
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- W2337299322 date "2016-05-01" @default.
- W2337299322 modified "2023-10-18" @default.
- W2337299322 title "360 The protective TYK2 I684S variant impairs IL-12 stimulated p-STAT4 response in skin-homing CD4+ and CD8+ memory T-cells" @default.
- W2337299322 doi "https://doi.org/10.1016/j.jid.2016.02.393" @default.
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