Abstract
TYK2 belongs to the JAK protein tyrosine kinase family and mediates signaling of numerous antiviral and immunoregulatory cytokines (type I and type III IFNs, IL-10, IL-12, IL-22, IL-23) in immune and non-immune cells. After many years of genetic association studies, TYK2 is recognized as a susceptibility gene for some inflammatory and autoimmune diseases (AID). Seven TYK2 variants have been associated with AIDs in Europeans, and establishing their causality remains challenging. Previous work showed that a protective variant (P1104A) is hypomorphic and also a risk allele for mycobacterial infection. Here, we have studied two AID-associated common TYK2 variants: rs12720270 located in intron 7 and rs2304256, a non-synonymous variant in exon 8 that causes a valine to phenylalanine substitution (c.1084 G > T, Val362Phe). We found that this amino acid substitution does not alter TYK2 expression, catalytic activity or ability to relay signaling in EBV-B cell lines or in reconstituted TYK2-null cells. Based on in silico predictions that these variants may impact splicing of exon 8, we: i) analyzed TYK2 transcripts in genotyped EBV-B cells and in CRISPR/Cas9-edited cells, ii) measured splicing using minigene assays, and iii) performed eQTL (expression quantitative trait locus) analysis of TYK2 transcripts in primary monocytes and whole blood cells. Our results reveal that the two variants promote the inclusion of exon 8, which, we demonstrate, is essential for TYK2 binding to cognate receptors. In addition and in line with GTEx (Genetic Tissue Expression) data, our eQTL results show that rs2304256 mildly enhances TYK2 expression in whole blood. In all, these findings suggest that these TYK2 variants are not neutral but instead have a potential impact in AID.
Highlights
Genetic association studies have assigned to the TYK2 locus an impact on susceptibility to systemic lupus erythematosus (SLE) and other autoimmune diseases (AID)
The identification has been replicated in a number of recent analyses, and TYK2 is recognized as a susceptibility gene in a variety of inflammatory and autoimmune diseases, including type I diabetes (T1D), psoriasis and multiple sclerosis (Table 1)
It will be necessary to map causal single nucleotide polymorphisms (SNP)(s) within clustered SNPs that are in linkage disequilibrium (LD), validate their impact on TYK2 expression and function, define which signaling pathways and molecular processes are most affected by the variation and possibly identify the cell type(s) and/or cell state(s) driving the association in any given disease
Summary
Genetic association studies have assigned to the TYK2 locus an impact on susceptibility to systemic lupus erythematosus (SLE) and other autoimmune diseases (AID). It will be necessary to map causal SNP(s) within clustered SNPs that are in linkage disequilibrium (LD), validate their impact on TYK2 expression and function, define which signaling pathways and molecular processes are most affected by the variation and possibly identify the cell type(s) and/or cell state(s) driving the association in any given disease These represent major challenges, since TYK2 is a ubiquitous tyrosine kinase that relays signaling of many antiviral and immunoregulatory cytokines (type I and type III IFNs, IL-10, IL-12, IL-22, IL-23) acting on a variety of immune and non-immune cells [3, 4]. Another study showed that heterozygosity at rs12720356 (I684S), but not rs34536443 (P1104A), leads to reduced IL12 signaling in CD4+ and CD8+ T cells [10] While these findings underline a complex picture, they do converge on the view that these two hypomorphic alleles confer protection to auto-inflammatory and auto-immune conditions in European populations. Combined to cis expression quantitative trait locus (eQTL) analysis of TYK2 in monocytes and whole blood from genotyped individuals, our results revealed an impact of these variants on splicing of a small exon which is essential for TYK2 binding to cytokine receptors
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