Background/Purpose: SLE is a complex disease in need of novel therapies. Previously reported genome-wide association studies (GWAS) have identified a strong association between SLE and variants at the TYK2 locus, a well-known modulator of type 1 interferon and IL-12/23 signaling pathways. In this study we integrate SLE GWAS summary statistics and proteomics data from the UK Biobank resource to uncover additional pathways by which TYK2 modulates SLE pathogenesis. 

Methods: Summary statistics for a GWAS in SLE from the NHGRI-EBI GWAS Catalog were fine-mapped using susieR.  Fine-mapped variants were then subjected to a trans-protein-quantitative trait locus (pQTL) analysis using O-link data made available through UK Biobank. To assess whether TYK2 specific variants are uniquely driving signals in the region, we performed a GWAS on all proteins that were significant in the initial single-variant pQTL screen followed by fine-mapping and colocalization with the SLE GWAS summary statistics.  For pQTL associations that showed significant colocalization with SLE genetic susceptibility, we performed a protein level association analysis on SLE disease risk in UK Biobank. 

Results: Fine-mapping with the SLE GWAS resulted in two independent variant sets at the TYK2 locus, with one of those sets defined by the well-characterized TYK2 loss-of-kinase-function allele P1104A (rs34536443), a pharmacomimetic of TYK2 inhibition.  The initial pQTL screen identified 12 unique proteins as having at least one SLE based TYK2 variant association. Of these; IL12RB1, IFNAR1, BST2, CCL3, CCL4, CXCL10, CXCL11, LAG3, TNFRSF8, and TNFSF13B showed colocalization with SLE. Levels of these proteins were significantly increased in SLE cases compared to controls in the UK Biobank cohort. 

Conclusion: TYK2 genetic loss-of-kinase-function has previously been shown to be protective for a wide array of immune-mediated diseases. In this study, we aimed to uncover new protein pathways that may be influenced by TYK2 variation and furthermore contribute to SLE disease pathogenesis.  Novel T-cell and B-cell proteogenomic signatures were discovered to be mediated by TYK2 in the context of SLE. Two examples include LAG3 and TNFSF13B. LAG3 is a negative regulator of T-cell response; TNFSF13B is highly expressed in monocytes and acts in B-cell activation, differentiation, and proliferation. As a positive control, the results of our analyses corroborated the known association of TYK2 with IL12 and type 1 interferon pathways via modulation of IL12RB1 and IFNAR1 protein levels. Through systematic colocalization of trans-pQTL signals, we identified pathways beyond type I interferons that may contribute to the protective effect of TYK2 loss of function variants in autoimmune diseases.

« Back to ACR Convergence 2024

ACR Meeting Abstracts - https://acrabstracts.org/abstract/novel-role-of-tyk2mechanism-in-sle-pathogenesis-via-t-cell-and-b-cell-pathways/