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Lookup NU author(s): Dr Joe Berry, Professor Fai Ng
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© The Author(s) 2026.The 3′ − 5′ DNA exonuclease, TREX1, is a negative regulator of the type I interferon response, while TREX1 variants are considered to confer risk for non-monogenic systemic lupus erythematosus (SLE). Here we analyse TREX1 sequences in 469,229 UK Biobank participants together with multi-omics data from the UK Biobank Pharma Proteomics Project to reappraise the contribution of reported TREX1 risk variants in SLE. We find that TREX1 variants are not associated with increased risk for SLE in UK Biobank, and most reported risk variants are functionally neutral in mutagenesis experiments. Deriving an oligoprotein interferon signature from broad capture proteomics, we find that this signature is associated with elevated SLE risk, but is not elevated in TREX1 variant carriers. Furthermore, TREX1 variants are not associated with other autoimmune diseases with a prominent oligoprotein interferon signature. Finally, meta-analysis of published studies confirms the lack of support for the association between SLE and TREX1 risk variants. In summary, we find that, while oligoprotein type I interferon signatures increase risk of SLE, TREX1 variants do not.
Author(s): Rioux B, McGlasson S, Forbes D, Reid KR, Klingseisen A, Berry J, Dhaun N, Ng WF, Whiteley W, Hunt DPJ
Publication type: Article
Publication status: Published
Journal: Nature Communications
Year: 2026
Volume: 17
Online publication date: 27/01/2026
Acceptance date: 05/12/2025
Date deposited: 09/02/2026
ISSN (electronic): 2041-1723
Publisher: Springer Nature
URL: https://doi.org/10.1038/s41467-025-67832-z
DOI: 10.1038/s41467-025-67832-z
Data Access Statement: All data are included in the Supplementary Information or available from the authors, as are unique reagents used in this Article. The raw numbers for charts and graphs are available in the Source Data file whenever possible. UK Biobank data supporting the findings can be accessed through application to the resource: https://www.ukbiobank.ac.uk/enable-your-research/apply-for-access. Source data are provided with this paper.
PubMed id: 41593088
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