| Title: | Oligoprotein type I interferon signatures, but not TREX1 variants, increase risk of systemic lupus erythematosus in UK Biobank |
| Journal: | Nature Communications |
| Published: | 27 Jan 2026 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/41593088/ |
| DOI: | https://doi.org/10.1038/s41467-025-67832-z |
| URL: | https://www.nature.com/articles/s41467-025-67832-z_reference.pdf |
Publication 18456
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Abstract
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.</p>
16 Keywords
- Adult
- Biological Specimen Banks
- Exodeoxyribonucleases
- Female
- Genetic Predisposition to Disease
- Humans
- Interferon Type I
- Lupus Erythematosus, Systemic
- Male
- Middle Aged
- Phosphoproteins
- Polymorphism, Single Nucleotide
- Proteomics
- Risk Factors
- UK Biobank
- United Kingdom
10 Authors
- Bastien Rioux
- Sarah McGlasson
- Deborah Forbes
- Katy R. Reid
- Anna Klingseisen
- Joe Berry
- Neeraj Dhaun
- Wan Fai Ng
- William Whiteley
- David P. J. Hunt
1 Application
| Application ID | Title |
|---|---|
| 93160 | The role of interferons in the risk of cerebrovascular disease |
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