Oligoprotein type I interferon signatures, but not TREX1 variants, increase risk of systemic lupus erythematosus in UK Biobank

TL;DR

This study finds that TREX1 gene variants do not increase the risk of lupus, but a specific interferon signature does.

Contribution

The study reevaluates TREX1's role in lupus using large-scale data and finds no link between TREX1 variants and lupus risk.

Findings

TREX1 variants are not associated with increased risk of systemic lupus erythematosus (SLE) in UK Biobank.

An oligoprotein type I interferon signature is associated with elevated SLE risk.

TREX1 variants are not linked to other autoimmune diseases with similar interferon signatures.

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.

Genetic variants of TREX1, a negative regulator of type I interferon responses, have been linked previously to non-monogenic systemic lupus erythematosus (SLE). Here the authors analyze UK Biobank multi-omics data to show that, while a derived oligoprotein interferon signature associates with increased SLE risk, TREX1 variants do not.

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