Renaudineau, Yves;
Sposito, Francesca;
Natoli, Valentina;
Charras, Amandine;
Hawkes, Jenny;
Roachdown, Joni;
Fusaro, Mathieu;
... Sridhar, Arani; + view all
(2025)
Common Toll-like receptor 7 variants define disease risk and phenotypes in juvenile-onset systemic lupus erythematosus.
Journal of Autoimmunity
, 155
, Article 103451. 10.1016/j.jaut.2025.103451.
(In press).
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Abstract
Toll-like receptor (TLR)7 contributes to type I interferon (IFN) expression in systemic lupus erythematosus (SLE). This study investigated genetic variability of TLR7 in 319 juvenile-onset (j)SLE patients from the UK. New generation sequencing was used to associate “common” TLR7 variants with demographic and clinical features. Three jSLE-associated variants with in silico predicted impact on gene function presented minor allele frequencies ≥5 %: rs2302267/n.-20T > G (TLR7 promoter); rs179008/p.Gln11Leu (missense variant with predicted loss-offunction); and rs3853839/c.*881C > G (TLR7 3′UTR). The risk to develop jSLE was increased in African/ Caribbean girls carrying rs3853839 GC/GG (OR: 1.8; 95 %-CI: 1.2–2.9), while the risk associated with this variant was reduced in European girls (OR: 0.5; 95 %-CI: 0.4–0.7). At inclusion, rs3853839 minor G allele carrier status associated with activity in the mucocutaneous BILAG domain (p = 0.004), “older” age at diagnosis (p = 0.003, Asian), C3 consumption (p = 0.015, boys), and higher anti-dsDNA antibody levels (p = 0.015, African/ Caribbean). The negative linkage disequilibrium between rs179008 (T-C/TT) and rs3853839 (CC) associated with increased global disease activity (pBILAG-2004), and activity in the constitutional and musculoskeletal pBILAG domains. Functionally, rs2302267/n.-20T > G, may protect from leukopenia through reduced TLR7 promoter activity, while rs3853839/c.*881C > G-3′UTR increases TLR7 mRNA stability contributing to increased gene expression. In conclusion, common TLR7 variants may influence jSLE risk and organ involvement in an ancestry-specific manner. Observations argue for genetic risk stratification and future consideration of gene variants affecting TLR7 to guide personalized treatment and care strategies.
| Type: | Article |
|---|---|
| Title: | Common Toll-like receptor 7 variants define disease risk and phenotypes in juvenile-onset systemic lupus erythematosus |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1016/j.jaut.2025.103451 |
| Publisher version: | https://doi.org/10.1016/j.jaut.2025.103451 |
| Language: | English |
| Additional information: | © 2025 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). |
| Keywords: | SLE, Juvenile, TLR7, Haplotype, Gene, Allele |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10209905 |
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