Common Toll-like receptor 7 variants define disease risk and phenotypes in juvenile-onset systemic lupus erythematosus

Yves Renaudineau; Francesca Sposito; Valentina Natoli; Amandine Charras; Jenny Hawkes; Joni Roachdown; Mathieu Fusaro; Eve Md Smith; Michael W Beresford; Christian M Hedrich; UK jSLE Cohort Study

doi:10.1016/j.jaut.2025.103451

Common Toll-like receptor 7 variants define disease risk and phenotypes in juvenile-onset systemic lupus erythematosus

J Autoimmun. 2025 Jun 13:155:103451. doi: 10.1016/j.jaut.2025.103451. Online ahead of print.

Collaborators

UK jSLE Cohort Study:
Carla Roberts², Eslam Al-Abadi⁶, Kate Armon⁷, Kathryn Bailey⁸, Coziana Ciurtin⁹, Janet Gardner-Medwin¹⁰, Kirsty Haslam¹¹, Daniel P Hawley¹², Alice Leahy¹³, Valentina Leone¹⁴, Flora McErlane¹⁵, Gita Modgil¹⁶, Clarissa Pilkington¹⁷, Athimalaipet V Ramanan¹⁸, Satyapal Rangaraj¹⁹, Phil Riley²⁰, Arani Sridhar²¹

Affiliations

¹ Immunology Department Laboratory, Referral Medical Biology Laboratory, Institut Fédératif de Biologie, Toulouse University Hospital Center, France; INFINITy, Toulouse Institute for Infectious and Inflammatory Diseases, INSERM, U1291, CNRS U5051, University Toulouse III, Toulouse, France.
² Department of Women's & Children's Health, Institute of Life Course and Medical Sciences, University of Liverpool, UK.
³ Department of Women's & Children's Health, Institute of Life Course and Medical Sciences, University of Liverpool, UK; Università Degli Studi di Genova, Dipartimento di Neuroscienze, Riabilitazione, Oftalmologia, Genetica e Scienze Materno-infantili, DINOGMI, Genoa, Italy.
⁴ Department of Women's & Children's Health, Institute of Life Course and Medical Sciences, University of Liverpool, UK; Department of Rheumatology, Alder Hey Children's NHS Foundation Trust, Liverpool, UK.
⁵ Department of Women's & Children's Health, Institute of Life Course and Medical Sciences, University of Liverpool, UK; Department of Rheumatology, Alder Hey Children's NHS Foundation Trust, Liverpool, UK. Electronic address: christian.hedrich@liverpool.ac.uk.
⁶ Department of Rheumatology, Birmingham Children's Hospital, Birmingham, UK.
⁷ Department of Paediatric Rheumatology, Cambridge University Hospitals, Cambridge, UK.
⁸ Department of Paediatric Rheumatology, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.
⁹ Centre for Adolescent Rheumatology, University College London, London, UK.
¹⁰ Department of Child Health, University of Glasgow, Glasgow, UK.
¹¹ Department of Paediatrics, Bradford Royal Infirmary, Bradford, UK.
¹² Department of Paediatric Rheumatology, Sheffield Children's Hospital, Sheffield, UK.
¹³ Department of Paediatric Rheumatology, Southampton General Hospital, Southampton, UK.
¹⁴ Department of Paediatric Rheumatology, Leeds Children Hospital, Leeds, UK.
¹⁵ Paediatric Rheumatology, Great North Children's Hospital, Royal Victoria Infirmary, Institute of Cellular Medicine, Newcastle University, Newcastle Upon Tyne, UK.
¹⁶ Department of Paediatrics, Musgrove Park Hospital, Taunton, UK.
¹⁷ Department of Paediatric Rheumatology, Great Ormond Street Hospital, London, UK.
¹⁸ University Hospitals Bristol NHS Foundation Trust & Bristol Medical School, University of Bristol, Bristol, UK.
¹⁹ Department of Paediatric Rheumatology, Nottingham University Hospitals, Nottingham, UK.
²⁰ Department of Paediatric Rheumatology, Royal Manchester Children's Hospital, Manchester, UK.
²¹ Department of Paediatrics, Leicester Royal Infirmary, Leicester, UK.

PMID: 40516124
DOI: 10.1016/j.jaut.2025.103451

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-of-function); 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.

Keywords: Allele; Gene; Haplotype; Juvenile; SLE; TLR7.