Type I interferon associated epistasis may contribute to early disease-onset and high disease activity in juvenile-onset lupus

• Published in: Clinical immunology (Orlando, Fla.) Vol. 262; p. 110194
• Main Authors: Renaudineau, Yves, Charras, Amandine, Natoli, Valentina, Fusaro, Mathieu, Smith, Eve M.D., Beresford, Michael W., Hedrich, Christian M.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.05.2024; Elsevier
• Subjects: Adult; Child; Epistasis; Epistasis, Genetic; Humans; Interferon; Interferon Regulatory Factors - genetics; Interferon Type I - genetics; Interferon-Induced Helicase, IFIH1; jSLE; Juvenile-onset systemic lupus erythematosus; Life Sciences; Lupus Erythematosus, Systemic - complications; Lupus Erythematosus, Systemic - genetics; MicroRNAs; QTL; SLEDAI-2 K; Toll-Like Receptor 7 - genetics; QTL; Interferon; Epistasis; jSLE; Juvenile-onset systemic lupus erythematosus; SLEDAI-2 K; SLEDAI-2 K
• ISSN: 1521-6616; 1521-7035
• DOI: 10.1016/j.clim.2024.110194

Pathologic type I interferon (T1IFN) expression is a key feature in systemic lupus erythematosus (SLE) that associates with disease activity. When compared to adult-onset disease, juvenile-onset (j)SLE is characterized by increased disease activity and damage, which likely relates to increased genetic burden. To identify T1IFN-associated gene polymorphisms (TLR7, IRAK1, miR-3142/miR-146a, IRF5, IRF7, IFIH1, IRF8, TYK2, STAT4), identify long-range linkage disequilibrium and gene:gene interrelations, 319 jSLE patients were genotyped using panel sequencing. Coupling phenotypic quantitative trait loci (QTL) analysis identified 10 jSLE QTL that associated with young age at onset (<12 years; IRAK1 [rs1059702], TLR7 [rs3853839], IFIH1 [rs11891191, rs1990760, rs3747517], STAT4 [rs3021866], TYK2 [rs280501], IRF8 [rs1568391, rs6638]), global disease activity (SLEDAI-2 K >10; IFIH1 [rs1990760], STAT4 [rs3021866], IRF8 [rs903202, rs1568391, rs6638]), and mucocutaneous involvement (TLR7 [rs3853839], IFIH1 [rs11891191, rs1990760]). This study suggests T1IFN-associated polymorphisms and gene:gene interrelations in jSLE. Genotyping of jSLE patients may allow for individualized treatment and care. •Gene:gene interrelations affecting type I interferons associate with jSLE phenotype.•Endoplasmic and cytosolic type I interferon pathways contribute to jSLE.•Disease activity in jSLE associates with cytosolic type I interferon engagement.•Genetic risk assessment may allow for future individualized treatment and care.