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Background: Systemic lupus erythematosus (SLE) is a rare systemic autoimmune inflammatory disease that is characterized by profound immune dysregulation, tissue damage and organ failure. Pathologic activation of the type I interferons (T1IFN) is a key feature in SLE and associates with disease-associated polymorphisms in adult-onset disease (aSLE). Juvenile-onset (j)SLE is characterized by increased disease activity and damage, which likely relates to increased genetic burden. Currently, the exact contribution of T1IFN-associated polymorphisms to disease expression, clinical phenotypes and outcomes remains unclear. Objectives: This study aimed to identify T1IFN-associated gene variants and extended haplotypes in jSLE patients from the UK JSLE Cohort Study (http://www.liv.ac.uk/ukjsle) to associate genotypes with disease presentations, outcomes, and to predict gene:gene interactions (epistasis). Methods: A target enrichment next-generation sequencing approach focusing on nine T1IFN-associated genes (TLR7, IRAK1, miR-3142/miR-146a, IRF5, IRF7, IFIH1, IRF8, TYK2, STAT4) was conducted in jSLE patients (N=319) from the UK JSLE Cohort Study. Linkage disequilibrium (LD), coupled with phenotypic analysis of quantitative trait loci (QTL) from clinical/biological factors, was investigated using SNPstats (http://bioinfo.iconcologia.net/SNPstats), Pubmed (https://pubmed.ncbi.nlm.nih.gov/), ClinVar (https://www.ncbi.nlm.nih.gov/clinvar), GWAS catalogue (https://www.ebi.ac.uk/gwas/) and GTEx (https://gtexportal.org/). Results were integrated with demographic information and clinical datasets, including paediatric British Isles Lupus Assessment Group (pBILAG) organ domain and Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) scores, and the Systemic Lupus International Collaborative Clinics (SLICC) damage index. Results: Associations between jSLE disease expression, demographic and clinical characteristics, and polymorphisms in genes involved in endoplasmic (TLR7, IRAK1, miR-3142 which codes for miR-146a, IRF5, IRF7) and cytosolic (IFIH1, IRF8) nucleic acid sensing, and transcriptional control of T1IFNs (TYK2, STAT4) were identified. The chosen approach revealed associations with early disease-onset (before the 12th birthday; IRAK1, TLR7, IFIH1, STAT4, TYK2, IRF8), 'high' disease activity (SLEDAI-2K >10: IFIH1, STAT4, IRF8) and mucocutaneous involvement (TLR7, IFIH1). Furthermore, genetic impact on disease expression and associated phenotypes may be enhanced by gene:gene interrelationships. Comparing allele frequencies between jSLE patients and healthy controls, we identified 10 SLE QTL with a central relationship to T1IFN expression that confer an increased risk of developing SLE. Conclusion: In jSLE, an interrelation exists between gene variants affecting T1IFN expression, phenotypic features and disease outcomes. Genotyping may represent a future tool for patient stratification towards individualized treatment and care. Studies of larger, unrelated and multi-ethnic cohorts are needed to confirm results. REFERENCES: NIL. Acknowledgements: This work has been supported by LUPUS UK (CMH, MWB), Versus Arthritis UK for the EATC4Children (CMH, MWB), and the NIHR (GOSH BRC PEI, CMH). Disclosure of Interests: Amandine Charras: None declared, Yves Renaudineau: None declared, Valentina Natoli: None declared, Mathieu Fusaro: None declared, Eve MD Smith: None declared, Michael W Beresford: None declared, Christian Hedrich Merck to study lupus nephritis.
Charras et al. (Sat,) studied this question.