Background/Purpose: Systemic Lupus Erythematosus (SLE) is a potentially life-threatening autoimmune disease. Childhood-onset SLE (cSLE) patients have early disease onset and incur more organ damage than adults and thus may have a larger genetic burden. Previous studies describing the common variant contribution in cSLE were done in smaller, targeted cohorts. To address this gap, we completed whole genome sequencing (WGS) of cSLE patients enrolled in the Childhood Arthritis and Rheumatology Research Alliance (CARRA) Lupus Registry and Atherosclerosis Prevention in Pediatric Lupus Erythematosus (APPLE) study. We aim to common variant burden and investigate the association of common SLE risk variants with clinical features in 2 cSLE cohorts.

Methods: We recruited prevalent and incident cSLE (age of diagnosis < 19 years) patients enrolled and consented for in the CARRA Lupus Registry, and historical patients enrolled in the completed APPLE trial. All met ACR classification criteria. DNA samples were sequenced via whole genome sequencing using Illumina HiSeq X Ten (mean depth coverage 36x). Demographic and clinical data was available for both cohorts. Genetic ancestry was inferred using PEDDY and ADMIXTURE. We calculated additive HLA and non-HLA SLE polygenic risk scores and tested the association with age of SLE diagnosis and lupus nephritis (LN), adjusted for sex and ancestry separately by cohort, then meta-analyzed.

Results: Our study included n=394 (CLUE: 199; APPLE: 195). The majority were female, median age of diagnosis at 13.5 years, and approximately half of patients have lupus nephritis (Table1). We observed a significant association between HLA-PRS and LN (OR: 1.69 (95% CI:1.05, 2.74), P=0.03) (Figure 1), however HLA-PRS was not significantly associated with age of cSLE diagnosis. The non-HLA PRS was not significantly associated with either LN or of diagnosis.  

Conclusion: We observed an association between common SLE HLA risk variants and LN  in 2 cSLE cohorts. Our findings indicate that large, diverse cohorts of cSLE patients will be important for understanding genetic contributions to SLE pathogenesis. Future studies will investigate rare variants and the relationship to common variant burden in cSLE. The comprehensive genetic studies of the largest cSLE cohorts sequenced to date will improve our understanding of biologic mechanisms with genetic basis in cSLE.

Demographics and features cSLE patients enrolled in the CLUE and APPLE

Association between HLA SLE PRS and Lupus Nephritis, meta-analysis of CLUE and APPLE

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/understanding-etiology-clue-study-whole-genome-sequencing-of-childhood-onset-systemic-lupus-erythematosus/