Genetic variability associates with ancestry, age at disease onset, organ involvement and disease severity in juvenile-onset systemic lupus erythematosus.

Juvenile-onset systemic lupus erythematosus (jSLE) is a complex autoimmune/inflammatory disease in which genetic factors likely contribute to pathophysiology and clinical expression. This study explored associations between general (alternate allele counts; AAC) and gene-specific (alternate allele scores; GAAS) sequence variability, age at onset, sex, ancestry, disease activity/severity, organ involvement and treatments in jSLE. 289 participants from the UK JSLE Cohort Study underwent panel sequencing of 62 genes/genomic regions. Weighted AAC and GAAS were calculated. Correlation analyses and generalized linear models assessed associations between genetic burden, ancestry, age at diagnosis and clinical variables. AAC inversely correlated with age at diagnosis (R = -0.15, p = 0.01), primarily driven by South Asians (R = -0.28, p < 0.001). African/Caribbean patients exhibited higher AAC (p < 0.001). Clinical variables, including severity of renal involvement (ACP5, ITGAM, LYN, p < 0.001; TNFAIP3, p = 0.007), associated with GAAS. Genetic variability likely contributes to early disease expression and severity in jSLE, supporting patient stratification and personalised care.