Alternate allele counts associate with ancestry, age at disease onset, organ involvement and disease severity in juvenile systemic lupus erythematosus

Background: Juvenile systemic lupus erythematosus (jSLE) is more severe when compared to adult- onset disease, with higher disease activity, more organ damage and less favourable outcomes. Genetic factors have been suggested to influence age at disease onset, disease phenotypes and severity of SLE. Aims: This study explored associations between genetic burden, approximated through alternate allele counts (AAC), and age at disease onset, sex, ancestry, disease activity/severity, organ involvement and treatments in jSLE. Methods: 289 participants from the UK jSLE Cohort Study were studied applying a panel sequencing approach covering 62 genes/genomic regions. Clinico-demographic features, disease activity and treatments were recorded. Panel-wide AAC and gene-level alternate allele scores (GAAS) were generated by counting and weighting alternate alleles considering their in silico predicted impact on gene function. Correlation analyses were applied to investigate associations between genetic burden, ancestry and age at diagnosis. Generalised linear models, adjusted for ancestry, sex and family history of autoimmune/inflammatory diseases, were used to interrogate associations with organ involvement and disease activity/severity. Results: A weak inverse correlation was found between age at diagnosis and AAC (R=-0.15, p=0.01) that was primarily driven by a moderate inverse correlation in South Asians (R=-0.28, p<0.001). Black African/Caribbean patients exhibited higher AAC compared to remaining ancestral groups (p<0.001). Constitutional (p<0.001), renal (p=0.001), haematological (p=0.001) and neuropsychiatric (p=0.03) involvement and treatment intensity (p<0.001) were associated with AAC. GAAS associated with clinical variables, including severity of neuropsychiatric (ACP5, TYK2, RNASEH2A, p<0.001; RASGRP3, p=0.04) and renal (ACP5, ITGAM, LYN, p<0.001; TNFAIP3, p=0.007) involvement. Conclusions: Genetic variability likely contributes to early disease expression in South Asian patients. GAAS associate with organ involvement and disease activity/severity across ancestries. Observations from this study argue for genetic risk assessment and future patient stratification towards personalised treatment and care.