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

Lookup NU author(s): Dr Megan Hasoon, Dr Flora McErlane

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).

Abstract

© 2025 The Author(s). 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.

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Author(s): Natoli V, Charras A, Hasoon MSR, Jorgensen AL, Smith EMD, Caamano Gutierrez E, Beresford MW, Hedrich CM, Roberts C, Al-Abadi E, Armon K, Bailey K, Ciurtin C, Gardner-Medwin J, Haslam K, Hawley DP, Leahy A, Leone V, McErlane F, Modgil G, Pilkington C, Ramanan AV, Rangaraj S, Riley P, Sridhar A

Publication type: Article

Publication status: Published

Journal: Clinical Immunology

Year: 2025

Volume: 279

Print publication date: 01/10/2025

Online publication date: 15/06/2025

Acceptance date: 06/06/2025

Date deposited: 10/07/2025

ISSN (print): 1521-6616

ISSN (electronic): 1521-7035

Publisher: Academic Press Inc.

URL: https://doi.org/10.1016/j.clim.2025.110540

DOI: 10.1016/j.clim.2025.110540

Data Access Statement: Because not all results from this study have been published yet, raw sequencing data and processed dcc files will be made available upon reasonable request. Code to reproduce the analysis and figures is available at https://github.com/CBFLivUni/jSLE_paper

PubMed id: 40527401

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