Identified genetic locus for longitudinal disease activity in adults with systemic lupus erythematosus.

Objectives: Genetics significantly impact systemic lupus erythematosus (SLE) risk, disease manifestations, and damage. Our aim was to identify genetic risk loci for disease activity burden over time.
Methods: We included participants from a tertiary care Lupus Clinic. Participants met ACR and/or SLICC classification criteria for SLE, were genotyped on one of three arrays, and had > =3 measures of disease activity (SLE Disease Activity Index 2000 [SLEDAI-2K]) to derive adjusted mean SLEDAI-2K and glucocorticoid scores (AMSG). We completed a genome-wide association study (GWAS) of AMSG, adjusted for sex and 5 PCs, and stratified by array, then meta-analyzed GWAS (P < 5x10-8). Meta-GWAS results were used in colocalization analyses with expression quantitative trait loci in multiple tissues. In a subset of patients, we examined the association between the top SNP for AMSG and interferon-stimulated gene expression.
Results: The cohort included 538 individuals with SLE (88% female), with a median age at diagnosis of 30.7 years (IQR = 23.3, 41.7 years). Most patients (75%) had a first clinic visit within 1 year of SLE diagnosis and were followed for a mean of 4.5 years (SD = 0.95). The median AMSG was 5.5 (Q25, Q75 = 3.2,8.8). Meta-GWAS identified a genome-wide significant SNP for AMSG (rs4561613) on chromosome 2, intronic to AGAP1 (Beta = 0.34, SE = 0.06, p = 4.16x1 0 -9). Colocalization analysis did not identify a significant difference in gene expression for the top SNP. Interferon gene scores were significantly associated with AMSG (Beta = 0.02, SE = 8.70x10-3, p = 0.006).
Conclusion: We identified a genome-wide significant locus intronic to AGAP1 for SLE disease activity burden as measured by AMSG.
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