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

Genetics significantly impacts systemic lupus erytematosus (SLE) risk, disease manifestations, and damage. Our aim was to identify genetic risk loci for disease activity burden over time.

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 [SLEDAI 2000 (SLEDAI-2K)] to derive adjusted mean SLEDAI-2K and glucocorticoid (AMSG) scores. We completed a genome-wide association study (GWAS) of AMSG, adjusted for sex and five PCs, and stratified by array, then meta-analysed GWAS (P < 5 × 10-8). 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 single nucleotide polymorphism (SNP) for AMSG and interferon-stimulated gene expression.

The cohort included 538 individuals with SLE (88% female), with a median age at diagnosis of 30.7 years (interquartile range = 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 = 4.16 × 10-9). 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 = 8.70 × 10-3, P = 0.006).

We identified a genome-wide significant locus intronic to AGAP1 for SLE disease activity burden as measured by AMSG.