Genome-wide methylation profiling identifies signatures of pain, fatigue, and health scores in women with systemic lupus erythematosus

Rheumatology (Oxford). 2026 Jul 30:keag392. doi: 10.1093/rheumatology/keag392. Online ahead of print.

ABSTRACT

OBJECTIVES: People with Systemic Lupus Erythematosus (SLE) experience high levels of pain and fatigue with poor overall health, which persist in those with low disease activity. By performing epigenome-wide DNA methylation analysis, this study aims to identify epigenetic alterations associated with self-reported scores for pain, fatigue, and health in women with SLE.

METHODS: Forty-eight women with SLE from the SLEGOT cohort were included. Study participants exhibited low disease activity (median SLEDAI-2K= 0) and minimal damage (median SLICC damage index=0). An epigenome-wide DNA methylation analysis in whole blood identified 704,237 CpG loci, with 511,673 annotated to known genes.

RESULTS: We identified 485, 591, and 577 differentially methylated CpGs linked to pain, fatigue, and poor health, respectively. The association of reported pain with CpGs in GPR107, SPHK2, HBA1, and RERE genes suggested a potential role for neuromodulation in pain perception in SLE. For fatigue, enrichment analysis highlighted pathways related to neuronal development, morphogenesis, and synaptic signalling. Nine genes, including BDNF and TGIF1, showed strong correlations with all three scores, suggesting a shared epigenetic influence that may underline pain, fatigue, and poor health in SLE. Specific microRNA genes were differentially methylated in relation to pain and fatigue.

CONCLUSION: By studying a cohort of women with well-controlled SLE, we identified several CpGs and genes associated with pain, fatigue, and general health. Our findings suggest that epigenetic changes in genes involved in neuronal modulation, rather than inflammatory pathways, could be involved in the development of these symptoms in patients with SLE.

PMID:42530360 | DOI:10.1093/rheumatology/keag392