| Summary: | Epigenetic dysregulation is implicated in the pathogenesis of lupus. We performed a longitudinal analysis to assess changes in DNA methylation in lupus neutrophils over 4 years of follow-up and across disease activity levels using 229 patient samples. We demonstrate that DNA methylation profiles in lupus are partly determined by ancestry-associated genetic variations and are highly stable over time. DNA methylation levels in 2 CpG sites correlated significantly with changes in lupus disease activity. Progressive demethylation in SNX18 was observed with increasing disease activity in African American patients. Importantly, demethylation of a CpG site located within GALNT18 was associated with the development of active lupus nephritis. Differentially methylated genes between African American and European American lupus patients include type I IFN–response genes such as IRF7 and IFI44, and genes related to the NF-κB pathway. TREML4, which plays a vital role in TLR signaling, was hypomethylated in African American patients and demonstrated a strong cis–methylation quantitative trait loci (cis-meQTL) effect among 8855 cis-meQTL associations identified in our study.
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