Abstract
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.
Highlights
Systemic lupus erythematosus (SLE or lupus) is an autoimmune disease of incompletely understood etiology
Using repeated sampling of lupus patients followed longitudinally, we can account for these factors and detect potentially novel changes in DNA methylation that are associated with disease activity over time
In the African American cohort, we identified a total of 8 CpG sites that met our suggestive FDR-adjusted P < 0.1 (Figure 1A and Table 1)
Summary
Systemic lupus erythematosus (SLE or lupus) is an autoimmune disease of incompletely understood etiology. Lupus is characterized by the production of autoantibodies against nuclear antigens and a remitting-relapsing disease course that can target multiple organ systems [2]. Lupus is associated with changes in gene expression, including prominent type I IFN and neutrophil gene signatures in the peripheral blood [4,5,6,7]. Increased disease activity in lupus is associated with transcriptional profiles implicating different innate and adaptive peripheral immune cells in individual patients followed longitudinally [7]. Progression to active nephritis in lupus patients was associated with gradual enrichment in neutrophil transcripts [7]. A prominent role for neutrophils in the pathogenesis of lupus is being more clearly elucidated [8]
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