Background/Purpose: Genetic factors and epigenetic dysregulation are implicated in the pathogenesis of lupus. We performed a longitudinal analysis of DNA methylation in lupus patients for the first time. We assessed epigenetic changes over time and across disease activity status. Combining genomic and epigenomic analyses, we also examined ancestry-specific DNA methylation and DNA methylation changes influenced by genetic variants across the genome.

Methods: A total of 54 female lupus patients, including 32 European-American and 22 African-American, were followed over a period of up to 43 months. Blood samples were obtained at routine follow up visits and during disease flares, with a total of 229 samples collected. Disease activity at each blood draw was determined by SLEDAI. Granulocytes were isolated and DNA extracted. Genotyping was performed using the Infinium Global Screening Array v2.0, and genome-wide DNA methylation was assessed at each time-point using the Infinium MethylationEPIC array. Ancestry-specific DNA methylation changes were determined, and methylation quantitative trait loci (meQTL) analysis was performed. A linear mixed effects model was implemented to identify DNA methylation alterations that vary with disease activity.

Results: We identified 487 hypomethylated and 420 hypermethylated CpG sites in African-American compared to European-American lupus patients, annotated to 391 and 316 unique genes, respectively. Differentially methylated genes include type I interferon-response genes such as IRF7 and IFI44, and genes related to the NFkB pathway. After adjusting for age, medications, and genetic background, DNA methylation levels in 142 (15.7%) differentially methylated sites were found to be allele-specific and influenced by at least one genetic variant located within 1kb. TREML4, which plays a vital role in toll-like receptor signaling, was hypomethylated in African-American patients and demonstrated a strong cis-meQTL association (R²=0.91). The associated genetic variant (rs9369265) significantly differs in allele frequencies between African-American and European-American patients, and is located within an active enhancer region in neutrophils and modifies TREML4 expression. Interestingly, the DNA methylome was highly stable across different disease activity levels and over time. Methylation levels in SNX18 and FGD1 showed correlation with disease activity in African-American patients (P= 4.6 x 10^-8 and P= 3.7 x 10^-7, respectively). FGD1 is a guanine nucleotide exchange factor that activates the GTPase Cdc42 which has been shown to regulate neutrophil morphology during migration and apoptotic response to immune complex signaling.

Conclusion: Lupus granulocytes demonstrate significant differences in DNA methylation patterns between African-American and European-American patients. DNA methylation profiles in lupus patients are influenced by ancestry-specific genetic variants and are highly stable over time independent of disease activity levels. Progressive demethylation in SNX18 and FGD1 was observed with increasing disease activity in granulocytes from African-American lupus patients.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/genetic-epigenetic-interaction-and-the-relationship-between-dna-methylation-patterns-and-disease-activity-in-a-longitudinal-cohort-of-lupus-patients/