Background/Purpose: Systemic sclerosis (SSc) is a multisystem autoimmune disorder that has an unclear etiology and disproportionately affects individuals of African ancestry (AA). Despite this, AA individuals are dramatically underrepresented in SSc research. Additionally, monocytes show heightened activation in SSc, and in AA relative to European ancestry (EA) individuals. Monocytes are thus a good target tissue for elucidating disease mechanisms. In this study, we sought to identify changes in genome-wide DNA methylation and gene expression levels in classical monocytes from AA SSc patients and unaffected AA controls.

Methods: Classical monocytes (CD14++CD16-) were FACS-isolated from 17 SSc cases and 18 controls. All patients met the 2013 ACR/EULAR classification criteria for SSc. All participants were self-reported AA female. DNA methylation was profiled using Illumina’s MethylationEPIC BeadChip to identify differentially methylated CpGs. RNA-seq was performed to identify differentially expressed genes. Expression quantitative trait methylation (eQTM) analysis was computed to identify CpGs associated with changes in gene expression.

Results: Many of the top differentially methylated CpGs map to genes with roles in immune pathways, including T-cell surface glycoprotein CD5, oligoadenylate synthetase OAS3, and DNA repair FANCC. The SSc monocyte transcriptome showed an enrichment of genes in the AMPK signaling pathway, genes involved in chromatin organization, transcription factor binding, and glycogen storage diseases. The top differentially expressed genes include heparanase HPSE, collagen COL9A2, and chromatin regulator SMARCA4. The top eQTM genes included transcriptional repressor homolog PCGF1, RNA helicase DDX27, transcription factor E2F4, and hydrolase KYNU.

Conclusion: To the best of our knowledge, this is the first study to investigate DNA methylation and gene expression signatures in classical monocytes from SSc patients of African ancestry. The relatively modest differences in DNA methylation and gene expression observed between patients and controls is consistent with prior evidence of stronger inflammatory signatures in AA relative to EA individuals. These data support a possible role for DNA methylation and gene expression differences in mediating sustained monocyte activation and susceptibility to SSc in AA individuals.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/genome-wide-dna-methylation-and-gene-expression-signatures-in-classical-monocytes-from-african-ancestry-patients-with-systemic-sclerosis/