Session Type: Poster Session (Monday)
Session Time: 9:00AM-11:00AM
Background/Purpose: Systemic sclerosis (SSc) is a rare, fibrotic autoimmune disorder characterized by cutaneous and visceral fibrosis, immune dysregulation, and vasculopathy. It disproportionately affects individuals of African ancestry (AA) who, despite the higher disease severity, are dramatically underrepresented in research. Monocytes show heightened activation in SSc, and in AA relative to European ancestry individuals. Monocytes are thus a good target tissue for elucidating disease mechanisms. In this study, we sought to identify differentially methylated loci associated with SSc in classical monocytes from AA patients.
Methods: We profiled DNA methylation patterns on FACS-isolated classical monocytes (CD14++CD16-) from 12 female AA SSc cases and 12 female AA controls using Illumina’s MethylationEPIC BeadChip. All patients met the 2013 ACR/EULAR classification criteria for SSc. After QC and data normalization, a linear mixed model analysis was computed to examine DNA methylation differences between patients and controls, including disease status as a random effect and the first two principal components as fixed effects. The best model was selected based off on the QQ plot. Associated CpGs identified as significant were used to identify the closest gene and then those genes were analyzed for common pathways and functions.
Results: In addition to CpGs near several pseudogenes, top differentially methylated CpGs (P< 10E-05) included those near the cilia and flagellar motility CFAP44 gene, the T-cell surface glycoprotein CD5, the ubiquitin ligase TRIM4, the angiopoietin ANGPTL4, the DNA repair FANCC, the synthetase OAS3, and the transporter SLC41A2. The top genes have known immune, angiogenic, and transcription regulation roles.
Conclusion: These data support a role for DNA methylation differences in mediating sustained monocyte activation and susceptibility to SSc in AA. Many of the differentially methylated genes comprise pseudogenes and non-coding RNA genes, supporting a contribution of dysregulated regulatory elements to disease. Although DNA methylation studies in skin fibroblasts revealed an enrichment of extracellular matrix and focal adhesion genes, our results in monocytes support a dysregulation of genes involved in immune processes, which is consistent with gene expression studies in different peripheral blood subsets. Collectively, these results support the need to understand the regulatory architecture of SSc in different cell types and in individuals of different ancestries.
To cite this abstract in AMA style:Allen P, Wirth J, Wilson N, Oates J, Cunningham M, Absher D, Ramos P. Genome-Wide DNA Methylation Signatures in Classical Monocytes from African Ancestry Patients with Systemic Sclerosis [abstract]. Arthritis Rheumatol. 2019; 71 (suppl 10). https://acrabstracts.org/abstract/genome-wide-dna-methylation-signatures-in-classical-monocytes-from-african-ancestry-patients-with-systemic-sclerosis/. Accessed April 13, 2021.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/genome-wide-dna-methylation-signatures-in-classical-monocytes-from-african-ancestry-patients-with-systemic-sclerosis/