Hypomethylation of the <em>Dual Specificity Phosphatase</em> (<em>DUSP22</em>) Promoter in Cell-Free DNA (cf-DNA) Is Associated with Rheumatoid Arthritis and Joint Space Narrowing

Background/Objective: While several advances have been made in the last decade, reliable biomarkers for diagnosis, prognosis, and especially for the treatment of rheumatoid arthritis (RA) have yet to be identified. In previous studies, DUSP22 DNA methylation changes were found to be associated with RA and erosive disease. We conducted a pilot study to investigate plasma cell-free DNA (cfDNA) methylation in DUSP22 in a cohort of RA patients and healthy controls. We also investigate DUSP22 DNA methylation associations with RA clinical characteristics and treatment. Methods: DNA was isolated from plasma from twenty-seven RA patients who satisfied the ACR criteria, and eighteen healthy controls. DUSP22 DNA methylation was determined by pyrosequencing. Statistical analysis identified group differences and associations with RA clinical measures. Results: RA patients had lower mean promoter cfDNA DUSP22 DNA methylation when compared to controls (36.47±16.17% vs. 47.05±10.28%, p=0.025). Hypomethylation of one CpG site in this region was also associated with increased joint space narrowing (ρCpG2=-0.41, p=0.04). Conclusion: Our pilot study is the first to show that cfDNA methylation might be an important biomarker in RA. Our hypothesis-generating findings suggest that hypomethylation of DUSP22 in cfDNA is associated with RA, and if replicated in future studies, our results point to the potential of cfDNA methylation to be a non-invasive biomarker for this disease.