Need Help?
Copied to clipboard!

DNA Methylation and its Relation to Anti-citrullinated Protein Antibody Positivity and Rheumatoid Arthritis from a General Population-based Sample

Objective: To compare DNA methylation in subjects positive vs. negative for anti-citrullinated protein antibodies (ACPA), a key serological marker of rheumatoid arthritis (RA) risk.Methods: Using banked serum from a random subset (N=3,600) of a large general population cohort (N=20,000), we identified subjects who were ACPA positive, and compared these to age and sex matched ACPA negative controls. We used a custom-designed methylome panel to conduct targeted bisulphite sequencing based investigation of 5M CpGs located in regulatory or hypomethylated regions of circulating blood cells. Using binomial regression model, we investigated the differentially methylated regions (DMRs) between ACPA positive versus negative subjects, and in an independent set of T-cells assayed in patients with RA.Results: We measured methylation in blood samples from 137 subjects, 63, 66 and 8 of which were ACPA positive, ACPA negative, and self-report RA, respectively. We identified 1,252 DMRs by considering dose-dependent effects where half (614) of them are underlined genetic effects. These DMRs are enriched in exon, intergenic CpG islands (CGI) and CGI shore regions as well as enhancer-like regions of several blood cell sub-types. Furthermore, the genes associated with these DMRs were enriched in pathways related to immune response such as osteoclast differentiation and MAPK signaling pathway. In addition, 42 (30%) of 142 RA-specific DMRs were well replicated in T-cells cohort.Conclusions: Our results highlight the advantages of sequencing-based high-resolution methylome mapping to reveal biological relevant DNA methylation changes in ACPA positive and negative subjects as well as RA patients.