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Objective.  Polymorphisms in human major histocompatibility complex (MHC) are the strongest genetic associations with rheumatoid arthritis (RA). Epigenome-wide methylation studies suggest DNA methylation changes within MHC may contribute to disease susceptibility. We profiled MHC-specific methylated CpG (5′–C–phosphate–G–3′) in autoantibody-positive patients with RA and matched unaffected anticitrullinated protein antibodies–negative first-degree relatives (ACPA−/FDR) from an indigenous North American (INA) population that is known to have prevalent RA.    Methods.  DNA was isolated from whole blood and targeted bisulfite sequencing was used to profile methylated CpG in patients with RA and ACPA−/FDR. Differentially methylated CpG loci (DML) were mapped and gene annotated. Ingenuity pathway analysis (IPA) was used for curating biomolecular networks of mapped genes. Transcript abundance was determined by quantitative (q)PCR.    Results.  We identified 74 uniquely methylated CpG sites within the MHC region that were differentially methylated in patients with RA (p &lt; 0.05), compared to ACPA−/FDR. Of these, 32 DML were located on 22 genes. IPA showed these genes are involved in regulating the nuclear factor–κB complex and processes involved in antigen presentation, and immune cell crosstalk in autoimmunity. Pearson correlation analysis demonstrated a negative association between differentially methylated CpG in the  C6ORF10  gene and risk factors associated with RA. Analysis by qPCR confirmed differential abundance of  C6ORF10 ,  TNXB,  and  HCG18  mRNA in patients with RA compared to ACPA−/FDR.    Conclusion.  Our results confirm the presence of differential methylation at specific gene loci within the MHC region of INA patients with RA. These epigenetic signatures may precede disease onset, or alternatively, may be a result of developing RA.

Whole Blood Targeted Bisulfite Sequencing and Differential Methylation in the C6ORF10 Gene of Patients with Rheumatoid Arthritis