Date: Sunday, October 21, 2018
Session Title: Rheumatoid Arthritis – Etiology and Pathogenesis Poster I
Session Type: ACR Poster Session A
Session Time: 9:00AM-11:00AM
Human major histocompatibility complex (MHC) is strongly associated with rheumatoid arthritis (RA) pathogenesis. Epigenome-wide association study by Liu et al showed that differential DNA methylation within the MHC region can mediate RA genetic risk and contribute significantly to disease susceptibility . Our study objective was to validate Liu et al study findings in an independent study cohort genetically predisposed for developing clinically imminent RA. Therefore, we sequenced MHC-specific methylated CpGs in autoantibody-positive RA patients and matched disease-free healthy controls from a high-risk indigenous North American (INA) population.
DNA was isolated from whole blood (WB) samples and targeted bisulfite pyrosequencing was used to profile methylated CpGs. Differentially methylated CpG loci (DMLs) were mapped and gene-annotated using R package. mRNA expression of identified genes with multiple DMLs was verified using quantitative real-time PCR (qPCR) in an independent cohort of RA patients and HCs.
We identified 74 uniquely methylated CpG sites within the MHC region that were differentially methylated in the WB of RA patients (q < 0.05), compared to HCs. Of these, 36 DMLs were located on 19 genes. IPA network analyses showed these genes regulate NF-kB complex and processes involved in antigen presentation, immune cell crosstalk and inflammation in autoimmunity and insulin-dependent diabetes mellitus. By qPCR, we also demonstrated a deregulated expression of mRNAs corresponding to C6ORF10, TNXB and HCG18.
Our results demonstrate presence of specific differentially methylated loci within the genomic region encompassing MHC region in whole blood DNA of indigenous RA patients. While some of these genes (C6ORF10 and TNXB) confirm the findings of previous publication, we believe they might be involved in RA pathogenesis in high-risk INA individuals.
1. Liu, Y., et al., Epigenome-wide association data implicate DNA methylation as an intermediary of genetic risk in rheumatoid arthritis. Nat Biotechnol, 2013. 31(2): p. 142-7.
To cite this abstract in AMA style:Anaparti V, Smolik I, Agarwal P, Mookherjee N, El-Gabalawy H. Whole Blood Targeted Bisulfite Pyrosequencing Identifies Differentially Methylated Regions within Major Histocompatibility Complex (MHC) of Patients with Rheumatoid Arthritis [abstract]. Arthritis Rheumatol. 2018; 70 (suppl 10). https://acrabstracts.org/abstract/whole-blood-targeted-bisulfite-pyrosequencing-identifies-differentially-methylated-regions-within-major-histocompatibility-complex-mhc-of-patients-with-rheumatoid-arthritis/. Accessed July 23, 2019.
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