DNA Methylation Profiles That Distinguish Rheumatoid Arthritis from Osteoarthritis in Fibroblast-like Synoviocytes Can be Detected in Immune Cells from Peripheral Blood

Brooke Rhead¹, Calliope Holingue², Michael Cole², Xiaorong Shao², Hong L. Quach³, Diana Quach³, Lisa F. Barcellos³ and Lindsey A. Criswell⁴, ¹Genetic Epidemiology and Genomics Laboratory, Division of Epidemiology, University of California, Berkeley, Berkeley, CA, ²Genetic Epidemiology and Genomics Lab, Division of Epidemiology, University of California, Berkeley, Berkeley, CA, ³Epidemiology, University of California, Berkeley, Berkeley, CA, ⁴Medicine, University of California, San Francisco, Rosalind Russell / Ephraim P. Engleman Rheumatology Research Center, San Francisco, CA

Meeting: 2014 ACR/ARHP Annual Meeting

Keywords: DNA Methylation and rheumatoid arthritis (RA)

Session Information

Title: Rheumatoid Arthritis - Human Etiology and Pathogenesis

Session Type: Abstract Submissions (ACR)

Background/Purpose: Rheumatoid arthritis (RA) is a chronic inflammatory disease with potential to cause substantial disability, primarily due to the erosive and deforming process in joints. RA etiology is complex, with contributions from genetic and non-genetic factors. Epigenetic changes, such as altered patterns of DNA methylation, are also present in RA. Recent work by Firestein and colleagues (Nakano, 2013) compared genome-wide DNA methylation profiles in synovium-derived fibroblast-like synoviocytes (FLS) from RA patients and osteoarthritis controls and identified a set of differentially methylated genes that appear to distinguish these two forms of arthritis. Given the greater accessibility of peripheral blood compared to synovium-derived FLS, we set out to determine whether similar methylome signatures were present in immune cell subsets in peripheral blood.

Methods: We generated over 400 genome-wide DNA methylation profiles for 101 women (70 cases and 31 controls) using Illumina HumanMethylation450 BeadChips. Four FACS-sorted immune cell types were assayed for each individual: CD14+ monocytes, CD19+ B cells, CD4+ memory T cells, and CD4+ naive T cells. All samples were background subtracted using the lumi Bioconductor package and normalized using all sample mean normalization (ASMN) followed by beta-mixture quantile normalization (BMIQ). All study individuals were fully characterized for whole genome SNP profiles using the Illumina OmniExpress BeadChip. We excluded CpG sites near SNPs known to be common (>1%) from analysis, as well as sites with a low detection p-value, leaving 367,704 sites for analysis.

Results: We examined the top differentially hypo- and hypermethylated (n = 17 and 18, respectively) loci from the Firestein study in each immune cell type and found strong evidence for overlapping RA methylome signatures between FLS and immune cells. The most significantly differentially methylated genes in cases vs. controls include STK24, ADAMTS2, CABLES1, CD55, COL4A1, COL4A2, CYFIP1, FOXO1, ITGB8, ITGBL1, MAP3K1, PHLPP1, PTPN14, RXRA, TGFBR2, and TIMP2. The strongest evidence for replication of differential methylation in candidate gene regions was observed for naive CD4+ T cells; more than 20% of CpG sites tested were hypermethylated in cases compared to controls.

Conclusion: Methylation patterns that distinguish RA cases from controls in FLS are also present in immune cells from peripheral blood. Our investigation of DNA methylation underscores the importance of epigenetic mechanisms in RA pathogenesis and represents the largest study, to date, of methylome profiles derived from immune cells.

Disclosure:

B. Rhead,
None;

C. Holingue,
None;

M. Cole,
None;

X. Shao,
None;

H. L. Quach,
None;

D. Quach,
None;

L. F. Barcellos,
None;

L. A. Criswell,
None.

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