ACR Meeting Abstracts

ACR Meeting Abstracts

Abstract Number: 1610

DNA Methylation Changes Observed in Rheumatoid Arthritis Joint Tissue Are Detectable in CD4+ Naive T Cells from Peripheral Blood

Calliope Holingue1, Brooke Rhead1, Michael Cole1, Xiaorong Shao1, Hong L. Quach1, Diana Quach1, Elizabeth Sinclair2, Jonathan D. Graf3, Thomas M. Link4, Ruby Harrison5, Vladimir Chernitskiy6, Wei Wang7, Gary S. Firestein8, Lisa F. Barcellos1 and Lindsey A. Criswell5, 1Genetic Epidemiology and Genomics Laboratory, University of California, Berkeley, Berkeley, CA, 2Division of Laboratory Medicine, University of California, San Francisco, San Francisco, CA, 3Div Of Rheumatology, Division of Rheumatology, UCSF, San Francisco, CA, 4Musculoskeletal Quantitative Imaging Research Group, Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, CA, 5Rosalind Russell / Ephraim P. Engleman Rheumatology Research Center, University of California, San Francisco, San Francisco, CA, 6Rheumatology, University of California, San Francisco, San Francisco, CA, 7Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA, 8Division of Rheumatology, Allergy and Immunology, University of California, San Diego, La Jolla, CA

Meeting: 2015 ACR/ARHP Annual Meeting

Date of first publication: September 29, 2015

Keywords: ,

Session Information

Date: Monday, November 9, 2015

Title: Rheumatoid Arthritis - Human Etiology and Pathogenesis Poster II

Session Type: ACR Poster Session B

Session Time: 9:00AM-11:00AM

Background/Purpose:

Aberrant DNA methylation patterns have previously been associated with rheumatoid arthritis (RA) [MIM 180300]. Our study aimed to determine whether differentially methylated CpGs in synovium-derived fibroblast-like synoviocytes (FLS) of RA patients were also differentially methylated in peripheral blood samples. 

Methods:

DNA methylation was measured by generating 371 genome-wide DNA methylation profiles for 63 RA cases (all satisfied the ACR classification criteria, 57 were seropositive), and 31 controls using Illumina HumanMethylation450 (450k) BeadChips. Cells from peripheral blood were FACS-sorted and CD14+ monocytes, CD19+ B cells, CD4+ memory T cells, and CD4+ naive T cells were assayed for each individual. One-tailed Wilcoxon rank sum tests were used to analyze case-control differences in the FLS candidates within these four cell types. Receiver operating characteristic (ROC) curve analysis was employed to test the predictive power of a hypermethylation score based on the differentially methylated sites we observed. 

Results:

Of the 5,532 hypermethylated FLS candidates, 1,056 (19%) were hypermethylated in CD4+ naive T cells of our RA cases compared to controls (FDR q<0.05). No other CpG candidates achieved significance in the other cell types. A hypermethylation score was calculated based on these results and had an area under the curve (AUC) of 0.73 when predicting RA case status. This hypermethylation score was compared to having the HLA-DRB1 shared epitope (SE) (yes/no) and a continuous genetic risk score consisting of 43 non-HLA SNPs (Yarwood 2013 and Eyre 2012). The SE model had an AUC of 0.66 (0.56-0.77), and the genetic risk score had an AUC of 0.51 (0.38-0.63). A combined model of shared epitope, GRS and the methylation score had an AUC of 0.78, which was the best predictive model. Both methylation score and SE remained significant (p<0.05) when included in a multivariable logistic model of methylation score, SE and genetic risk score, with RA case-status as the outcome. Although the methylation score had a greater AUC than the SE (0.73 versus 0.66), the SE had a larger odds ratio in the multivariable logistic regression model (5.31 versus 1.06). 

Conclusion:

Our results suggest that measurement of DNA methylation in CD4+ naive T cells of peripheral blood may have diagnostic or prognostic value and represents one of the first steps towards precision medicine in RA.

Disclosure: C. Holingue, None; B. Rhead, None; M. Cole, None; X. Shao, None; H. L. Quach, None; D. Quach, None; E. Sinclair, None; J. D. Graf, None; T. M. Link, None; R. Harrison, None; V. Chernitskiy, None; W. Wang, None; G. S. Firestein, None; L. F. Barcellos, None; L. A. Criswell, None.

To cite this abstract in AMA style:

Holingue C, Rhead B, Cole M, Shao X, Quach HL, Quach D, Sinclair E, Graf JD, Link TM, Harrison R, Chernitskiy V, Wang W, Firestein GS, Barcellos LF, Criswell LA. DNA Methylation Changes Observed in Rheumatoid Arthritis Joint Tissue Are Detectable in CD4+ Naive T Cells from Peripheral Blood [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). https://acrabstracts.org/abstract/dna-methylation-changes-observed-in-rheumatoid-arthritis-joint-tissue-are-detectable-in-cd4-naive-t-cells-from-peripheral-blood/. Accessed .

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