scholarly journals Differential Methylation as a Biomarker of Response to Etanercept in Patients With Rheumatoid Arthritis

2016 ◽  
Vol 68 (6) ◽  
pp. 1353-1360 ◽  
Author(s):  
Darren Plant ◽  
Amy Webster ◽  
Nisha Nair ◽  
James Oliver ◽  
Samantha L. Smith ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Differential Methylation

scholarly journals A DNA-Methylated Sight on Autoimmune Inflammation Network across RA, pSS, and SLE

2018 ◽  
Vol 2018 ◽  
pp. 1-13 ◽  
Author(s):  
Xingqiang Wang ◽  
Dongyun Lei ◽  
Jie Ding ◽  
Shuang Liu ◽  
Li Tao ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Lupus Erythematosus ◽  
Inflammatory Process ◽  
Methylation Status ◽  
Differential Methylation ◽  
Promoter Regions ◽  
Bioinformatics Analyses ◽  
Epigenetic Biomarkers ◽  
The Difference ◽  
Autoimmune Tautology

Methylation variabilities of inflammatory cytokines play important roles in the development of systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and primary Sjögren’s syndrome (pSS). With heightened focus on personalized and precise medicine, it is necessary to compare and contrast the difference and similarity of cytokine methylation status between the 3 most classic autoimmune diseases (AIDs). In this study, we integrated 5 Cytokine-Chips from genome-wide DNA methylation datasets of the 3 kind of AIDs, delta-beta value was calculated for intergroup difference, and comprehensive bioinformatics analyses of cytokine genes with aberrant methylations were performed. 125 shared differential methylation variabilities (DMVs) were identified. There were 102 shared DMVs with similar methylation status; 3 hypomethylated differential methylation regions (DMRs) across the AIDs were found, and all 3 DMRs were hypomethylated. DMRs (AZU1, LTBR, and RTEL1) were likely to serve as activator in the inflammatory process. Particularly, AZU1 and LTBR with hypomethylated TSS and first exon located in the promoter regions were able to trigger inflammation signaling cascades and play critical roles in autoimmune tautology. Moreover, functional epigenetic module (FEM) algorithm showed that different inflammatory networks are involved in different AIDs; 5 hotspots were identified as biologically plausible pathways in inducing or perpetuating of inflammation which are epigenetically deregulated in AIDs. We concluded methylation variabilities among the same cytokines can greatly impact the perpetuation of inflammatory process or signal pathway of AIDs. Differentiating the cytokine methylation status will serve as valuable resource for researchers alike to gain better understanding of the epigenetic mechanisms of the three AIDs. Even more importantly, better understanding of cytokine methylation variability existing between the three classic AIDs will aid in identification of potential epigenetic biomarkers and therapeutic targets. This trial is registered with ChiCTR-INR-16010290, a clinical trial for the treatment of rheumatoid arthritis with Warming yang and Smoothening Meridians.

scholarly journals FRI0017 DIFFERENTIAL METHYLATION AS A PREDICTOR OF TOCILIZUMAB RESPONSE IN PATIENTS WITH RHEUMATOID ARTHRITIS

2019 ◽  
Author(s):  
Nisha Nair ◽  
Darren Plant ◽  
John Isaacs ◽  
Ann Morgan ◽  
Kimme Hyrich ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Differential Methylation

OP0051 Differential Methylation Related to Response to Etanercept in Patients with Rheumatoid Arthritis

2013 ◽  
Vol 72 (Suppl 3) ◽  
pp. A67.1-A67
Author(s):  
A. Webster ◽  
D. Plant ◽  
S. Eyre ◽  
E. Flynn ◽  
P. Martin ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Differential Methylation

scholarly journals GENETICS258. INVESTIGATION OF DIFFERENTIAL METHYLATION AS A POTENTIAL BIOMARKER OF METHOTREXATE RESPONSE IN PATIENTS WITH RHEUMATOID ARTHRITIS

Rheumatology ◽  
2017 ◽  
Vol 56 (suppl_2) ◽  
Author(s):  
Nisha Nair ◽  
Darren Plant ◽  
Suzanne M. Verstappen ◽  
John D. Isaacs ◽  
Ann W. Morgan ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Differential Methylation ◽  
Potential Biomarker

scholarly journals THU0022 DIFFERENTIAL DNA METHYLATION AS A PREDICTOR OF TOCILIZUMAB RESPONSE IN RHEUMATOID ARTHRITIS PATIENTS

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 224.1-224
Author(s):  
N. Nair ◽  
D. Plant ◽  
J. Isaacs ◽  
A. Morgan ◽  
K. Hyrich ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Dna Methylation ◽  
Disease Activity ◽  
Whole Blood ◽  
Differential Methylation ◽  
Poor Responders ◽  
Research Support ◽  
Response Status ◽  
Pre Treatment ◽  
Methylation Patterns

Background:Tocilizumab (TCZ) is a biological disease-modifying antirheumatic drug that blocks IL-6 signalling and is effective in ameliorating disease activity in rheumatoid arthritis (RA). However, approximately 50% of patients do not respond adequately to TCZ and some patients report adverse events. Considering there is growing evidence that DNA methylation is implicated in RA susceptibility and response to some biologics (1, 2), we investigated DNA methylation as a candidate biomarker for response to TCZ in RA.Objectives:To identify differential DNA methylation signatures in whole blood associated with TCZ response in patients with RA.Methods:Epigenome-wide DNA methylation patterns were measured using the Infinium EPIC BeadChip (Illumina) in whole blood-derived DNA samples from patients with RA. DNA was extracted from blood samples taken pre-treatment and following 3 months on therapy, and response was determined at 6 months using the Clinical Disease Activity Index (CDAI). Patients who had good response (n=10) or poor response (n=10) to TCZ by 6 months were selected. Samples from secondary poor responders (n=10) (patients who had an improvement of CDAI and were in remission at 3 months, followed by a worsening of CDAI at 6 months) were also analysed. Differentially methylated positions and regions (DMPs/DMRs) were identified using linear regression, adjusting for gender, age, cell composition, smoking status, and glucocorticoid use. Gene Set Enrichment Analysis (GSEA) was used to identify significant pathways associated with response and Functional Epigenetic Module analysis of interactome hotspots in regions of differential methylation.Results:20 DMPs were significantly associated with response status at 6 months in the pre-treatment samples. Another 21 DMPs were associated with response in the 3 month samples. Within good responders, 10 DMPs showed significant change in methylation level between pre-treatment and the 3 month samples (unadjusted P-value <10-6). One DMP, cg03121467, was significantly less methylated in good responders compared to poor responders in the pre-treatment samples. This DMP is close toEPB41L4Aand thought to have a role in β–catenin signalling. GSEA of DMRs in non- and secondary non- responders identified histone acetyltransferase pathways and included theKAT2Agene, which is a repressor of NF-κB. Additional analysis of interaction hotspots of differential methylation identified significant interactions withSTAMBPandPTPN12associated with response status.Conclusion:These preliminary results provide evidence that DNA methylation patterns may predict response to TCZ. Validation of these findings in other larger data sets is required.References:[1]Liu,Y., Aryee,M.J., Padyukov,L., Fallin,M.D., Hesselberg,E., Runarsson,A., Reinius,L., Acevedo,N., Taub,M., Ronninger,M.,et al.(2013) Epigenome-wide association data implicate DNA methylation as an intermediary of genetic risk in rheumatoid arthritis.Nat. Biotechnol.,31, 142–147.[2]Plant,D., Webster,A., Nair,N., Oliver,J., Smith,S.L., Eyre,S., Hyrich,K.L., Wilson,A.G., Morgan,A.W., Isaacs,J.D.,et al.(2016) Differential Methylation as a Biomarker of Response to Etanercept in Patients With Rheumatoid Arthritis.Arthritis Rheumatol. (Hoboken, N.J.),68, 1353–60.Disclosure of Interests:Nisha Nair: None declared, Darren Plant: None declared, John Isaacs Consultant of: AbbVie, Bristol-Myers Squibb, Eli Lilly, Gilead, Janssen, Merck, Pfizer, Roche, Ann Morgan Grant/research support from: I have received a grant from Roche Products Ltd to establish a registry for GCA patients treated with tocilizumab., Consultant of: I have undertaken consultancy work for Roche, Chugai, Regeneron, Sanofi and GSK in the area of GCA therapeutics., Speakers bureau: I have presented on tocilizumab therapy for GCA and glucocorticoid toxicity on behalf of Roche products ltd., Kimme Hyrich Grant/research support from: Pfizer, UCB, BMS, Speakers bureau: Abbvie, Anne Barton Consultant of: AbbVie, Anthony G Wilson: None declared

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

2019 ◽  
Vol 47 (11) ◽  
pp. 1614-1623 ◽  
Author(s):  
Vidyanand Anaparti ◽  
Prasoon Agarwal ◽  
Irene Smolik ◽  
Neeloffer Mookherjee ◽  
Hani El-Gabalawy
Keyword(s):  
Rheumatoid Arthritis ◽  
Whole Blood ◽  
Bisulfite Sequencing ◽  
Immune Cell ◽  
Pearson Correlation ◽  
Disease Onset ◽  
Differential Methylation ◽  
Specific Gene ◽  
Human Major Histocompatibility Complex ◽  
Targeted Bisulfite Sequencing

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 < 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.

scholarly journals THU0001 Differential methylation as a predictor of methotrexate response in patients with rheumatoid arthritis

2018 ◽  
Author(s):  
N. Nair ◽  
D. Plant ◽  
S.M. Verstappen ◽  
J.D. Isaacs ◽  
A.W. Morgan ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Differential Methylation

A8.03 Differential methylation as a biomarker of response to etanercept in patients with rheumatoid arthritis

2016 ◽  
Vol 75 (Suppl 1) ◽  
pp. A66.1-A66
Author(s):  
D Plant ◽  
A Webster ◽  
N Nair ◽  
J Oliver ◽  
S Smith ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Differential Methylation

scholarly journals Next-Generation Sequencing Profiles of the Methylome and Transcriptome in Peripheral Blood Mononuclear Cells of Rheumatoid Arthritis

2019 ◽  
Vol 8 (9) ◽  
pp. 1284 ◽  
Author(s):  
Tseng ◽  
Lin ◽  
Lin ◽  
Li ◽  
Yen ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Next Generation Sequencing ◽  
Differential Expression ◽  
Peripheral Blood Mononuclear Cells ◽  
Peripheral Blood ◽  
Mononuclear Cells ◽  
Differential Methylation ◽  
Peripheral Blood Mononuclear ◽  
Blood Mononuclear Cells ◽  
Generation Sequencing

Using next-generation sequencing to decipher methylome and transcriptome and underlying molecular mechanisms contributing to rheumatoid arthritis (RA) for improving future therapies, we performed methyl-seq and RNA-seq on peripheral blood mononuclear cells (PBMCs) from RA subjects and normal donors. Principal component analysis and hierarchical clustering revealed distinct methylation signatures in RA with methylation aberrations noted across chromosomes. Methylation alterations varied with CpG features and genic characteristics. Typically, CpG islands and CpG shores were hypermethylated and displayed the greatest methylation variance. Promoters were hypermethylated and enhancers/gene bodies were hypomethylated, with methylation variance associated with expression variance. RA genetically associated genes preferentially displayed differential methylation and differential expression or interacted with differentially methylated and differentially expressed genes. These differentially methylated and differentially expressed genes were enriched with several signaling pathways and disease categories. 10 genes (CD86, RAB20, XAF1, FOLR3, LTBR, KCNH8, DOK7, PDGFA, PITPNM2, CELSR1) with concomitantly differential methylation in enhancers/promoters/gene bodies and differential expression in B cells were validated. This integrated analysis of methylome and transcriptome identified novel epigenetic signatures associated with RA and highlighted the interaction between genetics and epigenetics in RA. These findings help our understanding of the pathogenesis of RA and advance epigenetic studies in regards to the disease.

SAT0009 Investigation of Differential Methylation as A Potential Biomarker of Methotrexate Response in Patients with Rheumatoid Arthritis

2016 ◽  
Vol 75 (Suppl 2) ◽  
pp. 667.1-667
Author(s):  
N. Nair ◽  
D. Plant ◽  
S.M. Verstappen ◽  
J.D. Isaacs ◽  
A.W. Morgan ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Differential Methylation ◽  
Potential Biomarker
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