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Abstract Number: 1886

Differential Methylation Related To Response To Etanercept In Patients With Rheumatoid Arthritis

Amy Webster1, Darren Plant2, Mark Lunt3, Stephen Eyre4, Edward Flynn4, Paul Martin5, A. G. Wilson6, A. W. Morgan7, John Isaacs8, Jane Worthington1,9 and Anne Barton2,4, 1Arthritis Research UK Centre for Genetics and Genomics, The University of Manchester, Manchester, United Kingdom, 2NIHR Manchester Musculoskeletal BRU, Central Manchester Foundation Trust and University of Manchester, Manchester Academic Health Science Centre, Manchester, United Kingdom, 3Arthritis Research UK Centre for Epidemiology, University of Manchester, Manchester, United Kingdom, 4Arthritis Research UK Epidemiology Unit, University of Manchester, Manchester, United Kingdom, 5Arthritis Research UK Epidemiology Unit, Manchester Academic Health Sciences Centre, Institute of Inflammation and Repair, The University of Manchester, Manchester, United Kingdom, 6Genomic Medicine, The University of Sheffield, Sheffield, United Kingdom, 7Leeds Institute of Molecular Medicine, University of Leeds, Leeds, United Kingdom, 8National Institute for Health Research, Newcastle Biomedical Research Centre, Newcastle Hospitals Foundation Trust and Newcastle University, Newcastle Upon Tyne, United Kingdom, 9The University of Manchester, Manchester, United Kingdom

Meeting: 2013 ACR/ARHP Annual Meeting

Keywords: anti-TNF therapy, DNA Methylation, etanercept and rheumatoid arthritis (RA)

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Session Information

Session Title: Genetics and Genomics of Rheumatic Disease II

Session Type: Abstract Submissions (ACR)

Background/Purpose: The introduction of biologic drug therapies targeting specific components of the inflammatory response represents a huge advance in the treatment of rheumatoid arthritis (RA). Despite this, up to 40% of patients fail to respond well to these therapies. Ideally, clinicians would like to identify patients who are likely to respond to therapy as early as possible in the disease course, making identification of reliable biomarkers of response an important area of research. Recent studies suggest that epigenetic control of gene expression may be important in RA; we have therefore hypothesized that epigenetic changes such as aberrant DNA methylation patterns may provide useful biomarkers of response to biologics.

Objectives: To identify a DNA methylation signature indicative of response to TNF-blockade therapy in patients with RA.

Methods: Patients were recruited from the Biologics in Rheumatoid Arthritis Genetics and Genomics Study Syndicate (BRAGGSS) longitudinal cohort. Patients (n=72) were selected based on having an extreme response phenotype after 3 months of treatment with etanercept; 36 were good responders defined as having an endpoint DAS28<2.6, and 36 were poor responders defined as having an improvement of <0.6 or between 0.6-1.2 with an endpoint DAS28 of >5.1. Whole blood DNA from each patient, sampled before initiation of etanercept therapy, was bisulfite converted and an epigenome wide association study was conducted using the HumanMethylation450 BeadChip (Illumina). A detection threshold was applied and probes with a detection p-value of greater than 0.01 were removed. Differentially methylated positions between responders and non responders were identified by linear regression following quantile normalisation.

Results: 4 CpG sites showed differences between responders and non-responders to etanercept passing a false discovery rate of 0.05 with a (p≤10-7): cg04857395, cg16426293, cg03277049, cg14862806. While none of the 4 CpG sites mapped to obvious candidate genes, the most differentially methylated probe mapped to exon 7 of LRPAP1, which is highly expressed in mononuclear cells. Statistical adjustment for whole blood cell composition did not qualitatively alter the results. 

Conclusion: This is the first methylome wide investigation of treatment response to TNF blockade therapy in RA and, while further well powered studies are required, these preliminary data identify methylation biomarkers of response.

Acknowledgements: This work was supported by the innovative medicines initiative joint undertaking (IMI JU) funded project BeTheCure, (contract number 115142-2). The work was supported by the NIHR Manchester Musculoskeletal Biomedical Research Unit. We also acknowledge support from Arthritis Research UK.


Disclosure:

A. Webster,
None;

D. Plant,
None;

M. Lunt,
None;

S. Eyre,
None;

E. Flynn,
None;

P. Martin,
None;

A. G. Wilson,
None;

A. W. Morgan,
None;

J. Isaacs,
None;

J. Worthington,
None;

A. Barton,
None.

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