RT Journal Article
SR Electronic
T1 OP0257 Differential DNA Methylation Related to Response to Adalimumab and Etanercept in Patients with Rheumatoid Arthritis
JF Annals of the Rheumatic Diseases
JO Ann Rheum Dis
FD BMJ Publishing Group Ltd and European League Against Rheumatism
SP 158
OP 159
DO 10.1136/annrheumdis-2014-eular.4104
VO 73
IS Suppl 2
A1 A. Webster
A1 D. Plant
A1 S. Eyre
A1 G. Wilson
A1 A. Morgan
A1 J. Isaacs
A1 J. Worthington
A1 A. Barton
YR 2014
UL http://ard.bmj.com/content/73/Suppl_2/158.3.abstract
AB Background Anti-TNF therapies have proved a huge advance for the treatment of rheumatoid arthritis (RA), however very good disease control or remission is achieved in just 30% of patients. This makes the identification of biomarkers predictive of response an important area of research. Such predictive biomarkers would allow the most effective treatment for a patient to be identified early in disease course. An increasing number of studies have identified a role for epigenetics in RA and other autoimmune disorders, thus we hypothesised that epigenetic changes, such as DNA methylation, may provide potential biomarkers of response to anti-TNFs. Objectives To identify methylation signatures predictive of response to anti-TNF therapies in patients with RA. Methods Patients were selected from the Biologics in Rheumatoid Arthritis Genetics and Genomics Study Syndicate (BRAGGSS) longitudinal cohort. Patients (n=119) were selected based on having an extreme response phenotype after 3 months of treatment with etanercept or adalimumab; 36 were good responders to etanercept and 30 to adalimumab defined as having an endpoint DAS28<2.6, and 35 were poor responders to etanercept and 18 to adalimumab defined as having an improvement of <0.6 or between 0.6-1.2 with an endpoint DAS28 of >5.1. DNA from each patient, sampled before initiation of therapy, was bisulfite converted and an epigenome-wide association study was conducted using the HumanMethylation450 BeadChip (Illumina). The results from each drug were analysed separately using the minfi package in R and probes with a detection-p value >0.01 were removed. Differentially methylated positions between responders and non-responders were identified using the F-test following quantile normalisation. Results In the etanercept study, four CpG sites showed differential DNA methylation that passed a false discovery rate of 0.05, while in the adalimumab study, two CpG sites passed this threshold. The most differentially methylated position in etanercept patients mapped to the LRPAP1 gene (p=1.46×10-8). This gene encodes a chaperone of low density lipoprotein receptor-related protein 1 (LRP1) which is known to influence TGF-β activity. Technical validation of methylation at this site by pyrosequencing showed very good correlation (Spearmans r=0.8). In the adalimumab patients, the most differentially methylated position maps to the MAD2L2 gene. Conclusions This is one of the largest methylome-wide investigations of treatment response to anti-TNF therapies in RA. These preliminary results identify DNA methylation as a potential biomarker of response for etanercept and adalimumab. Acknowledgements This work was supported by the innovative medicines initiative joint undertaking (IMI JU) funded project BeTheCure, (contract number 115142-2). Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.4104