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

Lookup NU author(s): Professor John IsaacsORCiD



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


OBJECTIVE: Biologic drug therapies represent a huge advance in the treatment of rheumatoid arthritis (RA). However, very good disease control is achieved in only 30% of patients, making identification of biomarkers of response a research priority. We undertook this study to test our hypothesis that differential DNA methylation patterns may provide biomarkers predictive of response to tumor necrosis factor inhibitor (TNFi) therapy in patients with RA. METHODS: An epigenome-wide association study was performed on pretreatment whole blood DNA from patients with RA. Patients who displayed good response (n = 36) or no response (n = 36) to etanercept therapy at 3 months were selected. Differentially methylated positions were identified using linear regression. Variance of methylation at differentially methylated positions was assessed for correlation with cis-acting single-nucleotide polymorphisms (SNPs). A replication experiment for prioritized SNPs was performed in an independent cohort of 1,204 RA patients. RESULTS: Five positions that were differentially methylated between responder groups were identified, with a false discovery rate of <5%. The top 2 differentially methylated positions mapped to exon 7 of the LRPAP1 gene on chromosome 4 (cg04857395, P = 1.39 x 10(-8) and cg26401028, P = 1.69 x 10(-8) ). The A allele of the SNP rs3468 was correlated with higher levels of methylation for both of the top 2 differentially methylated positions (P = 2.63 x 10(-7) and P = 1.05 x 10(-6) , respectively). Furthermore, the A allele of rs3468 was correlated with European League Against Rheumatism nonresponse in the discovery cohort (P = 0.03; n = 56) and in the independent replication cohort (P = 0.003; n = 1,204). CONCLUSION: We identify DNA methylation as a potential biomarker of response to TNFi therapy, and we report the association between response and the LRPAP1 gene, which encodes a chaperone of low-density lipoprotein receptor-related protein 1. Additional replication experiments in independent sample collections are now needed.

Publication metadata

Author(s): Plant D, Webster A, Nair N, Oliver J, Smith SL, Eyre S, Hyrich KL, Wilson AG, Morgan AW, Isaacs JD, Worthington J, Barton A

Publication type: Article

Publication status: Published

Journal: Arthritis & Rheumatology

Year: 2016

Volume: 68

Issue: 6

Pages: 1353-1360

Print publication date: 01/06/2016

Online publication date: 21/04/2016

Acceptance date: 28/01/2016

Date deposited: 28/06/2016

ISSN (print): 2326-5191

ISSN (electronic): 2326-5205

Publisher: John Wiley & Sons, Inc.


DOI: 10.1002/art.39590

PubMed id: 26814849


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Funder referenceFunder name
Manchester Academy of Health Sciences
NIHR Manchester Musculoskeletal Biomedical Research Unit
115142-2Innovative Medicines Initiative (IMI-JU funded project BTCure)
20385Arthritis Research UK