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A8.03 Differential methylation as a biomarker of response to etanercept in patients with rheumatoid arthritis
  1. D Plant1,*,
  2. A Webster2,*,
  3. N Nair2,
  4. J Oliver2,
  5. S Smith2,
  6. S Eyre2,
  7. KL Hyrich2,
  8. AG Wilson3,
  9. AW Morgan4,
  10. J Isaacs5,
  11. J Worthington1,2,
  12. A Barton1,2
  1. 1NIHR Manchester Musculoskeletal Biomedical Research Unit, Manchester Academy of Health Sciences, Manchester, UK
  2. 2Arthritis Research UK Centre for Genetics and Genomics, University of Manchester, Manchester, UK
  3. 3UCD School of Medicine and Medical Science, Conway Institute, UniversityCollege Dublin, Dublin
  4. 4NIHR Leeds Musculoskeletal Biomedical Research Unit, Leeds Teaching Hospitals NHS Trust and Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, UK
  5. 5NIHR Newcastle Biomedical Research Centre in Ageing and Chronic Disease, Newcastle University and Newcastle Upon Tyne NHS Foundation Trust, Newcastle-Upon-Tyne, UK
  6. *These Authors Contributed Equally to the Work


Background Biologic drug therapies represent a huge advance in the treatment of rheumatoid arthritis (RA). However, very good disease control is only achieved in 30% of patients, making identification of biomarkers of response a research priority. We therefore hypothesise that differential DNA methylation patterns may provide biomarkers predictive of response to TNF-inhibitor (TNFi) therapy in patients with RA.

Methods An epigenome-wide association study was performed on pre-treatment 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 (DMPs) were identified using linear regression. Variance of methylation at DMPs was assessed for correlation with cis-acting SNPs. A replication experiment for prioritised SNPs was performed in an independent cohort of 1,204 RA patients.

Results Five DMPs between responders groups were identified with a FDR <5%. The top two DMPs mapped to exon 7 of the LRPAP1 gene on chromosome 4 (cg04857395, p = 1.39E-08 and cg26401028, 1.96E-08). The A allele of the SNP rs3468 was correlated with higher levels of methylation for both of the top two DMPs (2.63E-07 and 1.05E-06, respectively). Further the A allele of rs3468 was correlated with EULAR non-response in the discovery cohort (n = 56; p = 0.03) and in the independent replication cohort (n = 1.204; p = 0.003).

Conclusions We identify DNA methylation as a potential biomarker of TNFi response and 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 required.

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