Epigenome wide association study of response to methotrexate in early rheumatoid arthritis patients.

Helen R Gosselt,Robert De Jonge,Erik Lubberts,Sandra G Heil,Pooja R Mandaviya,Costanza L Vallerga,Johanna M W Hazes,Toshi Shioda

doi:10.1371/journal.pone.0247709

Abstract

AimTo identify differentially methylated positions (DMPs) and regions (DMRs) that predict response to Methotrexate (MTX) in early rheumatoid arthritis (RA) patients.Materials and methodsDNA from baseline peripheral blood mononuclear cells was extracted from 72 RA patients. DNA methylation, quantified using the Infinium MethylationEPIC, was assessed in relation to response to MTX (combination) therapy over the first 3 months.ResultsBaseline DMPs associated with response were identified; including hits previously described in RA. Additionally, 1309 DMR regions were observed. However, none of these findings were genome-wide significant. Likewise, no specific pathways were related to response, nor could we replicate associations with previously identified DMPs.ConclusionNo baseline genome-wide significant differences were identified as biomarker for MTX (combination) therapy response; hence meta-analyses are required.

Highlights

Baseline differentially methylated positions (DMPs) associated with response were identified; including hits previously described in rheumatoid arthritis (RA)
No specific pathways were related to response, nor could we replicate associations with previously identified DMPs
No baseline genome-wide significant differences were identified as biomarker for MTX therapy response; meta-analyses are required

Summary

Results

14,184 probes out of 860,599 were removed during quality control. Hereafter, 69 subjects and 846,415 probes were included. N Sex, Female (%) Age (years) Baseline DAS28 BMI (kg/m2) ACPA positive, N (%) RF positive, N (%) Smoking score, median (IQR) Treatment, N (%). We did not observe genome-wide significant differences (0.05/846,415 = 5.9 x 10−8) nor DMPs located in certain chromosomes, as can be seen from the Manhattan plot (Fig 2). To examine if certain Gene Ontology (GO) terms were enriched, pathway analysis was performed on the top 1000 most significant DMP results, all at nominal p-values

Introduction

Discussion