Methotrexate Treatment of Newly Diagnosed RA Patients Is Associated With DNA Methylation Differences at Genes Relevant for Disease Pathogenesis and Pharmacological Action
Background: Methotrexate (MTX) is the ﬁ rst line treatment of rheumatoid arthritis (RA),
and methylation changes in bulk T cells have been reported after treatment with MTX. We
have investigated cell-type speci ﬁ c DNA methylation changes across the genome in naïve
and memory CD4
T cells before and after MTX treatment of RA patients. DNA
methylation pro ﬁ les of newly diagnosed RA patients (N=9) were assessed by reduced
representation bisul ﬁ te sequencing.
Results: We found that MTX treatment signi ﬁ cantly in ﬂ uenced DNA methylation levels at
multiple CpG sites in both cell populations. Interestingly, we identi ﬁ ed differentially
methylated sites annotated to two genes; TRIM15 and SORC2, previously reported to
predict treatment outcome in RA patients when measured in bulk T cells. Furthermore,
several of the genes, including STAT3, annotated to the signi ﬁ cant CpG sites are relevant
for RA susceptibility or the action of MTX.
Conclusion: We detected CpG sites that were associated with MTX treatment in CD4
naïve and memory T cells isolated from RA patients. Several of these sites overlap genetic
regions previously associated with RA risk and MTX treatment outcome.