Differential DNA methylation may help identify likely methotrexate responders
medwireNews: Changes in DNA methylation following initiation of methotrexate appear to correlate with response to the drug in patients with rheumatoid arthritis (RA), study findings indicate.
Therefore, combining CpG sites, that is, regions of DNA where a methyl group is added to a cytosine–guanine dinucleotide, with other early markers of methotrexate response “may predict improvement in disease activity at 6 months,” Anne Barton (University of Manchester, UK) and colleagues remark.
The researchers used 422,557 probes to measure DNA methylation in whole blood samples collected at baseline and after 4 weeks of methotrexate treatment in participants of the Rheumatoid Arthritis Medication Study who were ultimately good (n=34) or poor (n=34) responders according to the EULAR response criteria.
They found that, after adjustment for age, sex, cell composition, baseline DAS28 score, and smoking status, two CpG sites identified in the samples taken at 4 weeks had significantly different levels of methylation between the good and poor responders.
Writing in Rheumatology, Barton and co-authors point out that “[t]here was no differential methylation observed between good and poor responders in the baseline DNA samples, or between time points in either the good responder group or the poor responder group.”
This suggests that the differences observed at 4 weeks “were due to the effect of [methotrexate] acting differently on patients who by 6 months were in extreme responder groups,” they write.
Further analysis of methylation status according to the individual components of the EULAR response criteria identified three more differentially methylated positions associated with changes in tender joint count, as well as three associated with swollen joint count (SJC) changes and four associated with changes in C-reactive protein (CRP) levels.
Four of these twelve associations – two with SJC and two with CRP – were replicated in an independent cohort of 100 patients from the Rheumatoid Arthritis Medication Study. Specifically, Barton et al observed that small decreases in SJC or CRP significantly correlated with modest increases in methylation.
The researchers say that the four loci identified “are novel in the context of RA and [methotrexate] response” and may be associated with cellular adhesion pathways.
And although Barton and co-authors accept that the CpG sites “are insufficiently predictive alone to be clinically useful,” they say that the information “could be incorporated into algorithms including clinical data and other genetic, epigenetic, genomic and proteomic biomarkers, to provide a more robust predictor of response in RA and use of precision medicine approaches to guide treatment decisions.”
By Laura Cowen
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