Identification of cell‐specific differential DNA methylation associated with methotrexate treatment response in rheumatoid arthritis

Cameron Adams (Lead), Nisha Nair, Darren Plant, Suzanne Verstappen, Hong L. Quach, Diana L. Quach, Alex Carvidi, Joanne Nititham, Mary Nakamura, Anne Barton, Jonathan Graff, Lindsey A Criswell, Lisa F. Barcellos (Corresponding)

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Abstract

OBJECTIVE To estimate changes in cell-specific DNA methylation (DNAm) associated with methotrexate (MTX) response from whole-blood samples collected from rheumatoid arthritis (RA) patients before and after initiation of MTX treatment. METHODS Patients in this study were from the Rheumatoid Arthritis Medication Study (RAMS, n=66) and the University of California San Francisco Rheumatoid Arthritis study (UCSF-RA, n=11). All patients met the American College of Rheumatology RA classification criteria. Blood samples were collected at baseline and following treatment. DAS28-CRP was collected at baseline and after 3-6 months of treatment. Methylation profiles were generated with Illumina 450K and EPIC arrays using DNA from whole blood. MTX response was defined using the EULAR criteria (Responder: good/moderate response, Non-responder: no response). Differentially methylated positions (DMPs) were identified using limma and tensor composition analysis (TCA). TCA is a method for identifying cell-specific differential DNAm at the CpG level from bulk tissue. Differentially Methylated Regions (DMRs) were identified using Comb-p. RESULTS We found evidence for differential global methylation between treatment response groups. Further, we found patterns of cell-specific differential global methylation associated with MTX response. One DMP was associated at after correction for multiple tests with differential DNAm between responders and non-responders at baseline in CD4T, CD8T, and NK cells. Thirty-nine cell-specific DMRs associated with MTX response were identified. There were no significant findings in whole blood analyses. CONCLUSION We identified cell-specific changes in DNAm associated with MTX response in RA patients. Future studies of DNAm and MTX response should include measurements of DNAm from sorted cells.
Original languageEnglish
JournalArthritis & Rheumatology (Hoboken)
Early online date30 Jan 2023
DOIs
Publication statusE-pub ahead of print - 30 Jan 2023

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