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Clin Epigenetics. 2019 Jul 31;11(1):110. doi: 10.1186/s13148-019-0699-9.

Rheumatoid arthritis-relevant DNA methylation changes identified in ACPA-positive asymptomatic individuals using methylome capture sequencing.

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Department of Human Genetics, McGill University, Montréal, Canada.
The McGill University and Génome Québec Innovation Centre, Montréal, Canada.
Current address: Digital Technologies Research Centre, National Research Council Canada, Ottawa, Ontario, Canada.
Department of Medicine, McGill University, 5252 Boul. de Maisonneuve Ouest, Rm 3F.51, Montréal, H4A 3S5, Canada.
Division of Rheumatology, Jewish General Hospital, Montréal, Canada.
Lady Davis Institute, Jewish General Hospital, Montréal, Canada.
Division of Rheumatology, McGill University, Montréal, Canada.
Cumming School of Medicine, University of Calgary, Calgary, Canada.
Ontario Institute for Cancer Research, Toronto, Canada.
Department of Molecular Genetics, University of Toronto, Toronto, Canada.
Center for Pediatric Genomic Medicine, Children's Mercy, Kansas City, MO, USA.
Department of Medicine, McGill University, 5252 Boul. de Maisonneuve Ouest, Rm 3F.51, Montréal, H4A 3S5, Canada.
Division of Rheumatology, McGill University, Montréal, Canada.



To compare DNA methylation in subjects positive vs negative for anti-citrullinated protein antibodies (ACPA), a key serological marker of rheumatoid arthritis (RA) risk.


With banked serum from a random subset (N = 3600) of a large general population cohort, we identified ACPA-positive samples and compared them to age- and sex-matched ACPA-negative controls. We used a custom-designed methylome panel to conduct targeted bisulfite sequencing of 5 million CpGs located in regulatory or hypomethylated regions of DNA from whole blood (red blood cell lysed). Using binomial regression models, we investigated the differentially methylated regions (DMRs) between ACPA-positive vs ACPA-negative subjects. An independent set of T cells from RA patients was used to "validate" the differentially methylated sites.


We measured DNA methylation in 137 subjects, of whom 63 were ACPA-positive, 66 were ACPA-negative, and 8 had self-reported RA. We identified 1303 DMRs of relevance, of which one third (402) had underlying genetic effects. These DMRs were enriched in intergenic CpG islands (CGI) and CGI shore regions. Furthermore, the genes associated with these DMRs were enriched in pathways related to Epstein-Barr virus infection and immune response. In addition, 80 (38%) of 208 RA-specific DMRs were replicated in T cells from RA samples.


Sequencing-based high-resolution methylome mapping revealed biologically relevant DNA methylation changes in asymptomatic individuals positive for ACPA that overlap with those seen in RA. Pathway analyses suggested roles for viral infections, which may represent the effect of environmental triggers upstream of disease onset.


Anti-citrullinated protein antibody positivity; DNA methylation; Differentially methylated regions; Rheumatoid arthritis; Targeted bisulfite sequencing

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