Abstract
High levels of anti-citrullinated protein antibodies (ACPA) are often observed prior to a diagnosis of rheumatoid arthritis (RA). We undertook a replication study to confirm CpG sites showing evidence of differential methylation in subjects positive vs. negative for ACPA, in a new subset of 112 individuals sampled from the population cohort and biobank CARTaGENE in Quebec, Canada. Targeted custom capture bisulfite sequencing was conducted at approximately 5.3 million CpGs located in regulatory or hypomethylated regions from whole blood; library and protocol improvements had been instituted between the original and this replication study, enabling better coverage and additional identification of differentially methylated regions (DMRs). Using binomial regression models, we identified 19,472 ACPA-associated differentially methylated cytosines (DMCs), of which 430 overlapped with the 1909 DMCs reported by the original study; 814 DMRs of relevance were clustered by grouping adjacent DMCs into regions. Furthermore, we performed an additional integrative analysis by looking at the DMRs that overlap with RA related loci published in the GWAS Catalog, and protein-coding genes associated with these DMRs were enriched in the biological process of cell adhesion and involved in immune-related pathways.
Highlights
Rheumatoid arthritis (RA) is considered a chronic, systemic, inflammatory autoimmune disease characterized by synovial inflammation
2, we identified cis-single nucleotide polymorphisms (SNPs) associated with methylation levels, and included part of these cis-meQTLs in a second set of models testing for genetically adjusted association between methylation and anti-citrullinated protein antibodies (ACPA)
In our meQTL study, we detected local correlations between SNPs and differential methylation for part of our identified ACPA-associated differentially methylated cytosines (DMCs), showing that genotypes at specific loci can result in different patterns of DNA methylation
Summary
Rheumatoid arthritis (RA) is considered a chronic, systemic, inflammatory autoimmune disease characterized by synovial inflammation. DNA methylation is a key mechanism that integrates genetic and environmental causes of disease. Aberrant DNA methylation has been shown to mediate genotype and smoking interaction in the development of ACPA-positive RA [5], and with specific patterns in different cell types of RA patients [6]. It has been implicated in the abnormal proliferation and invasiveness of fibroblast-like synoviocytes [7,8], it is still not known if specific methylation signatures could be useful in predicting RA disease course
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