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Identical Twins With, Without Rheumatoid Arthritis Have Differentially Variable DNA Methylation

NEW YORK (GenomeWeb) – Researchers have uncovered variability in DNA methylation in pairs of identical twins discordant for rheumatoid arthritis (RA), suggesting epigenetic variability may be a key factor in autoimmune conditions.

RA causes joint pain and swelling, and affects some 1.3 million adults, according to the US National Institutes of Health. The autoimmune condition is thought to be influenced by environmental exposures.

A team led by researchers at the University of Manchester examined epigenetic differences in 79 twin pairs in which one twin has rheumatoid arthritis and the other does not. In their genome-wide DNA methylation assay, the researchers uncovered differentially variable methylation that appeared to implicate stress response in disease development.

"Through genome-wide analysis of DNA methylation in disease-discordant monozygotic twins, we have identified a differentially variable DNA methylation signature, in the absence of differential methylation in rheumatoid arthritis," Manchester's Jane Worthington and her colleagues wrote in Genome Medicine this week. "This finding supports the importance of epigenetic variability as an emerging component in autoimmune disorders."

The researchers obtained DNA samples from 62 twin pairs discordant for rheumatoid arthritis from the Nationwide Rheumatoid Arthritis Twin Study and 17 twin pairs from the TwinsUK cohort. Using the Illumina Infinium HumanMethylation450 BeadChip array, they examined genome-wide DNA methylation within the twins.

While the researchers did not find any differentially methylated positions between the twin groups, they did uncover differentially variable positions. In particular, they teased out 1,171 such differentially variable positions that differed with rheumatoid arthritis status. Of those, 763 were hypervariable in twins with rheumatoid arthritis and these tended to fall in the 3' UTR regions of gene bodies.

When the researchers annotated these genes and compared them to genes previously linked to rheumatoid arthritis, they found that five of the 98 disease-linked genes had at least one differentially variable position.

In addition, they found that the second and third top-ranked CpG sites overlapped with binding sites for the transcription factor RUNX3, which has been linked to other autoimmune disorders like Crohn's disease and psoriasis. In human cells and in mice, alterations to RUNX3 expression have led to changes in the function of regulatory T cells, suggesting to the researchers that the functional consequences of this methylation change should be examined further.

At the same time, they also found that a number of these differentially variable positions were enriched in certain pathways, particularly ones involved in cellular stress response. For instance, they noted an enrichment in the K63 protein ubiquitination pathway, which modulates oxidative stress response.

As stress kinases have some links to inflammatory pathways, Worthington and her colleagues said that the inflammatory aspect of rheumatoid arthritis could potentially induce the variability in DNA methylation seen in stress response pathways. These findings led the researchers to develop a new working model of rheumatoid arthritis that highlights this potential link between DNA methylation variability and stress response pathways in disease etiology.

The enrichment of rheumatoid arthritis-linked differentially variable positions in stress response pathways also supports the notion that stress-induced changes can alter the epigenetic landscape to contribute to disease, they added.

When the researchers compared their rheumatoid arthritis findings to a DNA methylation analysis of monozygotic twins discordant for type 1 diabetes, they uncovered a bit of an overlap in affected genes — nearly 500 overlapping genes, more than would be expected by chance. In addition, they found that inflammation and immune response appeared to be influenced by methylation variability in both conditions.

This, the team added, raises the possibility that there are common pathways in which DNA methylation is hypervariable in autoimmune disorders.