Abstract
BackgroundRheumatoid arthritis is a common autoimmune disorder influenced by both genetic and environmental factors. Epigenome-wide association studies can identify environmentally mediated epigenetic changes such as altered DNA methylation, which may also be influenced by genetic factors. To investigate possible contributions of DNA methylation to the aetiology of rheumatoid arthritis with minimum confounding genetic heterogeneity, we investigated genome-wide DNA methylation in disease-discordant monozygotic twin pairs.MethodsGenome-wide DNA methylation was assessed in 79 monozygotic twin pairs discordant for rheumatoid arthritis using the HumanMethylation450 BeadChip array (Illumina). Discordant twins were tested for both differential DNA methylation and methylation variability between rheumatoid arthritis and healthy twins. The methylation variability signature was then compared with methylation variants from studies of other autoimmune diseases and with an independent healthy population.ResultsWe have identified a differentially variable DNA methylation signature that suggests multiple stress response pathways may be involved in the aetiology of the disease. This methylation variability signature also highlighted potential epigenetic disruption of multiple RUNX3 transcription factor binding sites as being associated with disease development. Comparison with previously performed epigenome-wide association studies of rheumatoid arthritis and type 1 diabetes identified shared pathways for autoimmune disorders, suggesting that epigenetics plays a role in autoimmunity and offering the possibility of identifying new targets for intervention.ConclusionsThrough 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. This finding supports the importance of epigenetic variability as an emerging component in autoimmune disorders.
Highlights
Rheumatoid arthritis is a common autoimmune disorder influenced by both genetic and environmental factors
We have examined genome-wide DNA methylation in both a differentially methylated positions (DMPs) and Differentially variable positions (DVPs) context using the Infinium HumanMethylation450 BeadChip array (Illumina) in whole blood from 79 MZ twin pairs discordant for rheumatoid arthritis (RA) from two independent cohorts (Manchester and TwinsUK, see Fig. 1)
Patient characteristics DNA samples from 79 MZ twin pairs discordant for RA were available from the Nationwide Rheumatoid Arthritis Twin Study (n = 62 twin pairs) and from the TwinsUK cohort (n = 17 twin pairs)
Summary
Rheumatoid arthritis is a common autoimmune disorder influenced by both genetic and environmental factors. Epigenome-wide association studies can identify environmentally mediated epigenetic changes such as altered DNA methylation, which may be influenced by genetic factors. To investigate possible contributions of DNA methylation to the aetiology of rheumatoid arthritis with minimum confounding genetic heterogeneity, we investigated genome-wide DNA methylation in disease-discordant monozygotic twin pairs. Many putative environmental risk factors have been investigated, including exposure to cigarette smoke, Epigenetics is the study of heritable modifications of DNA which can alter gene expression without changing the DNA sequence and which can be influenced by environmental factors, such as smoking [4]. The most widely studied epigenetic phenomenon is DNA methylation, which may act as a composite measure of numerous environmental exposures, making it an intriguing candidate for investigation of diseases that involve both genetic and environmental factors, such as RA. Due to the small sample sizes of both studies, they were underpowered to detect subtle methylation differences [14] and have limited scope to characterise the epigenomic landscape of RA-discordant twins
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