Genome-scale case-control analysis of CD4+ T-cell DNA methylation in juvenile idiopathic arthritis reveals potential targets involved in disease

Methylation levels were significantly different (FDR adjusted p<0.1) at 145 loci. Removal of four samples exposed to methotrexate had a striking impact on the outcome of the analysis, reducing the number of differentially methylated loci to 11. The methotrexate-naive analysis identified reduced methylation at the gene encoding the pro-inflammatory cytokine IL32, which was subsequently replicated using a second analysis platform and a second set of case-control pairs.Our data suggests that differential T cell DNA methylation may be a feature of JIA, and that reduced methylation at IL32 is associated with this disease. Further work in larger prospective and longitudinal sample collections is required to confirm these findings, assess whether the identified differences are causal or consequential of disease, and further investigate the epigenetic modifying properties of therapeutic regimens.Juvenile Idiopathic Arthritis (JIA) is the most common autoimmune rheumatic disease of childhood. The aetiology of JIA remains largely unknown, but as for other autoimmune diseases, including adult rheumatoid arthritis, the interplay between genes and environment is likely to be important [1]. A potential conduit for such interactions to alter disease risk is via epigenetic modification, defined as “the structural adaptation of chromosomal regions so as to register, signal or perpetuate altered activity states” [2]. For example, methylation of CpG dinucleotides at gene promoters is generally associated with a reduction in gene expression. Folate, through one-carbon metabolism, is an important primary methyl donor (reviewed in [3]), and maternal folate intake has been shown to alter epigenetic profile and resultant phenotypes of offspring in rodents [4]. In humans, studies of monozygotic twin pairs have demonstrated modification of epigenetic profile across the life course in response to environmental exposure (reviewed in [5]).A growing body of evidence suggests that epigenetic modi