Epigenetic Mechanisms as an Intermediary of Genetic Risk
Recent research efforts tried to integrate epigenetic mechanisms into genetic susceptibility loci as causes of the disease. Liu et al. performed a genome-scale methylation and single nucleotide polymorphism (SNP) analysis in leukocytes derived from ACPA patients. The authors identified nine clusters of differentially methylated signatures in the MHC region and one outside on the same chromosome that likely mediate the genetic risk for RA. Furthermore, in a three-stage transethnic meta-analysis of GWAS data, an enrichment of non-MHC risk loci was assessed in epigenetic chromatin marks. Histone 3 lysine 4 trimethylation (H3K4me3), a mark that highlights active promoters and enhancers, was previously shown to be the histone mark that is most phenotypically cell-type specific. RA risk loci in biological candidate genes overlapped with H3K4me3 peaks in immune-related cells, especially in Treg.