**6. Epigenetic factors**

Epigenetics is the study of stable and heritable changes in the function of genes which occur without altering the DNA sequence and include DNA methylation, histone modification, and microRNAs [144]. MicroRNAs (miRNAs) are short noncoding RNAs are crucial in regulating multiple cellular processes, such as development, proliferation and apoptosis [145]. Several miRNAs have been associated with the susceptibility of BD disease, which includes many different inflammatory pathways [146]. Zhou et al. revealed miR155 expression was significantly decreased in dendritic cells from patients with BD with active compared to inactive uveitis [147]. In addition, the many SNPs in miRNA have been showed to be a risk for BD in association studies. Both of the TT genotype and T allele of rs11614913 located at pre-miR196a2 were found had increased frequency in patients with BD [148]. The microRNA-146a rs2910164 was associated with decreased frequency of CC genotype and C allele in patients with BD, whereas GG genotype was significantly increased in an Egyptian cohort [149]. Also, TT genotypes and T allele of rs3746444 miRNA-499 exhibited a significantly higher risk in patients with BD in a study of Turkish population [150]. In a Spanish cohort, the relative promoter methylation level of the IL-6 mRNA was found significantly lower in BD patients compared to controls [151]. The variant in the pre-miRNA region of miR-196a2, rs11614913, was associated with BD susceptibility, as well as BD arthritis [148]. In an Epigenome-wide association study with Chinese BD patients, the genetic variants of 10 CpG-SNPs were not associated with BD susceptibility [152].
