The first large, comprehensive epigenome-wide association study (EWAS) of patients with primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) has been conducted and recently published in the journal Hepatology Communications.
The study offers insight into the methylation profiles of these hepatic disorders, in an effort to support current concepts regarding mechanisms of disease and provide novel data that will generate future investigations.
PBC and PSC are known to be rare, immune-mediated liver diseases in which progressive fibrosis and biliary damage are reported. In patients with PBC, the biliary damage occurs in small intrahepatic ducts, whereas in those with PSC, the damage occurs mainly in medium- and large-sized extrahepatic and intrahepatic ducts. The pathogenesis and etiology involved in both disorders are multifaceted and remain to be elucidated. Some interacting combination of environmental and genetic factors appears to be implicated.
Learn more about PBC causes and risk factors
The epigenome, which is defined as “the set of modifications to DNA and associated molecules that control gene expression, cellular identify, and function,” plays a major role in in the mediation of cellular responses to outside factors. Therefore, assessment of the epigenetic state can help to provide an understanding of those cellular adaptations that take place during the disease course of PBC and PSC.
In the current analysis, the array-based platform Illumina MethylationEPIC Bead Chip was used to perform an EWAS among a large cohort of individuals with PBC and PSC, along with well-matched controls without hepatic disease. All study participants were chosen from the PSC Scientific Community Resource.
A total of 291 patients with PBC and 291 PBC controls were assessed in the study. Additionally, a total of 474 individuals with PSC and 484 PSC controls were evaluated. Both control groups were well matched in terms of gender, age, and race.
Participants with PBC and those with PSC exhibited an increased percentage of monocytes and reduced CD4 T cells compared with matched controls. In contrast, however, patients with PBC had an increased level of CD8 T cells, whereas in those with PSC, decreased levels of CD8 T cells were observed.
Confirmation of increased epigenetic age, along with differences in predicted immune cell composition, was reported in participants with PBC and PSC. In fact, participants’ epigenetic profiles revealed differences in predicted protein levels, including levels of tumor necrosis factor receptor superfamily member 1B, among patients with cirrhotic PBC and PSC, compared with individuals with noncirrhotic PBC and PSC.
EWAS analyses of PBC demonstrated “strong 5’-C-phosphate-G-3’ associations in genes[,] including NOD-like receptor family CARD domain containing 5, human leukocyte antigen-E, and PSMB8.” In fact, analyses acknowledged that “disease-associated canonical pathways and upstream regulators” were involved both in immune signaling, as well as in the activation of macrophages and T cells.
“Studies to corroborate our findings and expand into other–omics layers will be invaluable to further our understanding of these rare disease[,] with the goal [being] to improve and individualize prognosis and treatment,” the authors concluded.
