Genome-wide Resolution Peripheral Blood Methylome Profiling Reveals Signatures for Cholestatic Liver Disease

Abstract

Aim: To profile DNA methylation changes of primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC). Materials & methods: Patients with: PBC, PSC with inflammatory bowel disease (IBD), PSC without IBD, and age-, sex-matched controls were profiled for methylomes of peripheral blood by reduced representation bisulfite sequencing. Differentially methylated CpG (DMC) and differentially methylated region (DMR) were detected and compared. Results: We identified consistently altered DMCs and DMRs across diseases with involvement in key pathways. Many similarities noted between two subtypes of PSC, interestingly few existed between PBC and PSC. DMRs were highly enriched with transcription factor binding. Top DMC changes were validated in liver tissue of an independent cohort. Conclusion: Methylome profiling provides insights to PBC and PSC.

Epigenetic Signatures Discriminate Patients With Primary Sclerosing Cholangitis and Ulcerative Colitis From Patients With Ulcerative Colitis

“…The overall lack of large-scale differences in methylation between the various groups corroborates the observations made by Moore et al., where the authors did not observe large global methylation changes in the peripheral blood of patients with PSC compared to healthy controls and between patients with PSC with and without IBD ( 15 ). While peripheral blood is a practical tissue for biomarker use due to its ease of access, it contains a heterogeneous population of cells, which might be less representative for disease features, such as the PSC-UC-associated phenotypes that manifest primarily in the liver and gut tissue.…”

“…While having a same-sex cohort decreases variance, it makes the observations less translatable to the general PSC-IBD population. While previous EWAS have indicated that DNA methylation profiles differ between males and females ( 72 ), limited to no sex-associated difference were reported in PSC-associated EWAS ( 15 , 16 ). One study did show an enrichment of differentially methylated CpG sites located on chromosome X in patients with PSC-IBD and PSC without IBD compared to controls but did not make a comparison with the methylomes of patients with PSC alone ( 15 ).…”

“…While previous EWAS have indicated that DNA methylation profiles differ between males and females ( 72 ), limited to no sex-associated difference were reported in PSC-associated EWAS ( 15 , 16 ). One study did show an enrichment of differentially methylated CpG sites located on chromosome X in patients with PSC-IBD and PSC without IBD compared to controls but did not make a comparison with the methylomes of patients with PSC alone ( 15 ). While the majority of the patients with PSC are male, we acknowledge that further validation experiments in a larger and more heterogeneous population with both male and female subjects are necessary to properly ascertain the robustness of the predictive CpGs and the potential utility in the clinic in defining PSC-UC.…”

“…Similar observations have been made in colonic tissue of IBD patients ( 13 ). Furthermore, patients with PSC with and without IBD share common methylation differences compared to controls ( 15 ). Recently, it was reported that in patients with PSC the DNA methylation age, as estimated using the so-called Horvath clock, was higher than the chronological age ( 16 , 17 ).…”

Epigenetic disease markers in primary sclerosing cholangitis and primary biliary cholangitis—methylomics of cholestatic liver disease

“… 8 In blood, differential methylation was largely split between hypomethylation and hypermethylation and enriched pathways included inositol phosphate metabolism (both diseases), IL-17 signaling (PBC), and TGF-β signaling (PSC). 9 While epigenome-wide approaches were used in these studies, sample sizes were small, and the use of reduced representation bisulfite sequencing limited downstream analytics. Here, we report an EWAS of a large cohort of patients with PSC and PBC and well-matched control groups using an array-based platform, the Illumina MethylationEPIC Bead Chip.…”