Liver epigenome changes in patients with hepatopulmonary syndrome: A pilot study.

Nuria Mendoza,Eva Rivas,Alvar Agusti,Miquel Bruguera,Roberto Rodriguez-Roisin,Rosa Faner,Tamara Garcia,Y-H Taguchi

doi:10.1371/journal.pone.0245046

Abstract

The hepatopulmonary syndrome (HPS) is defined by the presence of pulmonary gas exchange abnormalities due to intrapulmonary vascular dilatations in patients with chronic liver disease. Changes in DNA methylation reflect the genomic variation. Since liver transplant (LT) reverts HPS we hypothesized that it may be associated with specific liver epigenetic changes. Thus, the aim of this study was to investigate the role of the liver epigenome in patients with HPS. We extracted DNA from paraffin embedded liver tissue samples from 10 patients with HPS and 10 age-, sex- and MELD (Model for End-stage Liver Disease)-matched controls. DNA methylation was determined using the 850K array (Illumina). Weighted Gene Co-expression Network Analysis (WGCNA) was used to identify modules related to defining physiologic characteristics of HPS. Only 12 out of the 20 liver biopsies (7 HPS and 5 controls) had sufficient quality to be analyzed. None of the 802,688 DNA probes analyzed in the case control comparison achieved a significant False Discovery Rate (FDR). WGCNA identified 5 co-methylated gene-modules associated to HPS markers, mainly related to nervous and neuroendocrine system, apoptotic processes, gut bacterial translocation, angiogenesis and vascular remodeling ontologies. To conclude, HPS is associated with nervous/neuroendocrine system and vascular remodeling related liver epigenetic changes.

Highlights

The hepatopulmonary syndrome (HPS) is defined by the presence of an arterial oxygenation defect caused by intrapulmonary vascular dilatations in patients with chronic liver disease, mostly liver cirrhosis (LC) [1,2,3,4,5]
We originally included in the study liver biopsies from 10 patients with and 10 without HPS, only 12 of them (7 with and 5 without HPS) passed the minfi quality control of the 850K (EPIC) methylation array results (S1 Table in S1 File) and could be included in the analysis
There were no significant differences between groups with respect to age, sex, etiology or severity of cirrhosis

Summary

Introduction

The hepatopulmonary syndrome (HPS) is defined by the presence of an arterial oxygenation defect caused by intrapulmonary vascular dilatations in patients with chronic liver disease, mostly liver cirrhosis (LC) [1,2,3,4,5]. The prevalence of the HPS in patients assessed for liver transplant (LT) ranges between 5–30% [6,7,8]. We were the first to show that patients with LC [9,10,11] exhibit reduced or abolished pulmonary vascular tone, distinctive of HPS. More recent studies have proposed a number of putative biological mechanisms [12,13,14,15,16,17], but the pathobiology of HPS still remains elusive to date.

Objectives

Results

Discussion

Conclusion