Common functional alterations identified in blood transcriptome of autoimmune cholestatic liver and inflammatory bowel diseases

Jerzy Ostrowski,Natalia Żeber‐Lubecka ,Anna Kluska,Agnieszka Rogowska,Jakub Karczmarski,Michalina Dąbrowska ,Izabella Łazowska ,Krzysztof Goryca,Filip Ambrożkiewicz ,Andrzej Habior,Maria Kulecka,Agnieszka Paziewska,Aneta Bałabas ,Magdalena Piątkowska ,Michał Mikula

doi:10.1038/s41598-019-43699-1

Abstract

Primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), and inflammatory bowel diseases (IBDs), including Crohn’s disease (CD) and ulcerative colitis (UC), are heterogeneous chronic autoimmune diseases that may share underlying pathogenic mechanisms. Herein, we compared simultaneously analyzed blood transcriptomes from patients with PBC, PSC, and IBD. Microarray-based measurements were conducted using RNA isolated from whole blood samples from 90, 45, 95 and 93 patients with PBC, PSC, CD, and UC, respectively, and 47 healthy controls. Expression levels of selected transcripts were analyzed by quantitative reverse-transcribed PCR using an independent cohort of 292, 71 and 727 patients with PBC, PSC, and IBD, respectively. Of 4026, 2650 and 4967 probe sets differentially expressed (adjusted p-value < 0.05) in samples from patients with PBC, PSC, and IBD, respectively, compared with healthy controls, 1946 were common to all three comparisons. Functional analyses indicated that most terms enriched for genes differentially expressed in PBC, PSC, and IBD patients compared with healthy controls were related to mitochondrial function, the vesicle endomembrane system, and GTPase-mediated processes. This study indicates that microarray-based profiling of blood gene expression supports research into the molecular mechanisms underlying disease, rather than being useful for selection of diagnostic biomarkers for use in clinical practice.

Highlights

Primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), and inflammatory bowel diseases (IBDs), including Crohn’s disease (CD) and ulcerative colitis (UC), are heterogeneous chronic autoimmune diseases that may share underlying pathogenic mechanisms
Transcriptome analysis was carried out using samples from patients with two cholestatic liver diseases (ChLDs), PBC and PSC, and two IBDs, CD and UC
Microarray-based assays were conducted by hybridization of 370 RNA samples to Human HT-12 v4 Expression BeadChip microarrays

Summary

Introduction

Primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), and inflammatory bowel diseases (IBDs), including Crohn’s disease (CD) and ulcerative colitis (UC), are heterogeneous chronic autoimmune diseases that may share underlying pathogenic mechanisms. Functional analyses indicated that most terms enriched for genes differentially expressed in PBC, PSC, and IBD patients compared with healthy controls were related to mitochondrial function, the vesicle endomembrane system, and GTPase-mediated processes. PSC manifests as cholangiocytic injuries associated with nonspecific inflammation In both of these cholangiopathies, progressive fibrous obliteration of the intrahepatic and extrahepatic biliary tree results in chronic cholestasis leading to liver cirrhosis[1,4,5,6]. PBC and PSC, and nonspecific IBDs, UC and CD, exhibit significant differences in their clinical presentation, chronic inflammation and dysregulated immune responses are common to both types of disorder. While several previous studies uncovered alterations of WBC gene expression in IBDs18–21, no comparable investigations of patients with PBC or PSC have been reported to date

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