Molecular signature with high accuracy for biliary atresia identifies a role for Interleukin-8 in pathogenesis of disease
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ABSTRACT:
ORGANISM(S): Mus musculus Homo sapiens
PROVIDER: GSE46995 | GEO | 2013/06/01
SECONDARY ACCESSION(S): PRJNA203250
REPOSITORIES: GEO
Similar Datasets
Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series
2013-06-01 | E-GEOD-46995 | biostudies-arrayexpress
Project description:UnlabelledBiliary atresia (BA) is a progressive fibroinflammatory obstruction of extrahepatic bile ducts that presents as neonatal cholestasis. Due to the overlap in clinical, biochemical, and histological features with other causes of cholestasis, the diagnosis requires an intraoperative cholangiogram. Thus, we determined whether diseased livers express a gene expression signature unique to BA. Applying stringent statistical analysis to a genome-wide liver expression platform of 64 infants with BA at the time of diagnosis, 14 age-appropriate subjects with intrahepatic cholestasis as diseased controls and seven normal controls, we identified 15 genes uniquely expressed in BA with an accuracy of 92.3%. Among these genes, IL8 and LAMC2 were sufficient to classify subjects with BA distinctly from diseased controls with an area under the curve of 0.934 (95% confidence interval [CI]: 0.84-1.03), sensitivity of 96.9%, and specificity of 85.7% using their combined first principal component. Direct measurement of interleukin (IL)8 protein in the serum, however, was not different between the two groups. To investigate whether the liver-restricted increase in IL8 was relevant to disease pathogenesis, we inactivated the signaling of IL8 homologs by genetic targeting of the Cxcr2 receptor in a murine model of experimental BA. Disruption of Cxcr2 shortened the duration of cholestasis, decreased the incidence of bile duct obstruction, and improved survival above wild-type neonatal mice.ConclusionThe hepatic expression of IL8 and LAMC2 has high sensitivity for BA at diagnosis and may serve as a biomarker of disease, with an important role for the IL8 signaling in experimental BA.
| S-EPMC4077977 | biostudies-literature
Project description:BackgroundBiliary atresia is a fibroinflammatory obstruction of extrahepatic bile duct that leads to end-stage liver disease in children. Despite advances in understanding the pathogenesis of biliary atresia, very little is known about the role of microRNAs (miRNAs) in onset and progression of the disease. In this study, we aimed to investigate the entire biliary transcriptome to identify miRNAs with potential role in the pathogenesis of bile duct obstruction.ResultsBy profiling the expression levels of miRNA in extrahepatic bile ducts and gallbladder (EHBDs) from a murine model of biliary atresia, we identified 14 miRNAs whose expression was suppressed at the times of duct obstruction and atresia (≥2 fold suppression, P < 0.05, FDR 5%). Next, we obtained 2,216 putative target genes of the 14 miRNAs using in silico target prediction algorithms. By integrating this result with a genome-wide gene expression analysis of the same tissue (≥2 fold increase, P < 0.05, FDR 5%), we identified 26 potential target genes with coordinate expression by the 14 miRNAs. Functional analysis of these target genes revealed a significant relevance of miR-30b/c, -133a/b, -195, -200a, -320 and -365 based on increases in expression of at least 3 target genes in the same tissue and 1st-to-3rd tier links with genes and gene-groups regulating organogenesis and immune response. These miRNAs showed higher expression in EHBDs above livers, a unique expression in cholangiocytes and the subepithelial compartment, and were downregulated in a cholangiocyte cell line after RRV infection.ConclusionsIntegrative genomics reveals functional relevance of miR-30b/c, -133a/b, -195, -200a, -320 and -365. The coordinate expression of miRNAs and target genes in a temporal-spatial fashion suggests a regulatory role of these miRNAs in pathogenesis of experimental biliary atresia.
| S-EPMC3819657 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series
2013-10-15 | E-GEOD-41595 | biostudies-arrayexpress
Project description:Biliary Atresia, a common basis for neonatal cholestasis and primary indication for Liver Transplantation, accounts for 60% of pediatric Liver Transplantations. While the pathogenesis of Biliary Atresia remains obscure, abnormalities within bile ducts and the liver, inflammation, fibrosis and cilia defects are thought to comprise the pathological basis for this condition. The findings of genetic variants in Biliary Atresia, such as Copy Number Variations and Single Nucleotide Polymorphism, are considered as essential factors in the development of this condition. In this review, we summarize and analyze these Biliary Atresia variants from a perspective of their pathological characteristics. In conclusion, such analyses may offer novel insights into the pathogenesis of Biliary Atresia and provide a foundation for future studies directed toward a better understanding and treatment of Biliary Atresia.
| S-EPMC9277099 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below.
2013-10-15 | GSE41595 | GEO
Project description:Cholestatic jaundice is one of the most common neonatal conditions. BA, a correctable cholangiopathy, presents with cholestatic jaundice within the first weeks of life. The inflammation of bile ducts leads to progressive fibrosclerosis involving biliary trees, followed by cirrhosis and liver failure. With the use of modern molecular studies, this research aimed to define a novel pathogenesis by exploring variations. We performed genetic discovery by using supervised and unsupervised approaches. Ultimately, a combination of genetic variations and survival data was analyzed to strengthen the novel concept in this study. In this study, coding regions were explored to identify rare deleterious variants within genes from the first analysis together with gene sets reported in PFIC, and diseases with hyperbilirubinemia. Our unsupervised prioritization was primarily designed to identify novel causal genes from nonsynonymous variants derived by three biostatistical algorithms: enrichment analysis, burden test, and trio study. Survival analysis was integratively evaluated with a combination of identified causal genes. The individuals with identified variants from the supervised approach were frequently related to the severity of cirrhosis and poor postoperative outcome. In the unsupervised approach, nonsynonymous variants were enriched. Cilium and muscle related pathways had a significant correlation. CCDC8 was statistically significant gene in which six cases carried mutations identified through burden analysis. Individuals who carried variants in corresponding genes and significant pathways had significantly lower native-liver survival than individuals in whom none of these variants were identified (log-rank p value 0.016). This study explored genetic variations by multiple strategies. Different pathways of cholestatic diseases have been found to be associated with BA. Therefore, BA may be characterized as a shared sequela of many cholestatic disorders. Susceptibility in those pathways suggested an association with BA and strengthened this proposed novel hypothesis. The results emphasized the consequences of many disruptive pathophysiologies.
| S-EPMC9645613 | biostudies-literature
Project description: Not available
| S-EPMC10831818 | biostudies-literature
Project description:Background & Aims: Age at diagnosis and response to surgery have been correlated with an improved survival with the native liver in children with biliary atresia. However, biological predictors of outcome are largely undefined. We investigated if gene expression profiles at diagnosis predict clinical outcome. Methods: Global gene expression was quantified by RNAseq of liver biopsies from 171 infants with BA at diagnosis and randomly assigned into discovery (N=121), validation (N=50) cohorts and 7 normal controls.
2019-08-20 | GSE122340 | GEO
Project description:The diagnosis of biliary atresia (BA) remains a clinical challenge because affected infants have signs, symptoms, and serum liver biochemistry that are also seen in those with other causes of neonatal cholestasis (non-BA). However, an early diagnosis and prompt surgical treatment are required to improve clinical outcome. Recently, the relative abundance of serum matrix metalloproteinase-7 (MMP-7) was suggested to have discriminatory features for infants with BA. To test the hypothesis that elevated serum concentration of MMP-7 is highly diagnostic for BA, we determined the normal serum concentration of MMP-7 in healthy control infants, and then in 135 consecutive infants being evaluated for cholestasis. The median concentration for MMP-7 was 2.86 ng/mL (interquartile range, IQR: 1.32-5.32) in normal controls, 11.47 ng/mL (IQR: 8.54-24.55) for non-BA, and 121.1 ng/mL (IQR: 85.42-224.4) for BA (P < 0.0001). The area under the curve of MMP-7 for the diagnosis of BA was 0.9900 with a cutoff value of 52.85 ng/mL; the diagnostic sensitivity and specificity were 98.67% and 95.00%, respectively, with a negative predictive value of 98.28%. Conclusion: Serum MMP-7 assay has high sensitivity and specificity to differentiate BA from other neonatal cholestasis, and may be a reliable biomarker for BA.
| S-EPMC6519383 | biostudies-literature