Dataset Information

Genetic Factors and Their Role in the Pathogenesis of Biliary Atresia.

ABSTRACT: 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.

SUBMITTER: Wu LN

PROVIDER: S-EPMC9277099 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Genetic Factors and Their Role in the Pathogenesis of Biliary Atresia.

Wu Li-Na LN Zhu Zhi-Jun ZJ Sun Li-Ying LY

Frontiers in pediatrics 20220629

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 c ...[more]

PMID: 35844731

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Project description:Background & aimsAltered extrahepatic bile ducts, gut, and cardiovascular anomalies constitute the variable phenotype of biliary atresia (BA).MethodsTo identify potential susceptibility loci, Caucasian children, normal (controls) and with BA (cases) at two US centers were compared at >550000 SNP loci. Systems biology analysis was carried out on the data. In order to validate a key gene identified in the analysis, biliary morphogenesis was evaluated in 2-5-day post-fertilization zebrafish embryos after morpholino-antisense oligonucleotide knockdown of the candidate gene ADP ribosylation factor-6 (ARF6, Mo-arf6).ResultsAmong 39 and 24 cases at centers 1 and 2, respectively, and 1907 controls, which clustered together on principal component analysis, the SNPs rs3126184 and rs10140366 in a 3' flanking enhancer region for ARF6 demonstrated higher minor allele frequencies (MAF) in each cohort, and 63 combined cases, compared with controls (0.286 vs. 0.131, P = 5.94x10-7, OR 2.66; 0.286 vs. 0.13, P = 5.57x10-7, OR 2.66). Significance was enhanced in 77 total cases, which included 14 additional BA genotyped at rs3126184 only (p = 1.58x10-2, OR = 2.66). Pathway analysis of the 1000 top-ranked SNPs in CHP cases revealed enrichment of genes for EGF regulators (p<1 x10-7), ERK/MAPK and CREB canonical pathways (p<1 x10-34), and functional networks for cellular development and proliferation (p<1 x10-45), further supporting the role of EGFR-ARF6 signaling in BA. In zebrafish embryos, Mo-arf6 injection resulted in a sparse intrahepatic biliary network, several biliary epithelial cell defects, and poor bile excretion to the gall bladder compared with uninjected embryos. Biliary defects were reproduced with the EGFR-blocker AG1478 alone or with Mo-arf6 at lower doses of each agent and rescued with arf6 mRNA.ConclusionsThe BA-associated SNPs identify a chromosome 14q21.3 susceptibility locus encompassing the ARF6 gene. arf6 knockdown in zebrafish implicates early biliary dysgenesis as a basis for BA, and also suggests a role for EGFR signaling in BA pathogenesis.

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.

Dataset Information

Genetic Factors and Their Role in the Pathogenesis of Biliary Atresia.

Publications

Genetic Factors and Their Role in the Pathogenesis of Biliary Atresia.

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