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Lui VCH. Organoids in biliary atresia. WORLD JOURNAL OF PEDIATRIC SURGERY 2025; 8:e001010. [PMID: 40385243 PMCID: PMC12083310 DOI: 10.1136/wjps-2025-001010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2025] [Accepted: 03/27/2025] [Indexed: 05/20/2025] Open
Abstract
Organoids are three-dimensional and self-organizing cell cultures of various lineages that resemble structures and functions of an organ in many ways, and they are versatile tools in disease modeling and patho-mechanistic study of human diseases affecting their tissues of origin. Biliary atresia (BA), a cholangiopathy affecting the bile ducts of the liver, is a heterogeneous and multifaceted liver disease of complex pathogenesis. Cholangiopathies refer to a category of liver diseases that affect the cholangiocytes, the epithelial cells lining the lumen of the biliary trees. Biliary organoids consist of cholangiocytes in a spherical monolayer epithelium, which favorably resembles the structures and functional properties of the bile duct cholangiocytes. Biliary tissue-derived cells, pluripotent stem cells or embryonic stem cells, and hepatic progenitor cells are capable of generating biliary organoids. In the last decade, a considerable advancement has been made in the generation of biliary organoids for modeling liver physiology and pathophysiology. Using biliary organoids, scientists have advanced our knowledge underlying the pathogenic roles of genetic susceptibility, dysregulated hepatobiliary development/structure, environmental factors, and dysregulated immune-inflammatory responses to an injury in BA. This review will summarize and discuss the derivation and the use of biliary organoids in the disease modeling and patho-mechanistic study of BA.
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Miller PN, Baskaran S, Nijagal A. Immunology of Biliary Atresia. Semin Pediatr Surg 2024; 33:151474. [PMID: 39862687 DOI: 10.1016/j.sempedsurg.2025.151474] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2024] [Accepted: 01/07/2025] [Indexed: 01/27/2025]
Abstract
Biliary atresia is a progressive neonatal cholangiopathy that leads to liver failure. Characterized by inflammation-mediated liver injury, the immune system plays a critical role in the pathogenesis of this disease. Though several types of immune cells and mediators have been implicated in animal models of biliary atresia, emerging literature reflects the complex interplay of components of the immune response that contributes to disease progression in humans. Novel therapies targeting the immune system are needed to mitigate the devastating effects of biliary atresia. This review highlights the current literature on the components of the immune system that have been in implicated in biliary atresia and the rich interplay between the major arms of the immune system- innate and adaptive immunity- to cause the highly morbid consequences of this disease.
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Affiliation(s)
- Phoebe N Miller
- Department of Surgery, University of California San Francisco, 505 Parnassus Avenue, San Francisco, CA 94143, USA
| | - Suruthi Baskaran
- Department of Surgery, University of Texas Health Science Center, 7703 Floyd Curl Drive San Antonio, TX 78229, USA
| | - Amar Nijagal
- Department of Surgery, University of California San Francisco, 505 Parnassus Avenue, San Francisco, CA 94143, USA; The Liver Center, University of California San Francisco, San Francisco, CA 94143; Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA 94143, USA; Eli and Edythe Broad Center of Regeneration Medicine, University of California San Francisco, San Francisco, CA 94143, USA.
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Lin Q, Tam PKH, Tang CSM. Genetics of biliary atresia: Approaches, pathological insights and challenges. Semin Pediatr Surg 2024; 33:151477. [PMID: 39862688 DOI: 10.1016/j.sempedsurg.2025.151477] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2024] [Accepted: 01/07/2025] [Indexed: 01/27/2025]
Abstract
Biliary atresia (BA) is a severe neonatal cholestatic disorder marked by fibro-obliteration of the extrahepatic and intrahepatic bile ducts. It is the most common cause of pediatric end-stage liver disease and the leading indication for liver transplantation in children. There is significant heterogeneity in the etiology, involving various genetic and environmental factors such as viral infection, immune dysregulation and genetic predisposition to defective hepatobiliary development. In this review, we discuss the strategies to uncover the genetic factors underlying BA and highlight their associated molecular and pathological mechanisms, as well as the challenges faced in this area of research.
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Affiliation(s)
- Qiongfen Lin
- Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
| | - Paul Kwong-Hang Tam
- Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China; Precision and Regenerative Medicine Research Centre, Medical Sciences Division, Macau University of Science and Technology, Macao, China.
| | - Clara Sze-Man Tang
- Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China; Dr Li Dak-Sum Research Centre, The University of Hong Kong - Karolinska Institutet Collaboration in Regenerative Medicine, Hong Kong, China.
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Ji Z, Wu X, Ren H, Feng J. Mechanism of biliary atresia caused by T follicular helper cells-induced immune injury. BMC Pediatr 2024; 24:669. [PMID: 39420296 PMCID: PMC11484220 DOI: 10.1186/s12887-024-05152-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/18/2023] [Accepted: 10/14/2024] [Indexed: 10/19/2024] Open
Abstract
BACKGROUND Biliary atresia (BA) has diverse and unclear pathogenesis, which may be related to immune response in response to a foreign stimulus. T follicular helper (Tfh) cells have been found to play an important role in various immune diseases. AIMS To investigate the expression of Tfh cells in BA and non-BA cholestatic diseases in children. METHODS Transcriptome sequencing and Gene Ontology (GO) enrichment analysis were performed to investigate the differences in gene expression between the BA group and the non-BA cholestasis group. Study the distribution of Tfh cells in liver tissues of the BA and non-BA cholestatic groups through single sample gene set enrichment analysis (ssGSEA). Tfh cells (CD3+Bcl6+) in liver tissues from BA patients were labeled by double immunofluorescent staining to verify their distribution in the liver. RESULTS Transcriptome sequencing showed differences in gene expression between the BA group and the non-BA cholestasis group. A total of 808 genes were up-regulated and 405 genes were down-regulated in BA, suggesting that there might be a specific immune response in BA. GO enrichment analysis showed that BA group had augmented response to foreign stimulus and increased metabolic process compared to the non-BA cholestatic group. The relative proportion of immune cells was analyzed by ssGSEA method. The proportions of Tfh cells, activated B cells, CD4+ T cells, memory B cells and Th2 cells were higher in the BA group than in the non-BA cholestatic group. Fluorescence immunostaining showed that Tfh cells were significantly increased in liver tissue samples of the BA group compared to the non-BA cholestasis group, which was consistent with the transcriptome sequencing results. CONCLUSION Tfh cells share in immune cascade involvement in BA. Our work support immune pathogenesis of the in response to a stimulus that might be foreign in BA.
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Affiliation(s)
- Ze Ji
- Shanxi Provincial Children's Hospital, Taiyuan, China
- Department of Pediatrics, Shanxi Medical University, Taiyuan, China
| | - Xiaoxia Wu
- Shanxi Provincial Children's Hospital, Taiyuan, China
| | - Hongxia Ren
- Shanxi Provincial Children's Hospital, Taiyuan, China.
| | - Jiexiong Feng
- Department of Pediatric Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
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Kamp JC, Madadi-Sanjani O, Uecker M, Werlein C, Neubert L, Kübler JF, Obed M, Junge N, Welte T, Ruwisch J, Jonigk DD, Stolk J, Vieten G, Janciauskiene S. Amyloid precursor protein as a fibrosis marker in infants with biliary atresia. Pediatr Res 2024:10.1038/s41390-024-03582-w. [PMID: 39341941 DOI: 10.1038/s41390-024-03582-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2024] [Revised: 07/29/2024] [Accepted: 08/21/2024] [Indexed: 10/01/2024]
Abstract
BACKGROUND Biliary atresia (BA) is a rare condition of unknown origin in newborns with jaundice. In BA bile ducts are non-functional, causing neonatal cholestasis and following liver fibrosis and failure. METHODS This retrospective study included liver biopsies of 14 infants with BA aged [mean ± SD] 63 ± 23 days. Patients were grouped according to the clinical course (jaundice-free vs recurrent jaundice vs required liver transplantation or liver fibrosis (Ishak fibrosis score)) and followed for 1.61-5.64 years (mean 4.03). Transcriptome profiles were assessed using a panel of 768 fibrosis-specific genes, reanalyzed via qRT-PCR, and confirmed via immunostaining. Plasma from an additional 30 BA infants and 10 age-matched controls were used for amyloid precursor protein (APP) quantification by ELISA. RESULTS Different clinical outcome groups showed a homogeneous mRNA expression. Altered amyloid-metabolism-related gene expression was found between cases with Ishak fibrosis score greater than 4. Immunostaining confirmed a distinct presence of APP in the livers of all BA subjects. APP plasma levels were higher in BA than in age-matched controls and correlated with the histological fibrosis grade. CONCLUSIONS These results suggest that amyloidosis may contribute to BA and liver fibrosis, indicating that APP could serve as a potential liquid biomarker for these conditions. IMPACT Biliary atresia patients with higher fibrosis scores according to Ishak have higher hepatic expression of amyloid-related genes while amyloid precursor protein accumulates in the liver and increases in the circulation. After a recent study revealed beta-amyloid deposition as a mechanism potentially involved in biliary atresia, we were able to correlate amyloid-metabolism-related transcript levels as well as amyloid precursor protein tissue and plasma levels with the degree of hepatic fibrosis. These findings suggest that amyloid precursor protein is a fibrosis marker in infants with biliary atresia, reinforcing the role of amyloid metabolism in the pathogenesis of this serious disease.
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Affiliation(s)
- Jan C Kamp
- Department of Respiratory and Infectious Medicine, Hannover Medical School, Hannover, Germany.
- Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), German Center for Lung Research (DZL), Hannover, Germany.
| | | | - Marie Uecker
- Centre of Pediatric Surgery, Hannover Medical School, Hannover, Germany
| | - Christopher Werlein
- Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), German Center for Lung Research (DZL), Hannover, Germany
- Institute of Pathology, Hannover Medical School, Hannover, Germany
| | - Lavinia Neubert
- Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), German Center for Lung Research (DZL), Hannover, Germany
- Institute of Pathology, Hannover Medical School, Hannover, Germany
| | - Joachim F Kübler
- Centre of Pediatric Surgery, Hannover Medical School, Hannover, Germany
| | - Mikal Obed
- Centre of Pediatric Surgery, Hannover Medical School, Hannover, Germany
| | - Norman Junge
- Division for Pediatric Gastroenterology and Hepatology, Department of Pediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School, Hannover, Germany
| | - Tobias Welte
- Department of Respiratory and Infectious Medicine, Hannover Medical School, Hannover, Germany
- Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), German Center for Lung Research (DZL), Hannover, Germany
| | - Jannik Ruwisch
- Department of Respiratory and Infectious Medicine, Hannover Medical School, Hannover, Germany
- Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), German Center for Lung Research (DZL), Hannover, Germany
| | - Danny D Jonigk
- Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), German Center for Lung Research (DZL), Hannover, Germany
- Institute of Pathology, RWTH Aachen University Medical Faculty, Aachen, Germany
| | - Jan Stolk
- Department of Pulmonology, Leiden University Medical Center, Member of European Reference Network Lung, Section Alpha-1-Antitrypsin Deficiency, Leiden, The Netherlands
| | - Gertrud Vieten
- Centre of Pediatric Surgery, Hannover Medical School, Hannover, Germany
| | - Sabina Janciauskiene
- Department of Respiratory and Infectious Medicine, Hannover Medical School, Hannover, Germany
- Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), German Center for Lung Research (DZL), Hannover, Germany
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Feng S, Cheng Y, Sheng C, Yang C, Li Y. Biliary atresia: the role of gut microbiome, and microbial metabolites. Front Cell Infect Microbiol 2024; 14:1411843. [PMID: 39104854 PMCID: PMC11298464 DOI: 10.3389/fcimb.2024.1411843] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2024] [Accepted: 07/05/2024] [Indexed: 08/07/2024] Open
Abstract
Biliary atresia (BA) is a progressive fibroinflammatory disease affecting both the extrahepatic and intrahepatic bile ducts, potentially leading to chronic cholestasis and biliary cirrhosis. Despite its prevalence, the exact mechanisms behind BA development remain incompletely understood. Recent research suggests that the gut microbiota and its metabolites may play significant roles in BA development. This paper offers a comprehensive review of the changing characteristics of gut microbiota and their metabolites at different stages of BA in children. It discusses their influence on the host's inflammatory response, immune system, and bile acid metabolism. The review also explores the potential of gut microbiota and metabolites as a therapeutic target for BA, with interventions like butyrate and gut microbiota preparations showing promise in alleviating BA symptoms. While progress has been made, further research is necessary to untangle the complex interactions between gut microbiota and BA, paving the way for more effective prevention and treatment strategies for this challenging condition.
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Affiliation(s)
| | | | | | | | - Yumei Li
- Department of pediatric intensive care unit, Children’s Medical Center, The First Hospital of Jilin University, Changchun, China
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Tam PKH, Wells RG, Tang CSM, Lui VCH, Hukkinen M, Luque CD, De Coppi P, Mack CL, Pakarinen M, Davenport M. Biliary atresia. Nat Rev Dis Primers 2024; 10:47. [PMID: 38992031 PMCID: PMC11956545 DOI: 10.1038/s41572-024-00533-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 06/10/2024] [Indexed: 07/13/2024]
Abstract
Biliary atresia (BA) is a progressive inflammatory fibrosclerosing disease of the biliary system and a major cause of neonatal cholestasis. It affects 1:5,000-20,000 live births, with the highest incidence in Asia. The pathogenesis is still unknown, but emerging research suggests a role for ciliary dysfunction, redox stress and hypoxia. The study of the underlying mechanisms can be conceptualized along the likely prenatal timing of an initial insult and the distinction between the injury and prenatal and postnatal responses to injury. Although still speculative, these emerging concepts, new diagnostic tools and early diagnosis might enable neoadjuvant therapy (possibly aimed at oxidative stress) before a Kasai portoenterostomy (KPE). This is particularly important, as timely KPE restores bile flow in only 50-75% of patients of whom many subsequently develop cholangitis, portal hypertension and progressive fibrosis; 60-75% of patients require liver transplantation by the age of 18 years. Early diagnosis, multidisciplinary management, centralization of surgery and optimized interventions for complications after KPE lead to better survival. Postoperative corticosteroid use has shown benefits, whereas the role of other adjuvant therapies remains to be evaluated. Continued research to better understand disease mechanisms is necessary to develop innovative treatments, including adjuvant therapies targeting the immune response, regenerative medicine approaches and new clinical tests to improve patient outcomes.
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Affiliation(s)
- Paul K H Tam
- Medical Sciences Division, Macau University of Science and Technology, Macau, China.
- Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China.
| | - Rebecca G Wells
- Division of Gastroenterology and Hepatology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Clara S M Tang
- Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
- Dr. Li Dak-Sum Research Centre, The University of Hong Kong, Hong Kong SAR, China
| | - Vincent C H Lui
- Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
- Dr. Li Dak-Sum Research Centre, The University of Hong Kong, Hong Kong SAR, China
| | - Maria Hukkinen
- Section of Paediatric Surgery, Paediatric Liver and Gut Research Group, New Children's Hospital, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
| | - Carlos D Luque
- Hospital de Niños Ricardo Gutiérrez, Buenos Aires, Argentina
| | - Paolo De Coppi
- NIHR Biomedical Research Centre, Great Ormond Street Hospital for Children NHS Foundation Trust and Great Ormond Street Institute of Child Health, University College London, London, UK
| | - Cara L Mack
- Department of Paediatrics, Division of Paediatric Gastroenterology, Hepatology and Nutrition, Medical College of Wisconsin, Children's Wisconsin, Milwaukee, WI, USA
| | - Mikko Pakarinen
- Section of Paediatric Surgery, Paediatric Liver and Gut Research Group, New Children's Hospital, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
- Department of Women's and Children's Health, Karolinska Institute, Stockholm, Sweden
| | - Mark Davenport
- Department of Paediatric Surgery, King's College Hospital, London, UK
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de Jong IEM, Wells RG. In Utero Extrahepatic Bile Duct Damage and Repair: Implications for Biliary Atresia. Pediatr Dev Pathol 2024; 27:291-310. [PMID: 38762769 PMCID: PMC11340255 DOI: 10.1177/10935266241247479] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 05/20/2024]
Abstract
Biliary atresia (BA) is a cholangiopathy affecting the extrahepatic bile duct (EHBD) of newborns. The etiology and pathophysiology of BA are not fully understood; however, multiple causes of damage and obstruction of the neonatal EHBD have been identified. Initial damage to the EHBD likely occurs before birth. We discuss how different developmental stages in utero and birth itself could influence the susceptibility of the fetal EHBD to damage and a damaging wound-healing response. We propose that a damage-repair response of the fetal and neonatal EHBD involving redox stress and a program of fetal wound healing could-regardless of the cause of the initial damage-lead to either obstruction and BA or repair of the duct and recovery. This overarching concept should guide future research targeted toward identification of factors that contribute to recovery as opposed to progression of injury and fibrosis. Viewing BA through the lens of an in utero damage-repair response could open up new avenues for research and suggests exciting new therapeutic targets.
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Affiliation(s)
- Iris E. M. de Jong
- Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA
- Center for Engineering MechanoBiology, University of Pennsylvania, Philadelphia, PA, USA
| | - Rebecca G. Wells
- Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA
- Center for Engineering MechanoBiology, University of Pennsylvania, Philadelphia, PA, USA
- Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA
- Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, USA
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Hai-Bing Y, Sivasankaran MS, Ottakandathil BR, Zhong-Luan W, Man-Ting S, Ho-Yu C(P, Kak-Yuen W(K, Kwong-Hang T(P, Chi-Hang L(V. Environmental Toxin Biliatresone-Induced Biliary Atresia-like Abnormal Cilia and Bile Duct Cell Development of Human Liver Organoids. Toxins (Basel) 2024; 16:144. [PMID: 38535810 PMCID: PMC10974618 DOI: 10.3390/toxins16030144] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2024] [Revised: 03/07/2024] [Accepted: 03/09/2024] [Indexed: 04/25/2025] Open
Abstract
Biliary atresia (BA) is a poorly understood and devastating obstructive bile duct disease of newborns. Biliatresone, a plant toxin, causes BA-like syndrome in some animals, but its relevance in humans is unknown. To validate the hypothesis that biliatresone exposure is a plausible BA disease mechanism in humans, we treated normal human liver organoids with biliatresone and addressed its adverse effects on organoid development, functions and cellular organization. The control organoids (without biliatresone) were well expanded and much bigger than biliatresone-treated organoids. Expression of the cholangiocyte marker CK19 was reduced, while the hepatocyte marker HFN4A was significantly elevated in biliatresone-treated organoids. ZO-1 (a tight junction marker) immunoreactivity was localized at the apical intercellular junctions in control organoids, while it was markedly reduced in biliatresone-treated organoids. Cytoskeleton F-actin was localized at the apical surface of the control organoids, but it was ectopically expressed at the apical and basal sides in biliatresone-treated organoids. Cholangiocytes of control organoids possess primary cilia and elicit cilia mechanosensory function. The number of ciliated cholangiocytes was reduced, and cilia mechanosensory function was hampered in biliatresone-treated organoids. In conclusion, biliatresone induces morphological and developmental changes in human liver organoids resembling those of our previously reported BA organoids, suggesting that environmental toxins could contribute to BA pathogenesis.
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Affiliation(s)
- Yue Hai-Bing
- Department of Surgery, School of Clinical Medicine, The University of Hong Kong, Hong Kong SAR, China; (Y.H.-B.); (M.S.S.); (B.R.O.); (W.Z.-L.); (S.M.-T.); (C.H.-Y.); (W.K.-Y.); (T.K.-H.)
| | - Menon Sudheer Sivasankaran
- Department of Surgery, School of Clinical Medicine, The University of Hong Kong, Hong Kong SAR, China; (Y.H.-B.); (M.S.S.); (B.R.O.); (W.Z.-L.); (S.M.-T.); (C.H.-Y.); (W.K.-Y.); (T.K.-H.)
| | - Babu Rosana Ottakandathil
- Department of Surgery, School of Clinical Medicine, The University of Hong Kong, Hong Kong SAR, China; (Y.H.-B.); (M.S.S.); (B.R.O.); (W.Z.-L.); (S.M.-T.); (C.H.-Y.); (W.K.-Y.); (T.K.-H.)
| | - Wu Zhong-Luan
- Department of Surgery, School of Clinical Medicine, The University of Hong Kong, Hong Kong SAR, China; (Y.H.-B.); (M.S.S.); (B.R.O.); (W.Z.-L.); (S.M.-T.); (C.H.-Y.); (W.K.-Y.); (T.K.-H.)
| | - So Man-Ting
- Department of Surgery, School of Clinical Medicine, The University of Hong Kong, Hong Kong SAR, China; (Y.H.-B.); (M.S.S.); (B.R.O.); (W.Z.-L.); (S.M.-T.); (C.H.-Y.); (W.K.-Y.); (T.K.-H.)
| | - Chung (Patrick) Ho-Yu
- Department of Surgery, School of Clinical Medicine, The University of Hong Kong, Hong Kong SAR, China; (Y.H.-B.); (M.S.S.); (B.R.O.); (W.Z.-L.); (S.M.-T.); (C.H.-Y.); (W.K.-Y.); (T.K.-H.)
- Dr. Li Dak-Sum Research Centre, The University of Hong Kong, Hong Kong SAR, China
| | - Wong (Kenneth) Kak-Yuen
- Department of Surgery, School of Clinical Medicine, The University of Hong Kong, Hong Kong SAR, China; (Y.H.-B.); (M.S.S.); (B.R.O.); (W.Z.-L.); (S.M.-T.); (C.H.-Y.); (W.K.-Y.); (T.K.-H.)
- Dr. Li Dak-Sum Research Centre, The University of Hong Kong, Hong Kong SAR, China
| | - Tam (Paul) Kwong-Hang
- Department of Surgery, School of Clinical Medicine, The University of Hong Kong, Hong Kong SAR, China; (Y.H.-B.); (M.S.S.); (B.R.O.); (W.Z.-L.); (S.M.-T.); (C.H.-Y.); (W.K.-Y.); (T.K.-H.)
- Dr. Li Dak-Sum Research Centre, The University of Hong Kong, Hong Kong SAR, China
- Faculty of Medicine, Macau University of Science and Technology, Macau SAR 999078, China
| | - Lui (Vincent) Chi-Hang
- Department of Surgery, School of Clinical Medicine, The University of Hong Kong, Hong Kong SAR, China; (Y.H.-B.); (M.S.S.); (B.R.O.); (W.Z.-L.); (S.M.-T.); (C.H.-Y.); (W.K.-Y.); (T.K.-H.)
- Dr. Li Dak-Sum Research Centre, The University of Hong Kong, Hong Kong SAR, China
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Eiamkulbutr S, Tubjareon C, Sanpavat A, Phewplung T, Srisan N, Sintusek P. Diseases of bile duct in children. World J Gastroenterol 2024; 30:1043-1072. [PMID: 38577180 PMCID: PMC10989494 DOI: 10.3748/wjg.v30.i9.1043] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2023] [Revised: 12/26/2023] [Accepted: 02/04/2024] [Indexed: 03/06/2024] Open
Abstract
Several diseases originate from bile duct pathology. Despite studies on these diseases, certain etiologies of some of them still cannot be concluded. The most common disease of the bile duct in newborns is biliary atresia, whose prognosis varies according to the age of surgical correction. Other diseases such as Alagille syndrome, inspissated bile duct syndrome, and choledochal cysts are also time-sensitive because they can cause severe liver damage due to obstruction. The majority of these diseases present with cholestatic jaundice in the newborn or infant period, which is quite difficult to differentiate regarding clinical acumen and initial investigations. Intraoperative cholangiography is potentially necessary to make an accurate diagnosis, and further treatment will be performed synchronously or planned as findings suggest. This article provides a concise review of bile duct diseases, with interesting cases.
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Affiliation(s)
- Sutha Eiamkulbutr
- Department of Pediatrics, King Chulalongkorn Memorial Hospital, Bangkok 10330, Thailand
| | - Chomchanat Tubjareon
- Department of Pediatrics, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Bangkok 10330, Thailand
| | - Anapat Sanpavat
- Department of Pathology, Chulalongkorn University, Bangkok 10330, Thailand
| | - Teerasak Phewplung
- Department of Radiology, Chulalongkorn University, Bangkok 10330, Thailand
| | - Nimmita Srisan
- Department of Surgery, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Bangkok 10330, Thailand
| | - Palittiya Sintusek
- Center of Excellence in Thai Pediatric Gastroenterology, Hepatology and Immunology, Division of Gastroenterology, Department of Pediatrics, King Chulalongkorn Memorial Hospital, Chulalongkorn University, Bangkok 10330, Thailand
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Quaglia A, Roberts EA, Torbenson M. Developmental and Inherited Liver Disease. MACSWEEN'S PATHOLOGY OF THE LIVER 2024:122-294. [DOI: 10.1016/b978-0-7020-8228-3.00003-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
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Glessner JT, Ningappa MB, Ngo KA, Zahid M, So J, Higgs BW, Sleiman PMA, Narayanan T, Ranganathan S, March M, Prasadan K, Vaccaro C, Reyes-Mugica M, Velazquez J, Salgado CM, Ebrahimkhani MR, Schmitt L, Rajasundaram D, Paul M, Pellegrino R, Gittes GK, Li D, Wang X, Billings J, Squires R, Ashokkumar C, Sharif K, Kelly D, Dhawan A, Horslen S, Lo CW, Shin D, Subramaniam S, Hakonarson H, Sindhi R. Biliary atresia is associated with polygenic susceptibility in ciliogenesis and planar polarity effector genes. J Hepatol 2023; 79:1385-1395. [PMID: 37572794 PMCID: PMC10729795 DOI: 10.1016/j.jhep.2023.07.039] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Revised: 07/07/2023] [Accepted: 07/18/2023] [Indexed: 08/14/2023]
Abstract
BACKGROUND & AIMS Biliary atresia (BA) is poorly understood and leads to liver transplantation (LT), with the requirement for and associated risks of lifelong immunosuppression, in most children. We performed a genome-wide association study (GWAS) to determine the genetic basis of BA. METHODS We performed a GWAS in 811 European BA cases treated with LT in US, Canadian and UK centers, and 4,654 genetically matched controls. Whole-genome sequencing of 100 cases evaluated synthetic association with rare variants. Functional studies included whole liver transcriptome analysis of 64 BA cases and perturbations in experimental models. RESULTS A GWAS of common single nucleotide polymorphisms (SNPs), i.e. allele frequencies >1%, identified intronic SNPs rs6446628 in AFAP1 with genome-wide significance (p = 3.93E-8) and rs34599046 in TUSC3 at sub-threshold genome-wide significance (p = 1.34E-7), both supported by credible peaks of neighboring SNPs. Like other previously reported BA-associated genes, AFAP1 and TUSC3 are ciliogenesis and planar polarity effectors (CPLANE). In gene-set-based GWAS, BA was associated with 6,005 SNPs in 102 CPLANE genes (p = 5.84E-15). Compared with non-CPLANE genes, more CPLANE genes harbored rare variants (allele frequency <1%) that were assigned Human Phenotype Ontology terms related to hepatobiliary anomalies by predictive algorithms, 87% vs. 40%, p <0.0001. Rare variants were present in multiple genes distinct from those with BA-associated common variants in most BA cases. AFAP1 and TUSC3 knockdown blocked ciliogenesis in mouse tracheal cells. Inhibition of ciliogenesis caused biliary dysgenesis in zebrafish. AFAP1 and TUSC3 were expressed in fetal liver organoids, as well as fetal and BA livers, but not in normal or disease-control livers. Integrative analysis of BA-associated variants and liver transcripts revealed abnormal vasculogenesis and epithelial tube formation, explaining portal vein anomalies that co-exist with BA. CONCLUSIONS BA is associated with polygenic susceptibility in CPLANE genes. Rare variants contribute to polygenic risk in vulnerable pathways via unique genes. IMPACT AND IMPLICATIONS Liver transplantation is needed to cure most children born with biliary atresia, a poorly understood rare disease. Transplant immunosuppression increases the likelihood of life-threatening infections and cancers. To improve care by preventing this disease and its progression to transplantation, we examined its genetic basis. We find that this disease is associated with both common and rare mutations in highly specialized genes which maintain normal communication and movement of cells, and their organization into bile ducts and blood vessels during early development of the human embryo. Because defects in these genes also cause other birth defects, our findings could lead to preventive strategies to lower the incidence of biliary atresia and potentially other birth defects.
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Affiliation(s)
- Joseph T Glessner
- Center for Applied Genomics (CAG), Children's Hospital of Philadelphia, Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Mylarappa B Ningappa
- Hillman Center for Pediatric Transplantation, UPMC-Children's Hospital of Pittsburgh, and Thomas E Starzl Transplant Institute, University of Pittsburgh, Pittsburgh, PA, USA
| | - Kim A Ngo
- Department of Bioengineering, University of California, San Diego, San Diego, La Jolla, CA, USA
| | - Maliha Zahid
- Department of Developmental Biology, University of Pittsburgh, Pittsburgh, PA, USA
| | - Juhoon So
- Department of Developmental Biology, University of Pittsburgh, Pittsburgh, PA, USA
| | - Brandon W Higgs
- Hillman Center for Pediatric Transplantation, UPMC-Children's Hospital of Pittsburgh, and Thomas E Starzl Transplant Institute, University of Pittsburgh, Pittsburgh, PA, USA
| | - Patrick M A Sleiman
- Center for Applied Genomics (CAG), Children's Hospital of Philadelphia, Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Tejaswini Narayanan
- Department of Bioengineering, University of California, San Diego, San Diego, La Jolla, CA, USA
| | - Sarangarajan Ranganathan
- Division of Pathology and Laboratory Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
| | - Michael March
- Center for Applied Genomics (CAG), Children's Hospital of Philadelphia, Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Krishna Prasadan
- Rangos Research Center Animal Imaging Core, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA, USA
| | - Courtney Vaccaro
- Center for Applied Genomics (CAG), Children's Hospital of Philadelphia, Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Miguel Reyes-Mugica
- Division of Pediatric Pathology, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA, USA
| | - Jeremy Velazquez
- Department of Pathology, School of Medicine, Pittsburgh Liver Research Center, McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA, USA
| | - Claudia M Salgado
- Division of Pediatric Pathology, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA, USA
| | - Mo R Ebrahimkhani
- Department of Pathology, School of Medicine, Pittsburgh Liver Research Center, McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA, USA
| | - Lori Schmitt
- Histology Core Laboratory Manager, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA, USA
| | - Dhivyaa Rajasundaram
- Department of Pediatrics, Division of Health Informatics, Children's Hospital of Pittsburgh, Pittsburgh, PA, USA
| | - Morgan Paul
- Hillman Center for Pediatric Transplantation, UPMC-Children's Hospital of Pittsburgh, and Thomas E Starzl Transplant Institute, University of Pittsburgh, Pittsburgh, PA, USA
| | - Renata Pellegrino
- Center for Applied Genomics (CAG), Children's Hospital of Philadelphia, Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - George K Gittes
- Surgeon-in-Chief Emeritus, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA, USA
| | - Dong Li
- Center for Applied Genomics (CAG), Children's Hospital of Philadelphia, Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Xiang Wang
- Center for Applied Genomics (CAG), Children's Hospital of Philadelphia, Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Jonathan Billings
- Center for Applied Genomics (CAG), Children's Hospital of Philadelphia, Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Robert Squires
- Pediatric Gastroenterology, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA, USA
| | - Chethan Ashokkumar
- Hillman Center for Pediatric Transplantation, UPMC-Children's Hospital of Pittsburgh, and Thomas E Starzl Transplant Institute, University of Pittsburgh, Pittsburgh, PA, USA
| | - Khalid Sharif
- Paediatric Liver Unit Including Intestinal Transplantation, Birmingham Women's and Children's NHS Foundation Trust, Birmingham, UK
| | - Deirdre Kelly
- Paediatric Liver Unit Including Intestinal Transplantation, Birmingham Women's and Children's NHS Foundation Trust, Birmingham, UK
| | - Anil Dhawan
- Paediatric Liver GI and Nutrition Center and MowatLabs, NHS Foundation Trust, King's College Hospital, London, UK
| | - Simon Horslen
- Pediatric Gastroenterology, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA, USA
| | - Cecilia W Lo
- Department of Developmental Biology, University of Pittsburgh, Pittsburgh, PA, USA
| | - Donghun Shin
- Department of Developmental Biology, University of Pittsburgh, Pittsburgh, PA, USA
| | - Shankar Subramaniam
- Department of Bioengineering, University of California, San Diego, San Diego, La Jolla, CA, USA; Department of Computer Science and Engineering, and Nanoengineering, University of California, San Diego, San Diego, La Jolla, CA, USA.
| | - Hakon Hakonarson
- Divisions of Human Genetics and Pulmonary Medicine, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
| | - Rakesh Sindhi
- Hillman Center for Pediatric Transplantation, UPMC-Children's Hospital of Pittsburgh, and Thomas E Starzl Transplant Institute, University of Pittsburgh, Pittsburgh, PA, USA.
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13
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de Jong IEM, Hunt ML, Chen D, Du Y, Llewellyn J, Gupta K, Li D, Erxleben D, Rivas F, Hall AR, Furth EE, Naji A, Liu C, Dhand A, Burdick JA, Davey MG, Flake AW, Porte RJ, Russo PA, Gaynor JW, Wells RG. A fetal wound healing program after intrauterine bile duct injury may contribute to biliary atresia. J Hepatol 2023; 79:1396-1407. [PMID: 37611641 PMCID: PMC10841314 DOI: 10.1016/j.jhep.2023.08.010] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2022] [Revised: 07/28/2023] [Accepted: 08/07/2023] [Indexed: 08/25/2023]
Abstract
BACKGROUND & AIMS Biliary atresia (BA) is an obstructive cholangiopathy that initially affects the extrahepatic bile ducts (EHBDs) of neonates. The etiology is uncertain, but evidence points to a prenatal cause. Fetal tissues have increased levels of hyaluronic acid (HA), which plays an integral role in fetal wound healing. The objective of this study was to determine whether a program of fetal wound healing is part of the response to fetal EHBD injury. METHODS Mouse, rat, sheep, and human EHBD samples were studied at different developmental time points. Models included a fetal sheep model of prenatal hypoxia, human BA EHBD remnants and liver samples taken at the time of the Kasai procedure, EHBDs isolated from neonatal rats and mice, and spheroids and other models generated from primary neonatal mouse cholangiocytes. RESULTS A wide layer of high molecular weight HA encircling the lumen was characteristic of the normal perinatal but not adult EHBD. This layer, which was surrounded by collagen, expanded in injured ducts in parallel with extensive peribiliary gland hyperplasia, increased mucus production and elevated serum bilirubin levels. BA EHBD remnants similarly showed increased HA centered around ductular structures compared with age-appropriate controls. High molecular weight HA typical of the fetal/neonatal ducts caused increased cholangiocyte spheroid growth, whereas low molecular weight HA induced abnormal epithelial morphology; low molecular weight HA caused matrix swelling in a bile duct-on-a-chip device. CONCLUSION The fetal/neonatal EHBD, including in human EHBD remnants from Kasai surgeries, demonstrated an injury response with prolonged high levels of HA typical of fetal wound healing. The expanded peri-luminal HA layer may swell and lead to elevated bilirubin levels and obstruction of the EHBD. IMPACT AND IMPLICATIONS Biliary atresia is a pediatric cholangiopathy associated with high morbidity and mortality rates; although multiple etiologies have been proposed, the fetal response to bile duct damage is largely unknown. This study explores the fetal pathogenesis after extrahepatic bile duct damage, thereby opening a completely new avenue to study therapeutic targets in the context of biliary atresia.
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Affiliation(s)
- Iris E M de Jong
- Section of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands; Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Mallory L Hunt
- Division of Cardiothoracic Surgery, Children's Hospital of Philadelphia, Philadelphia, PA, USA
| | - Dongning Chen
- Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, USA; Center for Engineering MechanoBiology, University of Pennsylvania, Philadelphia, PA, USA
| | - Yu Du
- Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Key Laboratory of Microgravity (National Microgravity Laboratory), Center of Biomechanics and Bioengineering, and Beijing Key Laboratory of Engineered Construction and Mechanobiology, Institute of Mechanics, Chinese Academy of Sciences, Beijing, China
| | - Jessica Llewellyn
- Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Kapish Gupta
- Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - David Li
- Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Dorothea Erxleben
- Virginia Tech-Wake Forest University School of Biomedical Engineering and Sciences, Wake Forest School of Medicine, Winston-Salem, NC, USA
| | - Felipe Rivas
- Virginia Tech-Wake Forest University School of Biomedical Engineering and Sciences, Wake Forest School of Medicine, Winston-Salem, NC, USA
| | - Adam R Hall
- Virginia Tech-Wake Forest University School of Biomedical Engineering and Sciences, Wake Forest School of Medicine, Winston-Salem, NC, USA; Comprehensive Cancer Center, Wake Forest School of Medicine, Winston-Salem, NC, USA
| | - Emma E Furth
- Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Ali Naji
- Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Chengyang Liu
- Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Abhishek Dhand
- Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, USA
| | - Jason A Burdick
- Department of Chemical and Biological Engineering, University of Colorado, Boulder, CO, USA
| | - Marcus G Davey
- The Center for Fetal Research, Department of Surgery, Children's Hospital of Philadelphia, Philadelphia, PA, USA
| | - Alan W Flake
- The Center for Fetal Research, Department of Surgery, Children's Hospital of Philadelphia, Philadelphia, PA, USA
| | - Robert J Porte
- Section of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Pierre A Russo
- Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, PA, USA
| | - J William Gaynor
- Division of Cardiothoracic Surgery, Children's Hospital of Philadelphia, Philadelphia, PA, USA
| | - Rebecca G Wells
- Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, USA; Center for Engineering MechanoBiology, University of Pennsylvania, Philadelphia, PA, USA; Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA.
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14
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Tamaoka S, Fukuda A, Nakabayashi K, Matsubara K, Ogata-Kawata H, Muranishi Y, Hata K, Kato-Fukui Y, Sakamoto S, Kasahara M, Fukami M. Rare sequence variants associated with the risk of non-syndromic biliary atresia. Hepatol Res 2023; 53:1134-1141. [PMID: 37491771 DOI: 10.1111/hepr.13946] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2023] [Revised: 07/20/2023] [Accepted: 07/22/2023] [Indexed: 07/27/2023]
Abstract
AIM The etiology of non-syndromic biliary atresia (BA) remains largely unknown. In this study, we performed genome-wide screening of genes associated with the risk of non-syndromic BA. METHODS We analyzed exome data of 15 Japanese patients with non-syndromic BA and 509 control individuals using an optimal sequence kernel association test (SKAT-O), a gene-based association study optimized for small-number subjects. Furthermore, we examined the frequencies of known BA-related single-nucleotide polymorphisms in the BA and control groups. RESULTS SKAT-O showed that rare damaging variants of MFHAS1, a ubiquitously expressed gene encoding a Toll-like receptor-associated protein, were more common in the BA group than in the control group (Bonferroni corrected p-value = 0.0097). Specifically, p.Val106Gly and p.Arg556Cys significantly accumulated in the patient group. These variants resided within functionally important domains. SKAT-O excluded the presence of other genes significantly associated with the disease risk. Of 60 known BA-associated single-nucleotide polymorphisms, only eight were identified in the BA group. In particular, p.Ile3421Met of MYO15A and p.Ala421Thr of THOC2 were more common in the BA group than in the control group. However, the significance of these two variants is questionable, because MYO15A has been linked to deafness, but not to BA, and the p.Ala421Thr of THOC2 represents a relatively common single-nucleotide polymorphism in Asia. CONCLUSIONS The results of this study indicate that rare damaging variants in MFHAS1 may constitute a risk factor for non-syndromic BA, whereas the contribution of other monogenic variants to the disease predisposition is limited.
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Affiliation(s)
- Satoshi Tamaoka
- Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo, Japan
- Department of Pediatrics, Keio University School of Medicine, Tokyo, Japan
| | - Akinari Fukuda
- Center for Organ Transplantation, National Center for Child Health and Development, Tokyo, Japan
| | - Kazuhiko Nakabayashi
- Department of Maternal-Fetal Biology, National Research Institute for Child Health and Development, Tokyo, Japan
| | - Keiko Matsubara
- Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo, Japan
- Division of Diversity Research, National Center for Child Health and Development, Tokyo, Japan
| | - Hiroko Ogata-Kawata
- Department of Maternal-Fetal Biology, National Research Institute for Child Health and Development, Tokyo, Japan
| | - Yuki Muranishi
- Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo, Japan
| | - Kenichiro Hata
- Department of Maternal-Fetal Biology, National Research Institute for Child Health and Development, Tokyo, Japan
| | - Yuko Kato-Fukui
- Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo, Japan
| | - Seisuke Sakamoto
- Center for Organ Transplantation, National Center for Child Health and Development, Tokyo, Japan
| | - Mureo Kasahara
- Center for Organ Transplantation, National Center for Child Health and Development, Tokyo, Japan
| | - Maki Fukami
- Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo, Japan
- Division of Diversity Research, National Center for Child Health and Development, Tokyo, Japan
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15
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Cui MM, Gong YM, Pan WH, Pei HY, Bai MR, Song HL, Han XR, Wu WJ, Yu WW, Gu BL, Cai W, Zhou Y, Chu X. Contribution of ADD3 and the HLA Genes to Biliary Atresia Risk in Chinese. Int J Mol Sci 2023; 24:14719. [PMID: 37834180 PMCID: PMC10572496 DOI: 10.3390/ijms241914719] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2023] [Revised: 09/22/2023] [Accepted: 09/26/2023] [Indexed: 10/15/2023] Open
Abstract
Nonsyndromic biliary atresia (BA) is a rare polygenic disease, with autoimmunity, virus infection and inflammation thought to play roles in its pathogenesis. We conducted a genome-wide association study in 336 nonsyndromic BA infants and 8900 controls. Our results validated the association of rs17095355 in ADD3 with BA risk (odds ratio (OR) = 1.70, 95% confidence interval (95% CI) = 1.49-1.99; p = 4.07 × 10-11). An eQTL analysis revealed that the risk allele of rs17095355 was associated with increased expression of ADD3. Single-cell RNA-sequencing data and immunofluorescence analysis revealed that ADD3 was moderately expressed in cholangiocytes and weakly expressed in hepatocytes. Immuno-fluorescent staining showed abnormal deposition of ADD3 in the cytoplasm of BA hepatocytes. No ADD3 auto-antibody was observed in the plasma of BA infants. In the HLA gene region, no variants achieved genome-wide significance. HLA-DQB1 residue Ala57 is the most significant residue in the MHC region (OR = 1.44, 95% CI = 1.20-1.74; p = 1.23 × 10-4), and HLA-DQB1 was aberrantly expressed in the bile duct cells. GWAS stratified by cytomegalovirus (CMV) IgM status in 87 CMV IgM (+) BA cases versus 141 CMV IgM (-) BA cases did not yield genome-wide significant associations. These findings support the notion that common variants of ADD3 account for BA risk. The HLA genes might have a minimal role in the genetic predisposition of BA due to the weak association signal. CMV IgM (+) BA patients might not have different genetic risk factor profiles compared to CMV IgM (-) subtype.
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Affiliation(s)
- Meng-Meng Cui
- Department of Pediatric Surgery, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai 200092, China; (M.-M.C.); (Y.-M.G.); (W.-H.P.); (W.-J.W.); (W.C.)
- Shanghai Institute of Pediatric Research, Shanghai 200092, China; (H.-Y.P.); (M.-R.B.); (H.-L.S.); (X.-R.H.); (W.-W.Y.); (B.-L.G.)
- Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai 200092, China
| | - Yi-Ming Gong
- Department of Pediatric Surgery, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai 200092, China; (M.-M.C.); (Y.-M.G.); (W.-H.P.); (W.-J.W.); (W.C.)
| | - Wei-Hua Pan
- Department of Pediatric Surgery, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai 200092, China; (M.-M.C.); (Y.-M.G.); (W.-H.P.); (W.-J.W.); (W.C.)
| | - Hao-Yue Pei
- Shanghai Institute of Pediatric Research, Shanghai 200092, China; (H.-Y.P.); (M.-R.B.); (H.-L.S.); (X.-R.H.); (W.-W.Y.); (B.-L.G.)
- Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai 200092, China
| | - Mei-Rong Bai
- Shanghai Institute of Pediatric Research, Shanghai 200092, China; (H.-Y.P.); (M.-R.B.); (H.-L.S.); (X.-R.H.); (W.-W.Y.); (B.-L.G.)
- Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai 200092, China
| | - Huan-Lei Song
- Shanghai Institute of Pediatric Research, Shanghai 200092, China; (H.-Y.P.); (M.-R.B.); (H.-L.S.); (X.-R.H.); (W.-W.Y.); (B.-L.G.)
- Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai 200092, China
| | - Xin-Ru Han
- Shanghai Institute of Pediatric Research, Shanghai 200092, China; (H.-Y.P.); (M.-R.B.); (H.-L.S.); (X.-R.H.); (W.-W.Y.); (B.-L.G.)
- Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai 200092, China
| | - Wen-Jie Wu
- Department of Pediatric Surgery, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai 200092, China; (M.-M.C.); (Y.-M.G.); (W.-H.P.); (W.-J.W.); (W.C.)
| | - Wen-Wen Yu
- Shanghai Institute of Pediatric Research, Shanghai 200092, China; (H.-Y.P.); (M.-R.B.); (H.-L.S.); (X.-R.H.); (W.-W.Y.); (B.-L.G.)
- Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai 200092, China
| | - Bei-Lin Gu
- Shanghai Institute of Pediatric Research, Shanghai 200092, China; (H.-Y.P.); (M.-R.B.); (H.-L.S.); (X.-R.H.); (W.-W.Y.); (B.-L.G.)
- Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai 200092, China
| | - Wei Cai
- Department of Pediatric Surgery, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai 200092, China; (M.-M.C.); (Y.-M.G.); (W.-H.P.); (W.-J.W.); (W.C.)
- Shanghai Institute of Pediatric Research, Shanghai 200092, China; (H.-Y.P.); (M.-R.B.); (H.-L.S.); (X.-R.H.); (W.-W.Y.); (B.-L.G.)
- Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai 200092, China
| | - Ying Zhou
- Department of Pediatric Surgery, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai 200092, China; (M.-M.C.); (Y.-M.G.); (W.-H.P.); (W.-J.W.); (W.C.)
| | - Xun Chu
- Department of Pediatric Surgery, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai 200092, China; (M.-M.C.); (Y.-M.G.); (W.-H.P.); (W.-J.W.); (W.C.)
- Shanghai Institute of Pediatric Research, Shanghai 200092, China; (H.-Y.P.); (M.-R.B.); (H.-L.S.); (X.-R.H.); (W.-W.Y.); (B.-L.G.)
- Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai 200092, China
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16
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Abstract
Biliary atresia (BA) is the most prevalent serious liver disease of infancy and childhood, and the principal indication for liver transplantation in pediatrics. BA is best considered as an idiopathic panbiliary cholangiopathy characterized by obstruction of bile flow and consequent cholestasis presenting during fetal and perinatal periods. While several etiologies have been proposed, each has significant drawbacks that have limited understanding of disease progression and the development of effective treatments. Recently, modern genetic analyses have uncovered gene variants contributing to BA, thereby shifting the paradigm for explaining the BA phenotype from an acquired etiology (e.g., virus, toxin) to one that results from genetically altered cholangiocyte development and function. Herein we review recently reported genetic contributions to BA, highlighting the enhanced representation of variants in biological pathways involving ciliary function, cytoskeletal structure, and inflammation. Finally, we blend these findings as a new framework for understanding the resultant BA phenotype as a developmental cholangiopathy.
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Affiliation(s)
- Dominick J Hellen
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Children's Healthcare of Atlanta and Emory University School of Medicine, Atlanta, Georgia
| | - Saul J Karpen
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Children's Healthcare of Atlanta and Emory University School of Medicine, Atlanta, Georgia
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17
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Sok P, Sabo A, Almli LM, Jenkins MM, Nembhard WN, Agopian AJ, Bamshad MJ, Blue EE, Brody LC, Brown AL, Browne ML, Canfield MA, Carmichael SL, Chong JX, Dugan-Perez S, Feldkamp ML, Finnell RH, Gibbs RA, Kay DM, Lei Y, Meng Q, Moore CA, Mullikin JC, Muzny D, Olshan AF, Pangilinan F, Reefhuis J, Romitti PA, Schraw JM, Shaw GM, Werler MM, Harpavat S, Lupo PJ. Exome-wide assessment of isolated biliary atresia: A report from the National Birth Defects Prevention Study using child-parent trios and a case-control design to identify novel rare variants. Am J Med Genet A 2023; 191:1546-1556. [PMID: 36942736 PMCID: PMC10947986 DOI: 10.1002/ajmg.a.63185] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2022] [Revised: 02/07/2023] [Accepted: 03/07/2023] [Indexed: 03/23/2023]
Abstract
The etiology of biliary atresia (BA) is unknown, but recent studies suggest a role for rare protein-altering variants (PAVs). Exome sequencing data from the National Birth Defects Prevention Study on 54 child-parent trios, one child-mother duo, and 1513 parents of children with other birth defects were analyzed. Most (91%) cases were isolated BA. We performed (1) a trio-based analysis to identify rare de novo, homozygous, and compound heterozygous PAVs and (2) a case-control analysis using a sequence kernel-based association test to identify genes enriched with rare PAVs. While we replicated previous findings on PKD1L1, our results do not suggest that recurrent de novo PAVs play important roles in BA susceptibility. In fact, our finding in NOTCH2, a disease gene associated with Alagille syndrome, highlights the difficulty in BA diagnosis. Notably, IFRD2 has been implicated in other gastrointestinal conditions and warrants additional study. Overall, our findings strengthen the hypothesis that the etiology of BA is complex.
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Affiliation(s)
- Pagna Sok
- Pediatrics, Baylor College of Medicine, Houston, Texas,
USA
| | - Aniko Sabo
- Human Genome Sequencing Center, Baylor College of Medicine,
Houston, Texas, USA
| | - Lynn M. Almli
- National Center on Birth Defects and Developmental
Disabilities, Centers for Disease Control and Prevention, Atlanta, Georgia,
USA
| | - Mary M. Jenkins
- National Center on Birth Defects and Developmental
Disabilities, Centers for Disease Control and Prevention, Atlanta, Georgia,
USA
| | - Wendy N. Nembhard
- Fay W. Boozman College of Public Health, University of
Arkansas for Medical Sciences, Little Rock, Arkansas, USA
| | - A. J. Agopian
- Department of Epidemiology, Human Genetics, and
Environmental Sciences, University of Texas School of Public Health, Houston, Texas,
USA
| | - Michael J. Bamshad
- Division of Genetic Medicine, Department of Pediatrics,
University of Washington, Seattle, Washington, USA
- Brotman Baty Institute for Precision Medicine, Seattle,
Washington, USA
| | - Elizabeth E. Blue
- Brotman Baty Institute for Precision Medicine, Seattle,
Washington, USA
- Division of Medical Genetics, Department of Medicine,
University of Washington, Seattle, Washington, USA
| | - Lawrence C. Brody
- Genetics and Environment Interaction Section, National
Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland,
USA
| | | | - Marilyn L. Browne
- Birth Defects Registry, New York State Department of
Health, Albany, New York, USA
- Department of Epidemiology and Biostatistics, School of
Public Health, University at Albany, Rensselaer, New York, USA
| | - Mark A. Canfield
- Birth Defects Epidemiology and Surveillance Branch, Texas
Department of State Health Services, Austin, Texas, USA
| | - Suzan L. Carmichael
- Department of Pediatrics, Stanford University School of
Medicine, Stanford, California, USA
| | - Jessica X. Chong
- Division of Genetic Medicine, Department of Pediatrics,
University of Washington, Seattle, Washington, USA
- Brotman Baty Institute for Precision Medicine, Seattle,
Washington, USA
| | - Shannon Dugan-Perez
- Human Genome Sequencing Center, Baylor College of Medicine,
Houston, Texas, USA
| | - Marcia L. Feldkamp
- Division of Medical Genetics, Department of Pediatrics,
University of Utah School of Medicine, Salt Lake City, Utah, USA
| | - Richard H. Finnell
- Department of Medicine, Center for Precision
Environmental Health, Baylor College of Medicine, Houston, Texas, USA
| | - Richard A. Gibbs
- Human Genome Sequencing Center, Baylor College of Medicine,
Houston, Texas, USA
| | - Denise M. Kay
- Division of Genetics, Wadsworth Center, New York State
Department of Health, Albany, New York, USA
| | - Yunping Lei
- Department of Medicine, Center for Precision
Environmental Health, Baylor College of Medicine, Houston, Texas, USA
| | - Qingchang Meng
- Human Genome Sequencing Center, Baylor College of Medicine,
Houston, Texas, USA
| | - Cynthia A. Moore
- National Center on Birth Defects and Developmental
Disabilities, Centers for Disease Control and Prevention, Atlanta, Georgia,
USA
| | - James C. Mullikin
- Genetics and Environment Interaction Section, National
Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland,
USA
| | - Donna Muzny
- Human Genome Sequencing Center, Baylor College of Medicine,
Houston, Texas, USA
| | - Andrew F. Olshan
- Department of Epidemiology, Gillings School of Global
Public Health, University of North Carolina, Chapel Hill, North Carolina, USA
| | - Faith Pangilinan
- Genetics and Environment Interaction Section, National
Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland,
USA
| | - Jennita Reefhuis
- National Center on Birth Defects and Developmental
Disabilities, Centers for Disease Control and Prevention, Atlanta, Georgia,
USA
| | - Paul A. Romitti
- Department of Epidemiology, University of Iowa College of
Public Health, Iowa City, Iowa, USA
| | | | - Gary M. Shaw
- Department of Pediatrics, Stanford University School of
Medicine, Stanford, California, USA
| | - Martha M. Werler
- Department of Epidemiology, Boston University, Boston,
Massachusetts, USA
| | - Sanjiv Harpavat
- Pediatrics, Baylor College of Medicine, Houston, Texas,
USA
- Gastroenterology, Hepatology and Nutrition, Texas
Children’s Hospital, Houston, Texas, USA
| | - Philip J. Lupo
- Pediatrics, Baylor College of Medicine, Houston, Texas,
USA
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18
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Xie S, Wei S, Ma X, Wang R, He T, Zhang Z, Yang J, Wang J, Chang L, Jing M, Li H, Zhou X, Zhao Y. Genetic alterations and molecular mechanisms underlying hereditary intrahepatic cholestasis. Front Pharmacol 2023; 14:1173542. [PMID: 37324459 PMCID: PMC10264785 DOI: 10.3389/fphar.2023.1173542] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2023] [Accepted: 05/16/2023] [Indexed: 06/17/2023] Open
Abstract
Hereditary cholestatic liver disease caused by a class of autosomal gene mutations results in jaundice, which involves the abnormality of the synthesis, secretion, and other disorders of bile acids metabolism. Due to the existence of a variety of gene mutations, the clinical manifestations of children are also diverse. There is no unified standard for diagnosis and single detection method, which seriously hinders the development of clinical treatment. Therefore, the mutated genes of hereditary intrahepatic cholestasis were systematically described in this review.
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Affiliation(s)
- Shuying Xie
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China
| | - Shizhang Wei
- Department of Anatomy, Histology and Embryology, School of Basic Medical Sciences, Health Science Center, Peking University, Beijing, China
| | - Xiao Ma
- Pharmacy College, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Ruilin Wang
- Department of Pharmacy, 5th Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Tingting He
- Department of Pharmacy, 5th Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Zhao Zhang
- Pharmacy College, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Ju Yang
- Pharmacy College, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Jiawei Wang
- Pharmacy College, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Lei Chang
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China
| | - Manyi Jing
- Department of Pharmacy, Chinese PLA General Hospital, Beijing, China
| | - Haotian Li
- Department of Pharmacy, Chinese PLA General Hospital, Beijing, China
| | - Xuelin Zhou
- Department of Pharmacology, School of Basic Medical Sciences, Capital Medical University, Beijing, China
| | - Yanling Zhao
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China
- Department of Pharmacy, Chinese PLA General Hospital, Beijing, China
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Li TF, Ke XY, Zhang YR, Zhan JH. The correlation between rs2501577 gene polymorphism and biliary atresia: a systematic review and meta-analysis. Pediatr Surg Int 2023; 39:206. [PMID: 37248361 DOI: 10.1007/s00383-023-05491-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 05/23/2023] [Indexed: 05/31/2023]
Abstract
IMPORTANCE Multiple studies indicate a possible correlation between ADD3 rs2501577 and biliary atresia susceptibility; however, a conclusive determination has yet to be made. OBJECTIVE Investigate the role of ADD3 rs2501577 in biliary atresia susceptibility across diverse populations. DATA SOURCES The study protocol has been registered on PROSPERO, an international platform for systematic review registration (PROSPERO ID: CRD42023384641). The following databases will be searched until February 1, 2023: PubMed, Embase, Cochrane, CBM, Web of Science, and CNKI. STUDY SELECTION Eight studies were selected from seven papers to assess the data. A total of 7651 participants were included, consisting of 1662 in the BA group and 5989 in the NC group. DATA EXTRACTION AND SYNTHESIS Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed while conducting the systematic reviews and meta-analyses. Two authors independently assessed the quality of the included studies using the Newcastle-Ottawa Quality Assessment Scale. The significance of the pooled odds ratio (OR) was evaluated with a Z test, and statistical heterogeneity across studies was assessed using the I2 and Q statistics. Publication bias was assessed using Egger's and Begg's tests. MAIN OUTCOME(S) AND MEASURE(S) The primary study outcome was the development of biliary atresia. Subgroup analysis was performed based on race, region, and assessment of Hardy-Weinberg equilibrium (HWE). RESULTS The studies indicate that the ADD3 rs2501577 susceptibility locus increases the risk of developing biliary atresia, regardless of allelic, homozygote, dominant, and recessive gene inheritance models. Furthermore, ADD3 has been found to be associated with apoptosis, cell cycle, and cell damage repair based on functional analysis. CONCLUSIONS AND RELEVANCE The ADD3 rs2501577 polymorphic locus is associated with an increased risk of biliary atresia, particularly in Asian populations. This study recommends further investigation of the ADD3 rs2501577 locus in Asian populations to validate its role in the diagnosis of biliary atresia.
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Affiliation(s)
- Teng-Fei Li
- Graduate School, Tianjin Medical University, Tianjin, 300070, China
- Department of General Surgery, Tianjin Children's Hospital, Tianjin, 300134, China
| | - Xing-Yuan Ke
- School of Basic Medical Sciences, Tianjin Medical University, Tianjin, 300070, China
| | - Yan-Ran Zhang
- School of Basic Medical Sciences, Tianjin Medical University, Tianjin, 300070, China
| | - Jiang-Hua Zhan
- Department of General Surgery, Tianjin Children's Hospital, Tianjin, 300134, China.
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20
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Bai MR, Pei HY, Zhou Y, Song HL, Pan WH, Gong YM, Wu WJ, Yu WW, Cui MM, Gu BL, Chu X, Cai W. Association analysis and functional follow-up identified common variants of JAG1 accounting for risk to biliary atresia. Front Genet 2023; 14:1186882. [PMID: 37255715 PMCID: PMC10225652 DOI: 10.3389/fgene.2023.1186882] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2023] [Accepted: 05/05/2023] [Indexed: 06/01/2023] Open
Abstract
Background: Biliary atresia (BA) is a destructive, obliterative cholangiopathy characterized by progressive fibro-inflammatory disorder and obliteration of intra- and extrahepatic bile ducts. The Jagged1 (JAG1) gene mutations have been found in some isolated BA cases. We aim to explore the association of common variants in JAG1 with isolated BA risk in the Chinese Han population. Methods: We genotyped 31 tag single nucleotide polymorphisms covering the JAG1 gene region in 333 BA patients and 1,665 healthy controls from the Chinese population, and performed case-control association analysis. The expression patterns of JAG1 homologs were investigated in zebrafish embryos, and the roles of jag1a and jag1b in biliary development were examined by morpholino knockdown in zebrafish. Results: Single nucleotide polymorphisms rs6077861 [P Allelic = 1.74 × 10-4, odds ratio = 1.78, 95% confidence interval: 1.31-2.40] and rs3748478 (P Allelic = 5.77 × 10-4, odds ratio = 1.39, 95% confidence interval: 1.15-1.67) located in the intron region of JAG1 showed significant associations with BA susceptibility. The JAG1 homologs, jag1a and jag1b genes were expressed in the developing hepatobiliary duct of zebrafish, especially at 72 and 96 h postfertilization. Knockdown of both jag1a and jag1b led to poor biliary secretion, sparse intrahepatic bile duct network and smaller or no gallbladders compared with control embryos in the zebrafish model. Conclusion: Common genetic variants of JAG1 were associated with BA susceptibility. Knockdown of JAG1 homologs led to defective intrahepatic and extrahepatic bile ducts in zebrafish. These results suggest that JAG1 might be implicated in the etiology of BA.
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Affiliation(s)
- Mei-Rong Bai
- Department of Pediatric Surgery, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China
- Shanghai Institute of Pediatric Research, Shanghai, China
- Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China
| | - Hao-Yue Pei
- Shanghai Institute of Pediatric Research, Shanghai, China
- Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China
| | - Ying Zhou
- Department of Pediatric Surgery, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Huan-Lei Song
- Shanghai Institute of Pediatric Research, Shanghai, China
- Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China
| | - Wei-Hua Pan
- Department of Pediatric Surgery, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Yi-Ming Gong
- Department of Pediatric Surgery, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Wen-Jie Wu
- Department of Pediatric Surgery, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Wen-Wen Yu
- Shanghai Institute of Pediatric Research, Shanghai, China
- Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China
| | - Meng-Meng Cui
- Shanghai Institute of Pediatric Research, Shanghai, China
- Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China
| | - Bei-Lin Gu
- Shanghai Institute of Pediatric Research, Shanghai, China
- Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China
| | - Xun Chu
- Department of Pediatric Surgery, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China
- Shanghai Institute of Pediatric Research, Shanghai, China
- Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China
| | - Wei Cai
- Department of Pediatric Surgery, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China
- Shanghai Institute of Pediatric Research, Shanghai, China
- Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China
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21
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Davenport M, Kronfli R, Makin E. Advances in understanding of biliary atresia pathogenesis and progression - a riddle wrapped in a mystery inside an enigma. Expert Rev Gastroenterol Hepatol 2023; 17:343-352. [PMID: 36908275 DOI: 10.1080/17474124.2023.2191188] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 03/14/2023]
Abstract
INTRODUCTION Biliary atresia is a potentially fatal condition of the bile ducts - both intra- and extrahepatic, for which we have no cure. Though principally a cholestatic condition, much of its pathology stems from its tendency to aggressively induce liver fibrosis and ultimately cirrhosis, only partially restrained by the portoenterostomy. AREAS COVERED This review is based on the current literature exploring the heterogeneous nature of biliary atresia. Thus, there are various phenotypes or variants of biliary atresia, each potentially with different etiological backgrounds caused by a number of hypothetical pathological mechanisms thought to be important in the genesis of the condition. Search methodology: the review (Oct. - Nov. 2022) is based on a search of PubMed (NLM) using main keyword 'biliary atresia' with supplementary searches using 'fibrosis'; 'inflammation'; 'BASM'; 'genetics'; 'surgery'; 'experimental'; 'etiology'; 'virology'; 'cases'; and 'syndromes.' EXPERT OPINION Future developments will be made on matching clinical variants with a more distinct pathophysiological discrimination and those pathways linking the initial cholestatic phase of biliary atresia to the early stages of fibrosis.
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Affiliation(s)
- Mark Davenport
- Department of Paediatric Surgery, Kings College Hospital, London, UK
| | - Rania Kronfli
- Department of Paediatric Surgery, Kings College Hospital, London, UK
| | - Erica Makin
- Department of Paediatric Surgery, Kings College Hospital, London, UK
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22
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Muntean A, Davenport M. Biliary atresia & choledochal malformation--Embryological and anatomical considerations. Semin Pediatr Surg 2022; 31:151235. [PMID: 36442454 DOI: 10.1016/j.sempedsurg.2022.151235] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
The two main biliary pathologies in paediatric practice, biliary atresia and choledochal malformations (CM), have their origins within prenatal life. Nevertheless, the actual mechanisms remain elusive with many unanswered questions. The extrahepatic bile duct develops as a funnel-like structure emerging from the foregut from about 3-4 weeks of gestation into the mesenchyme of the septum transversum. The cranial elements of this contain hepatoblasts - the precursors to the two key cell lines that will become hepatocytes and biliary epithelial cells. The intrahepatic bile ducts develop separately and emerge from a complex process involving the ductal plate surrounding the in-growing portal venous system from about the 7-8th week of gestation. A developmental defect at some point(s) in this process may be the cause of at least some variants of BA - the Biliary Atresia Splenic Malformation syndrome particularly - though evidence in the more common isolated BA is much more circumstantial. Similarly, some types of choledochal malformation, specifically the cystic type of CM, are invariably present during prenatal life although again an actual aetiological mechanism remains elusive.
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Affiliation(s)
- Ancuta Muntean
- Deptartment of Paediatric Surgery, Kings College Hospital, London
| | - Mark Davenport
- Deptartment of Paediatric Surgery, Kings College Hospital, London.
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23
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Laochareonsuk W, Surachat K, Chiengkriwate P, Sangkhathat S. A novel pathogenesis concept of biliary atresia approached by combined molecular strategies. PLoS One 2022; 17:e0277334. [PMID: 36350824 PMCID: PMC9645613 DOI: 10.1371/journal.pone.0277334] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2022] [Accepted: 10/24/2022] [Indexed: 11/11/2022] Open
Abstract
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.
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Affiliation(s)
- Wison Laochareonsuk
- Faculty of Medicine, Department of Surgery, Prince of Songkla University, Hat Yai, Songkhla, Thailand
- Faculty of Medicine, Translational Medicine Research Center, Prince of Songkla University, Hat Yai, Songkhla, Thailand
| | - Komwit Surachat
- Faculty of Medicine, Translational Medicine Research Center, Prince of Songkla University, Hat Yai, Songkhla, Thailand
- Faculty of Medicine, Department of Biomedical Sciences and Biomedical Engineering, Prince of Songkla University, Hat Yai, Songkhla, Thailand
| | - Piyawan Chiengkriwate
- Faculty of Medicine, Department of Surgery, Prince of Songkla University, Hat Yai, Songkhla, Thailand
| | - Surasak Sangkhathat
- Faculty of Medicine, Department of Surgery, Prince of Songkla University, Hat Yai, Songkhla, Thailand
- Faculty of Medicine, Translational Medicine Research Center, Prince of Songkla University, Hat Yai, Songkhla, Thailand
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24
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Laochareonsuk W, Kayasut K, Surachat K, Chiengkriwate P, Sangkhathat S. Impact of EFEMP1 on the survival outcome of biliary atresia in Thai infants. Sci Rep 2022; 12:15603. [PMID: 36114336 PMCID: PMC9481615 DOI: 10.1038/s41598-022-19457-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2022] [Accepted: 08/30/2022] [Indexed: 11/09/2022] Open
Abstract
Genome-wide association studies (GWASs) have identified a genetic associated between EFEMP1 and biliary atresia (BA). To examine the susceptibility of single nucleotide polymorphisms (SNPs) in EFEMP1 in Thai BA patients, we performed an analysis of the genetic associations and biological interactions with previously reported key SNPs in ADD3, a key gene associated with BA. The study also used high-throughput sequencing to detect novel variants in both genes. In addition, the clinical impact of EFEMP1 SNPs in terms of survival association was also evaluated. The genotypes of 60 BA patients and 179 controls were evaluated using a TaqMan genotyping assay for rs2501577 and rs17095355 in ADD3 and rs6761893 and rs727878 in EFEMP1. The genotype frequencies were analyzed together with the SNP-SNP interactions. Fine mapping by whole-exome sequencing was performed to identify deleterious variants within both genes, and the survival analysis results were analyzed with the EFEMP1 SNPs. The recessive genotypes of rs2501577, rs17095355 and rs6761893 showed significantly higher frequencies in the BA patients than the controls, and a logistic regression showed that minor alleles of those SNPs increased the BA risk by ORs of 1.86, 1.67, and 1.84, respectively. Moreover, the SNP-SNP interference suggested that a combination of recessive alleles from the 2 genes resulted in an additive risk to BA. In addition, rare missense variants in the gene coding sequences were identified in 7 cases. Immunohistochemical studies revealed a pattern of ADD3 downregulation and EFEMP1 overexpression in the bile ducts of BA patients. Patients with the AA genotype of rs6761893 had significantly lower 5-year native liver survival (34.0%) than those with AT/TT (75.0%), with a log-rank p value of 0.041. Variants in EFEMP1 are associated with the occurrence of BA in Thai patients. In addition, these variants have an additive influence on BA risk when combined with ADD3 variants. Moreover, rs6761893 in EFEMP1 was indicative of survival in Thai BA patients.
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Affiliation(s)
- Wison Laochareonsuk
- Department of Surgery and Translational Medicine Research Center, Faculty of Medicine, Prince of Songkla University, Hat Yai, 90110, Songkhla, Thailand
| | - Kanita Kayasut
- Department of Pathology, Faculty of Medicine, Prince of Songkla University, Hat Yai, Thailand
| | - Komwit Surachat
- Department of Biomedical Science and Biomedical Engineering, Faculty of Medicine, Prince of Songkla University, Hat Yai, Thailand
| | - Piyawan Chiengkriwate
- Department of Surgery, Faculty of Medicine, Prince of Songkla University, Hat Yai, Thailand
| | - Surasak Sangkhathat
- Department of Surgery and Translational Medicine Research Center, Faculty of Medicine, Prince of Songkla University, Hat Yai, 90110, Songkhla, Thailand.
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25
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Islek A, Tumgor G. Biliary atresia and congenital disorders of the extrahepatic bile ducts. World J Gastrointest Pharmacol Ther 2022; 13:33-46. [PMID: 36051179 PMCID: PMC9297290 DOI: 10.4292/wjgpt.v13.i4.33] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2022] [Revised: 03/10/2022] [Accepted: 06/13/2022] [Indexed: 02/06/2023] Open
Abstract
Biliary atresia (BA) and choledochal cysts are diseases of the intrahepatic and extrahepatic biliary tree. While their exact etiopathogeneses are not known, they should be treated promptly due to the potential for irreversible parenchymal liver disease. A diagnosis of BA may be easy or complicated, but should not be delayed. BA is always treated surgically, and performing the surgery before the age of 2 mo greatly increases its effectiveness and extends the time until the need for liver transplantation arises. While the more common types of choledochal cysts require surgical treatment, some can be treated with endoscopic retrograde cholangiopancreatography. Choledochal cysts may cause recurrent cholangitis and the potential for malignancy should not be ignored.
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Affiliation(s)
- Ali Islek
- Department of Pediatric Gastroenterology, Cukurova University School of Medicine, Adana 01320, Turkey
| | - Gokhan Tumgor
- Department of Pediatric Gastroenterology, Cukurova University School of Medicine, Adana 01320, Turkey
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26
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Ye Y, Wu W, Zheng J, Zhang L, Wang B. Role of long non-coding RNA-adducin 3 antisense RNA1 in liver fibrosis of biliary atresia. Bioengineered 2022; 13:6222-6230. [PMID: 35246014 PMCID: PMC8974046 DOI: 10.1080/21655979.2022.2041321] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
Biliary atresia (BA) is a devastating liver disease in neonates. Liver fibrosis is regarded as a universal and prominent feature of BA. Studies have revealed that long non-coding RNAs (lncRNAs) regulate cellular processes during the development of liver fibrosis in BA. Long non-coding RNA-adducin 3 antisense RNA1 (lnc-ADD3-AS1) has been shown to increase susceptibility to BA. However, the role of lnc-ADD3-AS1 in liver fibrosis in BA remains unclear. Here, we investigated the role of lnc-ADD3-AS1 in the proliferation, migration, and apoptosis of the immortalized human hepatic stellate cell (HSC) line, LX-2. We successfully overexpressed and silenced lnc-ADD3-AS1 in LX-2 cells using adenovirus vectors and evaluated the proliferation of transfected cells using the Cell Counting Kit-8 (CCK8) assay. Cell apoptosis was detected using annexin V-fluorescein isothiocyanate (FITC)/propidium iodide (PI) double staining and flow cytometry. We then analyzed cell migration by performing wound-scratch and transwell migration assays. Our results show that lnc-ADD3-AS1 significantly promoted LX-2 cell proliferation and attenuated apoptosis. More importantly, lncRNA-ADD3-AS1 significantly accelerated the migration of LX-2 cells. Our data indicated that lncRNA-ADD3-AS1 plays a role in the pathogenesis of liver fibrosis in patients with BA and may serve as a potential diagnostic marker for monitoring liver fibrosis in BA or as a therapeutic target for the disease.
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Affiliation(s)
- Yongqin Ye
- Department of General Surgery, Shenzhen Children’s Hospital, Shenzhen, China
| | - Weifang Wu
- Department of Pediatric Surgery, Shantou University Medical College, Shantou, China
| | - Jiachen Zheng
- Department of Pediatric Surgery, Shantou University Medical College, Shantou, China
| | - Lihui Zhang
- Department of Traditional Chinese Medicine, Shenzhen Children’s Hospital, Shenzhen, China
- CONTACT Lihui Zhang Department of Traditional Chinese Medicine, Shenzhen Children’s Hospital, Shenzhen, China
| | - Bin Wang
- Department of General Surgery, Shenzhen Children’s Hospital, Shenzhen, China
- Bin Wang Department of General Surgery, Shenzhen Children’s Hospital, Shenzhen, China
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27
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Wu LN, Zhu ZJ, Sun LY. Genetic Factors and Their Role in the Pathogenesis of Biliary Atresia. Front Pediatr 2022; 10:912154. [PMID: 35844731 PMCID: PMC9277099 DOI: 10.3389/fped.2022.912154] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/04/2022] [Accepted: 06/08/2022] [Indexed: 12/12/2022] Open
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.
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Affiliation(s)
- Li-Na Wu
- Department of Critical Liver Diseases, Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China.,Liver Transplantation Center, National Clinical Research Center for Digestive Diseases, Beijing Friendship Hospital, Capital Medical University, Beijing, China.,Clinical Center for Pediatric Liver Transplantation, Capital Medical University, Beijing, China
| | - Zhi-Jun Zhu
- Liver Transplantation Center, National Clinical Research Center for Digestive Diseases, Beijing Friendship Hospital, Capital Medical University, Beijing, China.,Clinical Center for Pediatric Liver Transplantation, Capital Medical University, Beijing, China
| | - Li-Ying Sun
- Department of Critical Liver Diseases, Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China.,Liver Transplantation Center, National Clinical Research Center for Digestive Diseases, Beijing Friendship Hospital, Capital Medical University, Beijing, China.,Clinical Center for Pediatric Liver Transplantation, Capital Medical University, Beijing, China
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28
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Sun P, Xiao M, Chen H, Zhong Z, Jiang H, Feng X, Luo Z. A joint transcriptional regulatory network and protein activity inference analysis identifies clinically associated master regulators for biliary atresia. Front Pediatr 2022; 10:1050326. [PMID: 36440333 PMCID: PMC9691841 DOI: 10.3389/fped.2022.1050326] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/21/2022] [Accepted: 10/26/2022] [Indexed: 11/13/2022] Open
Abstract
Biliary atresia (BA) is a devastating cholangiopathy in neonate. Transcription factors (TFs), a type of master regulators in biological processes and diseases, have been implicated in pathogenesis of BA. However, a global view of TFs and how they link to clinical presentations remain explored. Here, we perform a joint transcriptional regulatory network and protein activity inference analysis in order to investigate transcription factor activity in BA. By integration of three independent human BA liver transcriptome datasets, we identify 22 common master regulators, with 14 activated- and 8 repressed TFs. Gene targets of activated TFs are enriched in biological processes of SMAD, NF-kappaB and TGF-beta, while those of repressed TFs are related to lipid metabolism. Mining the clinical association of TFs, we identify inflammation-, fibrosis- and survival associated TFs. In particular, ZNF14 is predictive of poor survival and advanced live fibrosis. Supporting this observation, ZNF14 is positively correlated with T helper cells, cholangiocytes and hepatic stellate cells. In sum, our analysis reveals key clinically associated master regulators for BA.
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Affiliation(s)
- Panpan Sun
- Department of Pediatric Surgery, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China.,Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Manhuan Xiao
- Department of Pediatric Surgery, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China.,Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Huadong Chen
- Department of Pediatric Surgery, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Zhihai Zhong
- Department of Pediatric Surgery, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Hong Jiang
- Department of Pediatric Surgery, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Xuyang Feng
- Department of Pediatric Surgery, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China.,Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Zhenhua Luo
- Department of Pediatric Surgery, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China.,Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
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Biliary Atresia: Clinical Phenotypes and Aetiological Heterogeneity. J Clin Med 2021; 10:jcm10235675. [PMID: 34884377 PMCID: PMC8658215 DOI: 10.3390/jcm10235675] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2021] [Revised: 11/22/2021] [Accepted: 11/30/2021] [Indexed: 12/11/2022] Open
Abstract
Biliary atresia (BA) is an obliterative condition of the biliary tract that presents with persistent jaundice and pale stools typically in the first few weeks of life. While this phenotypic signature may be broadly similar by the time of presentation, it is likely that this is only the final common pathway with a number of possible preceding causative factors and disparate pathogenic mechanisms-i.e., aetiological heterogeneity. Certainly, there are distinguishable variants which suggest a higher degree of aetiological homogeneity such as the syndromic variants of biliary atresia splenic malformation or cat-eye syndrome, which implicate an early developmental mechanism. In others, the presence of synchronous viral infection also make this plausible as an aetiological agent though it is likely that disease onset is from the perinatal period. In the majority of cases, currently termed isolated BA, there are still too few clues as to aetiology or indeed pathogenesis.
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Tran KT, Le VS, Dao LTM, Nguyen HK, Mai AK, Nguyen HT, Ngo MD, Tran QA, Nguyen LT. Novel findings from family-based exome sequencing for children with biliary atresia. Sci Rep 2021; 11:21815. [PMID: 34750413 PMCID: PMC8575792 DOI: 10.1038/s41598-021-01148-y] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Accepted: 10/21/2021] [Indexed: 12/13/2022] Open
Abstract
Biliary atresia (BA) is a progressive inflammation and fibrosis of the biliary tree characterized by the obstruction of bile flow, which results in liver failure, scarring and cirrhosis. This study aimed to explore the elusive aetiology of BA by conducting whole exome sequencing for 41 children with BA and their parents (35 trios, including 1 family with 2 BA-diagnosed children and 5 child-mother cases). We exclusively identified and validated a total of 28 variants (17 X-linked, 6 de novo and 5 homozygous) in 25 candidate genes from our BA cohort. These variants were among the 10% most deleterious and had a low minor allele frequency against the employed databases: Kinh Vietnamese (KHV), GnomAD and 1000 Genome Project. Interestingly, AMER1, INVS and OCRL variants were found in unrelated probands and were first reported in a BA cohort. Liver specimens and blood samples showed identical variants, suggesting that somatic variants were unlikely to occur during morphogenesis. Consistent with earlier attempts, this study implicated genetic heterogeneity and non-Mendelian inheritance of BA.
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Affiliation(s)
- Kien Trung Tran
- Vinmec Research Institute of Stem Cell and Gene Technology, 458 Minh Khai, Hai Ba Trung District, Hanoi, Vietnam.
| | - Vinh Sy Le
- Vinmec Research Institute of Stem Cell and Gene Technology, 458 Minh Khai, Hai Ba Trung District, Hanoi, Vietnam
- University of Engineering and Technology, Vietnam National University Hanoi, 144 Xuan Thuy, Cau Giay District, Hanoi, Vietnam
| | - Lan Thi Mai Dao
- Vinmec Research Institute of Stem Cell and Gene Technology, 458 Minh Khai, Hai Ba Trung District, Hanoi, Vietnam
| | - Huyen Khanh Nguyen
- Bioequivalence Center, National Institute of Drug Quality Control, 11/157 Bang B, Hoang Mai District, Hanoi, Vietnam
| | - Anh Kieu Mai
- Vinmec International Hospital, 458 Minh Khai, Hai Ba Trung District, Hanoi, Vietnam
| | - Ha Thi Nguyen
- Vinmec International Hospital, 458 Minh Khai, Hai Ba Trung District, Hanoi, Vietnam
| | - Minh Duy Ngo
- Vinmec International Hospital, 458 Minh Khai, Hai Ba Trung District, Hanoi, Vietnam
| | - Quynh Anh Tran
- Vietnam National Children's Hospital, 18/879 La Thanh, Dong Da District, Hanoi, Vietnam
| | - Liem Thanh Nguyen
- Vinmec Research Institute of Stem Cell and Gene Technology, 458 Minh Khai, Hai Ba Trung District, Hanoi, Vietnam
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31
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Zhou JL, Zhao YZ, Wang SS, Chen MX, Zhou S, Chen C. RNA Splicing: A Versatile Regulatory Mechanism in Pediatric Liver Diseases. Front Mol Biosci 2021; 8:725308. [PMID: 34651015 PMCID: PMC8505697 DOI: 10.3389/fmolb.2021.725308] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Accepted: 08/23/2021] [Indexed: 12/03/2022] Open
Abstract
With the development of high-throughput sequencing technology, the posttranscriptional mechanism of alternative splicing is becoming better understood. From decades of studies, alternative splicing has been shown to occur in multiple tissues, including the brain, heart, testis, skeletal muscle, and liver. This regulatory mechanism plays an important role in physiological functions in most liver diseases. Currently, due to the absence of symptoms, chronic pediatric liver diseases have a significant impact on public health. Furthermore, the progression of the disease is accelerated in children, leading to severe damage to their liver tissue if no precautions are taken. To this end, this review article summarizes the current knowledge of alternative splicing in pediatric liver diseases, paying special attention to liver damage in the child stage. The discussion of the regulatory role of splicing in liver diseases and its potential as a new therapeutic target is also included.
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Affiliation(s)
- Jian-Li Zhou
- Division of Gastroenterology, Shenzhen Children's Hospital, Shenzhen, China
| | - Yu-Zhen Zhao
- Division of Gastroenterology, Shenzhen Children's Hospital, Shenzhen, China
| | - Shan-Shan Wang
- School of Life Sciences and Biopharmaceutics, Guangdong Pharmaceutical University, Guangzhou, China
| | - Mo-Xian Chen
- Co-Innovation Center for Sustainable Forestry in Southern China, College of Biology and the Environment, Nanjing Forestry University, Nanjing, China
| | - Shaoming Zhou
- Division of Gastroenterology, Shenzhen Children's Hospital, Shenzhen, China
| | - Chen Chen
- Department of Infectious Disease, Nanjing Second Hospital, Nanjing University of Chinese Medicine, Nanjing, China
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Zhao X, Yongchun Z, Qian H, Sanhui G, Jie L, Hong Y, Yanfei Z, Guizhen W, Yunchao H, Guangbiao Z. Identification of a potential tumor suppressor gene, UBL3, in non-small cell lung cancer. Cancer Biol Med 2021; 17:76-87. [PMID: 32296577 PMCID: PMC7142850 DOI: 10.20892/j.issn.2095-3941.2019.0279] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2019] [Accepted: 10/24/2019] [Indexed: 12/24/2022] Open
Abstract
Objective: Oncogenes have been shown to be drivers of non-small cell lung cancer (NSCLC), yet the tumor suppressing genes involved in lung carcinogenesis remain to be systematically investigated. This study aimed to identify tumor suppressing ubiquitin pathway genes (UPGs) that were critical to lung tumorigenesis. Methods: The 696 UPGs were silenced by an siRNA screening in NSCLC cells; the potential tumor suppressing UPGs were analyzed, and their clinical significance was investigated. Results: We reported that silencing of 11 UPGs resulted in enhanced proliferation of NSCLC cells, and four UPGs (UBL3, TRIM22, UBE2G2, and MARCH1) were significantly downregulated in tumor samples compared to that in normal lung tissues and their expression levels were positively associated with overall survival (OS) of NSCLC patients. Among these genes, UBL3 was the most significant one. UBL3 expression was decreased in tumor samples compared to that in paired normal lung tissues in 59/86 (68.6%) NSCLCs, was correlated with TNM stage and sex of NSCLC patients, and was significantly higher in non-smoking patients than in smoking patients. Silencing UBL3 accelerated cell proliferation and ectopic expression of UBL3 suppressed NSCLC in vitro and in vivo. Conclusions: These results showed that UBL3 represented a tumor suppressor in NSCLC and may have potential for use in therapeutics and for the prediction of clinical outcome of patients.
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Affiliation(s)
- Xinchun Zhao
- School of Life Sciences, University of Science and Technology of China, Hefei 230026, China.,State Key Laboratory of Molecular Oncology, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China.,State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
| | - Zhou Yongchun
- Department of Thoracic Surgery, the Third Affiliated Hospital of Kunming Medical University, Kunming 650106, China
| | - Hu Qian
- State Key Laboratory of Molecular Oncology, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China.,School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Gao Sanhui
- State Key Laboratory of Molecular Oncology, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China.,State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
| | - Liu Jie
- State Key Laboratory of Molecular Oncology, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China.,State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
| | - Yu Hong
- State Key Laboratory of Molecular Oncology, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China.,School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Zhang Yanfei
- State Key Laboratory of Molecular Oncology, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China.,State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
| | - Wang Guizhen
- State Key Laboratory of Molecular Oncology, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China.,State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
| | - Huang Yunchao
- Department of Thoracic Surgery, the Third Affiliated Hospital of Kunming Medical University, Kunming 650106, China
| | - Zhou Guangbiao
- State Key Laboratory of Molecular Oncology, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China.,State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
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33
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Lam WY, Tang CSM, So MT, Yue H, Hsu JS, Chung PHY, Nicholls JM, Yeung F, Lee CWD, Ngo DN, Nguyen PAH, Mitchison HM, Jenkins D, O'Callaghan C, Garcia-Barceló MM, Lee SL, Sham PC, Lui VCH, Tam PKH. Identification of a wide spectrum of ciliary gene mutations in nonsyndromic biliary atresia patients implicates ciliary dysfunction as a novel disease mechanism. EBioMedicine 2021; 71:103530. [PMID: 34455394 PMCID: PMC8403738 DOI: 10.1016/j.ebiom.2021.103530] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2021] [Revised: 07/09/2021] [Accepted: 07/27/2021] [Indexed: 12/12/2022] Open
Abstract
Background Biliary atresia (BA) is the most common obstructive cholangiopathy in neonates, often progressing to end-stage cirrhosis. BA pathogenesis is believed to be multifactorial, but the genetic contribution, especially for nonsyndromic BA (common form: > 85%) remains poorly defined. Methods We conducted whole exome sequencing on 89 nonsyndromic BA trios to identify rare variants contributing to BA etiology. Functional evaluation using patients’ liver biopsies, human cell and zebrafish models were performed. Clinical impact on respiratory system was assessed with clinical evaluation, nasal nitric oxide (nNO), high speed video analysis and transmission electron microscopy. Findings We detected rare, deleterious de novo or biallelic variants in liver-expressed ciliary genes in 31.5% (28/89) of the BA patients. Burden test revealed 2.6-fold (odds ratio (OR) [95% confidence intervals (CI)]= 2.58 [1.15–6.07], adjusted p = 0.034) over-representation of rare, deleterious mutations in liver-expressed ciliary gene set in patients compared to controls. Functional analyses further demonstrated absence of cilia in the BA livers with KIF3B and TTC17 mutations, and knockdown of PCNT, KIF3B and TTC17 in human control fibroblasts and cholangiocytes resulted in reduced number of cilia. Additionally, CRISPR/Cas9-engineered zebrafish knockouts of KIF3B, PCNT and TTC17 displayed reduced biliary flow. Abnormally low level of nNO was detected in 80% (8/10) of BA patients carrying deleterious ciliary mutations, implicating the intrinsic ciliary defects. Interpretation Our findings support strong genetic susceptibility for nonsyndromic BA. Ciliary gene mutations leading to cholangiocyte cilia malformation and dysfunction could be a key biological mechanism in BA pathogenesis. Funding The study is supported by General Research Fund, HMRF Commissioned Paediatric Research at HKCH and Li Ka Shing Faculty of Medicine Enhanced New Staff Start-up Fund.
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Affiliation(s)
- Wai-Yee Lam
- Division of Paediatric Surgery, Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, LKS Faculty of Medicine Building, 21 Sassoon Road, Hong Kong SAR, China; Dr Li Dak-Sum Research Centre, The University of Hong Kong, Hong Kong SAR, China
| | - Clara Sze-Man Tang
- Division of Paediatric Surgery, Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, LKS Faculty of Medicine Building, 21 Sassoon Road, Hong Kong SAR, China; Dr Li Dak-Sum Research Centre, The University of Hong Kong, Hong Kong SAR, China
| | - Man-Ting So
- Division of Paediatric Surgery, Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, LKS Faculty of Medicine Building, 21 Sassoon Road, Hong Kong SAR, China
| | - Haibing Yue
- Division of Paediatric Surgery, Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, LKS Faculty of Medicine Building, 21 Sassoon Road, Hong Kong SAR, China
| | - Jacob Shujui Hsu
- Department of Psychiatry, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
| | - Patrick Ho-Yu Chung
- Division of Paediatric Surgery, Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, LKS Faculty of Medicine Building, 21 Sassoon Road, Hong Kong SAR, China
| | - John M Nicholls
- Department of Pathology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
| | - Fanny Yeung
- Division of Paediatric Surgery, Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, LKS Faculty of Medicine Building, 21 Sassoon Road, Hong Kong SAR, China
| | - Chun-Wai Davy Lee
- Department of Paediatrics and Adolescent Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
| | | | | | - Hannah M Mitchison
- Genetics and Genomic Medicine, UCL Great Ormond Street Institute of Child Health, University College London, London, United Kingdom
| | - Dagan Jenkins
- Genetics and Genomic Medicine, UCL Great Ormond Street Institute of Child Health, University College London, London, United Kingdom
| | - Christopher O'Callaghan
- Respiratory, Critical Care & Anaesthesia Section, UCL Great Ormond Street Institute of Child Health, University College London, London, United Kingdom
| | - Maria-Mercè Garcia-Barceló
- Division of Paediatric Surgery, Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, LKS Faculty of Medicine Building, 21 Sassoon Road, Hong Kong SAR, China
| | - So-Lun Lee
- Department of Paediatrics and Adolescent Medicine, Queen Mary Hospital, Hong Kong SAR, China
| | - Pak-Chung Sham
- Department of Psychiatry, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
| | - Vincent Chi-Hang Lui
- Division of Paediatric Surgery, Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, LKS Faculty of Medicine Building, 21 Sassoon Road, Hong Kong SAR, China; Dr Li Dak-Sum Research Centre, The University of Hong Kong, Hong Kong SAR, China.
| | - Paul Kwong-Hang Tam
- Division of Paediatric Surgery, Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, LKS Faculty of Medicine Building, 21 Sassoon Road, Hong Kong SAR, China; Dr Li Dak-Sum Research Centre, The University of Hong Kong, Hong Kong SAR, China.
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Ghaffari K, Pierce LX, Roufaeil M, Gibson I, Tae K, Sahoo S, Cantrell JR, Andersson O, Lau J, Sakaguchi TF. NCK-associated protein 1 like (nckap1l) minor splice variant regulates intrahepatic biliary network morphogenesis. PLoS Genet 2021; 17:e1009402. [PMID: 33739979 PMCID: PMC8032155 DOI: 10.1371/journal.pgen.1009402] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2020] [Revised: 04/08/2021] [Accepted: 02/09/2021] [Indexed: 11/18/2022] Open
Abstract
Impaired formation of the intrahepatic biliary network leads to cholestatic liver diseases, which are frequently associated with autoimmune disorders. Using a chemical mutagenesis strategy in zebrafish combined with computational network analysis, we screened for novel genes involved in intrahepatic biliary network formation. We positionally cloned a mutation in the nckap1l gene, which encodes a cytoplasmic adaptor protein for the WAVE regulatory complex. The mutation is located in the last exon after the stop codon of the primary splice isoform, only disrupting a previously unannotated minor splice isoform, which indicates that the minor splice isoform is responsible for the intrahepatic biliary network phenotype. CRISPR/Cas9-mediated nckap1l deletion, which disrupts both the primary and minor isoforms, showed the same defects. In the liver of nckap1l mutant larvae, WAVE regulatory complex component proteins are degraded specifically in biliary epithelial cells, which line the intrahepatic biliary network, thus disrupting the actin organization of these cells. We further show that nckap1l genetically interacts with the Cdk5 pathway in biliary epithelial cells. These data together indicate that although nckap1l was previously considered to be a hematopoietic cell lineage-specific protein, its minor splice isoform acts in biliary epithelial cells to regulate intrahepatic biliary network formation.
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Affiliation(s)
- Kimia Ghaffari
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, United States of America
| | - Lain X. Pierce
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, United States of America
| | - Maria Roufaeil
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, United States of America
| | - Isabel Gibson
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, United States of America
| | - Kevin Tae
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, United States of America
| | - Saswat Sahoo
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, United States of America
- Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, Ohio, United States of America
| | - James R. Cantrell
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, United States of America
| | - Olov Andersson
- Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden
| | - Jasmine Lau
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, United States of America
| | - Takuya F. Sakaguchi
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, United States of America
- Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, Ohio, United States of America
- * E-mail:
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35
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Cheung Y, Wu Z, Garcia-Barcelo MM, Tam PKH, Ma ACH, Lui VCH. Deletion of interleukin enhancer binding factor 2 (ILF2) resulted in defective biliary development and bile flow blockage. J Pediatr Surg 2021; 56:352-359. [PMID: 32709532 DOI: 10.1016/j.jpedsurg.2020.06.032] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2020] [Revised: 05/29/2020] [Accepted: 06/18/2020] [Indexed: 12/11/2022]
Abstract
PURPOSE Biliary atresia (BA) is a devastating obstructive bile duct disease of newborns. BA has the highest incidence in Asians (1/5000), and its pathogenesis is unclear. We identified BA-private rare copy number variants (CNVs; 22 duplications and 6 deletions). ILF2 gene locates in the chromosome region (Chr1:153410347-153,634,058) which was deleted in a nonsyndromic BA patient. However, it is still not known whether ILF2 plays a role in hepatobiliary development and its deletion impacts on the bile duct development. METHODS To investigate if ILF2 is required for biliary development, we knock-out the zebrafish homologs of ILF2 by CRISPR/Cas9 approach, and discover that deletion of ILF2 causes a defective biliary development and a lack of bile flow from the liver to the gall bladder in zebrafish, which is a resemblance of phenotypes of BA. RESULTS Our data indicate that ILF2 gene is required for biliary development; deletion of ILF2 impairs bile duct development and could contribute to BA pathogenesis. This will be the first study to functionally evaluate the genes interfered by BA-private CNVs in hepatobiliary development and in BA pathogenesis. CONCLUSIONS Such functional study may reveal the potential value of these BA-private CNVs in the disease pathogenesis for BA. LEVEL OF EVIDENCE N/A (animal and laboratory study).
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Affiliation(s)
- Yim Cheung
- Department of Surgery, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, 21 Sassoon Road, Pokfulam, Hong Kong
| | - Zhongluan Wu
- Department of Surgery, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, 21 Sassoon Road, Pokfulam, Hong Kong
| | - Maria-Mercedes Garcia-Barcelo
- Department of Surgery, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, 21 Sassoon Road, Pokfulam, Hong Kong; Dr. Li Dak-Sum Research Centre, The University of Hong Kong-Karolinska Institutet Collaboration in Regenerative Medicine, 5/F The Hong Kong Jockey Club Building for Interdisciplinary Research, The University of Hong Kong 5 Sassoon Road, Pokfulam, Hong Kong
| | - Paul Kwong Hang Tam
- Department of Surgery, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, 21 Sassoon Road, Pokfulam, Hong Kong; Dr. Li Dak-Sum Research Centre, The University of Hong Kong-Karolinska Institutet Collaboration in Regenerative Medicine, 5/F The Hong Kong Jockey Club Building for Interdisciplinary Research, The University of Hong Kong 5 Sassoon Road, Pokfulam, Hong Kong; Department of Surgery, The University of Hong Kong-Shenzhen Hospital, 1, Haiyuan 1st Road, Futian District, Shenzhen, Guangdong, P.R.C
| | - Alvin Chung Hang Ma
- Department of Health Technology and Informatics, The Hong Kong Polytechnic University, Hong Kong, 9/F, Lee Shau Kee Building, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong
| | - Vincent Chi Hang Lui
- Department of Surgery, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, 21 Sassoon Road, Pokfulam, Hong Kong; Dr. Li Dak-Sum Research Centre, The University of Hong Kong-Karolinska Institutet Collaboration in Regenerative Medicine, 5/F The Hong Kong Jockey Club Building for Interdisciplinary Research, The University of Hong Kong 5 Sassoon Road, Pokfulam, Hong Kong; Department of Surgery, The University of Hong Kong-Shenzhen Hospital, 1, Haiyuan 1st Road, Futian District, Shenzhen, Guangdong, P.R.C..
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36
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Beta-amyloid deposition around hepatic bile ducts is a novel pathobiological and diagnostic feature of biliary atresia. J Hepatol 2020; 73:1391-1403. [PMID: 32553668 DOI: 10.1016/j.jhep.2020.06.012] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2019] [Revised: 05/28/2020] [Accepted: 06/04/2020] [Indexed: 12/14/2022]
Abstract
BACKGROUND AND AIMS Biliary atresia (BA) is a poorly understood and devastating obstructive bile duct disease of newborns. It is often diagnosed late, is incurable and frequently requires liver transplantation. In this study, we aimed to investigate the underlying pathogenesis and molecular signatures associated with BA. METHODS We combined organoid and transcriptomic analysis to gain new insights into BA pathobiology using patient samples and a mouse model of BA. RESULTS Liver organoids derived from patients with BA and a rhesus rotavirus A-infected mouse model of BA, exhibited aberrant morphology and disturbed apical-basal organization. Transcriptomic analysis of BA organoids revealed a shift from cholangiocyte to hepatocyte transcriptional signatures and altered beta-amyloid-related gene expression. Beta-amyloid accumulation was observed around the bile ducts in BA livers and exposure to beta-amyloid induced the aberrant morphology in control organoids. CONCLUSION The novel observation that beta-amyloid accumulates around bile ducts in the livers of patients with BA has important pathobiological implications, as well as diagnostic potential. LAY SUMMARY Biliary atresia is a poorly understood and devastating obstructive bile duct disease of newborns. It is often diagnosed late, is incurable and frequently requires liver transplantation. Using human and mouse 'liver mini-organs in the dish', we unexpectedly identified beta-amyloid deposition - the main pathological feature of Alzheimer's disease and cerebral amyloid angiopathy - around bile ducts in livers from patients with biliary atresia. This finding reveals a novel pathogenic mechanism that could have important diagnostic and therapeutic implications.
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37
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Isaeva MK, Belova VA, Korostin DO, Degtyareva AV. Genetic aspects of biliary atresia etiology. BULLETIN OF RUSSIAN STATE MEDICAL UNIVERSITY 2020. [DOI: 10.24075/brsmu.2020.069] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Biliary atresia (BA) is a cholestatic disorder of infancy that is fatal if untreated. Despite years of study the etiology of BA remains unknown. Three etiopathogenic mechanisms may be involved, such as immune dysregulation, environmental factors and genetic susceptibility. Genetic predisposition is being actively studied. Candidate genes associated with BA in certain populations, genes affecting the cholangiocyte cilia function, as well as genes involved in stress responses have been identified. However, the long-term follow-up of twins with BA suggests that genotype is not of paramount importance for the disease development. Both epigenetic patterns and postzygotic somatic mutations may contribute to etiology of the disease. Recently, some evidence is being accumulated on the possible genetic predisposition to certain outcome of Kasai portoenterostomy performed in patients with BA. However, the presence of a number of factors contributing to the development of the disease makes it difficult to identify the genetic markers.
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Affiliation(s)
- MKh Isaeva
- Academician V. I. Kulakov Research Center for Obstetrics, Gynecology and Perinatology, Moscow, Russia
| | - VA Belova
- Pirogov Russian National Research Medical University, Moscow, Russia
| | - DO Korostin
- Pirogov Russian National Research Medical University, Moscow, Russia
| | - AV Degtyareva
- Academician V. I. Kulakov Research Center for Obstetrics, Gynecology and Perinatology, Moscow, Russia; I. M. Sechenov First Moscow State Medical University, Moscow, Russia
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The synthetic toxin biliatresone causes biliary atresia in mice. J Transl Med 2020; 100:1425-1435. [PMID: 32681026 DOI: 10.1038/s41374-020-0467-7] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2020] [Revised: 06/24/2020] [Accepted: 06/24/2020] [Indexed: 11/08/2022] Open
Abstract
Exposure to environmental toxins may be responsible for biliary atresia. The focus of this study was to investigate the effect of biliatresone on the development of the hepatobiliary system in mice. We successfully synthesized biliatresone with a purity of 98% and confirmed its biliary toxicity. Exposure to high doses of biliatresone caused abortion or death in pregnant mice. Neonatal mice injected with biliatresone developed clinical signs of biliary obstruction, and dysplasia or the absence of extrahepatic biliary tract lumen, which confirmed the occurrence of biliary atresia. In the portal tract of biliary atresia mice, signs of infiltration of inflammatory cells and liver fibrosis were observed. The signature of extrahepatic biliary gene expression in these mice mainly involved the cell adhesion process, and hepatic RNA-seq was highly linked to transcriptional evidence of oxidative stress. When compared with the control group, hepatic glutathione levels were markedly reduced after biliatresone injection. Taken together, these data confirm that biliatresone causes severe developmental abnormalities of the hepatobiliary system in mice. Furthermore, decreased levels of glutathione may play a mechanistic role in the pathogenesis of liver fibrosis in biliatresone-induced experimental biliary atresia.
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Yan C, Koda S, Wu J, Zhang BB, Yu Q, Netea MG, Tang RX, Zheng KY. Roles of Trained Immunity in the Pathogenesis of Cholangiopathies: A Therapeutic Target. Hepatology 2020; 72:1838-1850. [PMID: 32463941 DOI: 10.1002/hep.31395] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/05/2020] [Revised: 04/21/2020] [Accepted: 04/28/2020] [Indexed: 12/11/2022]
Affiliation(s)
- Chao Yan
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Laboratory of Infection and Immunity, Xuzhou Medical University, Xuzhou, People's Republic of China.,National Experimental Demonstration Center for Basic Medicine Education, Department of Clinical Medicine, Xuzhou Medical University, Xuzhou, People's Republic of China
| | - Stephane Koda
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Laboratory of Infection and Immunity, Xuzhou Medical University, Xuzhou, People's Republic of China
| | - Jing Wu
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Laboratory of Infection and Immunity, Xuzhou Medical University, Xuzhou, People's Republic of China
| | - Bei-Bei Zhang
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Laboratory of Infection and Immunity, Xuzhou Medical University, Xuzhou, People's Republic of China.,National Experimental Demonstration Center for Basic Medicine Education, Department of Clinical Medicine, Xuzhou Medical University, Xuzhou, People's Republic of China
| | - Qian Yu
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Laboratory of Infection and Immunity, Xuzhou Medical University, Xuzhou, People's Republic of China.,National Experimental Demonstration Center for Basic Medicine Education, Department of Clinical Medicine, Xuzhou Medical University, Xuzhou, People's Republic of China
| | - Mihai G Netea
- Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, the Netherlands.,Immunology and Metabolism, Life & Medical Sciences Institute, University of Bonn, Bonn, Germany
| | - Ren-Xian Tang
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Laboratory of Infection and Immunity, Xuzhou Medical University, Xuzhou, People's Republic of China.,National Experimental Demonstration Center for Basic Medicine Education, Department of Clinical Medicine, Xuzhou Medical University, Xuzhou, People's Republic of China
| | - Kui-Yang Zheng
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Laboratory of Infection and Immunity, Xuzhou Medical University, Xuzhou, People's Republic of China.,National Experimental Demonstration Center for Basic Medicine Education, Department of Clinical Medicine, Xuzhou Medical University, Xuzhou, People's Republic of China
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Cholangitis in Patients With Biliary Atresia Receiving Hepatoportoenterostomy: A National Database Study. J Pediatr Gastroenterol Nutr 2020; 71:452-458. [PMID: 32639448 DOI: 10.1097/mpg.0000000000002836] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
INTRODUCTION Biliary atresia (BA) is a progressive form of liver disease in the neonatal period usually requiring hepatoportoenterostomy (HPE). Cholangitis is a common sequelae of HPE but data about which patients are at risk for this complication are limited. OBJECTIVE The objective of the study was to determine risk factors associated with cholangitis in a large retrospective cohort after HPE. METHODS The Pediatric Health Information System (PHIS) was queried for BA (ICD-9 975.61) and HPE (ICD-9-CM 51.37) admissions from 2004 to 2013. We performed univariate analysis and linear regression with dependent variables of ≥ 2 or ≥ 5 episodes of cholangitis, and independent variables of age at time of HPE, race, ethnicity, gender, insurance, ursodeoxycholic acid (UDCA) use, steroid use, presence of esophageal varices (EV), and portal hypertension (PH). RESULTS We identified 1112 subjects with a median age at HPE of 63 days and median number of cholangitis episodes of 2 within 2 years. On multiple regression analysis, black race (odds ratio (OR) 1.51, P = 0.044) and presence of PH (OR 2.24, P < 0.001) were associated with increased risk of ≥ 2 episodes of cholangitis, whereas HPE at >90 days was associated with less risk (OR 0.46, P = 0.001). Among those with ≥5 episodes, Asian race (OR 2.66, P = 0.038), public insurance (OR 1.72, P = 0.043), EV (OR 1.81, P = 0.017), and PH (OR 2.88, P < 0.001) were associated with higher risk. CONCLUSIONS Complications, such as cholangitis remain a common problem for patients, after HPE, with median of 2 episodes within 2 years. Higher rates of cholangitis are associated with portal hypertension whereas lower rate is associated with age at HPE of >90 days. Asians, patients with public insurance, and those with portal hypertension are more likely to have recurrent cholangitis.
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Zhao X, Lorent K, Escobar-Zarate D, Rajagopalan R, Loomes KM, Gillespie K, Mesaros C, Estrada MA, Blair I, Winkler JD, Spinner NB, Devoto M, Pack M. Impaired Redox and Protein Homeostasis as Risk Factors and Therapeutic Targets in Toxin-Induced Biliary Atresia. Gastroenterology 2020; 159:1068-1084.e2. [PMID: 32505743 PMCID: PMC7856536 DOI: 10.1053/j.gastro.2020.05.080] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2019] [Revised: 05/08/2020] [Accepted: 05/27/2020] [Indexed: 12/23/2022]
Abstract
BACKGROUND & AIMS Extrahepatic biliary atresia (BA) is a pediatric liver disease with no approved medical therapy. Recent studies using human samples and experimental modeling suggest that glutathione redox metabolism and heterogeneity play a role in disease pathogenesis. We sought to dissect the mechanistic basis of liver redox variation and explore how other stress responses affect cholangiocyte injury in BA. METHODS We performed quantitative in situ hepatic glutathione redox mapping in zebrafish larvae carrying targeted mutations in glutathione metabolism genes and correlated these findings with sensitivity to the plant-derived BA-linked toxin biliatresone. We also determined whether genetic disruption of HSP90 protein quality control pathway genes implicated in human BA altered biliatresone toxicity in zebrafish and human cholangiocytes. An in vivo screening of a known drug library was performed to identify novel modifiers of cholangiocyte injury in the zebrafish experimental BA model, with subsequent validation. RESULTS Glutathione metabolism gene mutations caused regionally distinct changes in the redox potential of cholangiocytes that differentially sensitized them to biliatresone. Disruption of human BA-implicated HSP90 pathway genes sensitized zebrafish and human cholangiocytes to biliatresone-induced injury independent of glutathione. Phosphodiesterase-5 inhibitors and other cyclic guanosine monophosphate signaling activators worked synergistically with the glutathione precursor N-acetylcysteine in preventing biliatresone-induced injury in zebrafish and human cholangiocytes. Phosphodiesterase-5 inhibitors enhanced proteasomal degradation and required intact HSP90 chaperone. CONCLUSION Regional variation in glutathione metabolism underlies sensitivity to the biliary toxin biliatresone and may account for the reported association between BA transplant-free survival and glutathione metabolism gene expression. Human BA can be causatively linked to genetic modulation of protein quality control. Combined treatment with N-acetylcysteine and cyclic guanosine monophosphate signaling enhancers warrants further investigation as therapy for BA.
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Affiliation(s)
- Xiao Zhao
- Division of Gastroenterology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Kristin Lorent
- Division of Gastroenterology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Diana Escobar-Zarate
- Division of Gastroenterology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Ramakrishnan Rajagopalan
- Division of Genomic Diagnostics, Department of Pathology, The Children’s Hospital of Philadelphia and University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
| | - Kathleen M. Loomes
- Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, The Children’s Hospital of Philadelphia and University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
| | - Kevin Gillespie
- Department of System Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Clementina Mesaros
- Department of System Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | | | - Ian Blair
- Department of System Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Jeffrey D. Winkler
- Department of Chemistry, University of Pennsylvania, Philadelphia, PA, USA
| | - Nancy B. Spinner
- Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, The Children’s Hospital of Philadelphia and University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
| | - Marcella Devoto
- Division of Human Genetics, Children’s Hospital of Philadelphia, Philadelphia, PA, USA.,Departments of Pediatrics and of Biostatistics, Epidemiology and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.,Department of Translational and Precision Medicine, University La Sapienza, Rome, Italy
| | - Michael Pack
- Division of Gastroenterology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
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Abstract
Biliary atresia (BA) is a common cause of surgical jaundice during the neonatal period. It is currently considered as a spectrum of diseases with a common final pathology characterized by obliteration of the extrahepatic biliary tract and the absence of normally branching intrahepatic ducts. Though it is a global disease that can be found in all ethnicities there are some clear differences between BA arising in the East and the West. This is likely to be related to different genetic, environmental and cultural factors. BA is more frequently found in Far Eastern infants (both Chinese and Japanese) though the syndromic associations are much less common. Many Eastern countries have national screening programmes not seen in the West possibly due to debate over its cost effectiveness in countries where incidence is low. Kasai portoenterostomy (KPE) is considered as the primary treatment of BA but its outcome still remains unsatisfactory across the region. Given the complexity of BA, it is unlikely that strategic advances could be made by the sole effort of individual countries and we believe that collaboration between the East and West is the way forward.
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Association of common variation in ADD3 and GPC1 with biliary atresia susceptibility. Aging (Albany NY) 2020; 12:7163-7182. [PMID: 32315284 PMCID: PMC7202506 DOI: 10.18632/aging.103067] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2019] [Accepted: 03/29/2020] [Indexed: 02/06/2023]
Abstract
Biliary atresia (BA) is an idiopathic neonatal cholestatic disease. Recent genome-wide association study (GWAS) revealed that common variation of ADD3, GPC1, ARF6, and EFEMP1 gene was associated with BA susceptibility. We aimed to evaluate the association of these genes with BA in Chinese population. Twenty single nucleotide polymorphisms (SNPs) in these four genes were genotyped in 340 BA patients and 1,665 controls. Three SNPs in ADD3 were significantly associated with BA, and rs17095355 was the top SNP (PAllele = 3.23×10-6). Meta-analysis of published data and current data indicated that rs17095355 was associated with BA susceptibility in Asians and Caucasians. Three associated SNPs were expression quantitative trait loci (eQTL) for ADD3. Two GPC1 SNPs in high linkage disequilibrium (LD) showed nominal association with BA susceptibility (PAllele = 0.03 for rs6707262 and PAllele = 0.04 for rs6750380), and were eQTL of GPC1. Haplotype harboring these two SNPs almost reached the study-wide significance (P = 0.0035). No association for ARF6 and EFEMP1 was found with BA risk in the current population. Our study validated associations of ADD3 and GPC1 SNPs with BA risk in Chinese population and provided evidence of epistatic contributions of genetic factors to BA susceptibility.
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Vij M, Rela M. Biliary atresia: pathology, etiology and pathogenesis. Future Sci OA 2020; 6:FSO466. [PMID: 32518681 PMCID: PMC7273417 DOI: 10.2144/fsoa-2019-0153] [Citation(s) in RCA: 47] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2019] [Accepted: 01/30/2020] [Indexed: 02/06/2023] Open
Abstract
Biliary atresia is a progressive fibrosing obstructive cholangiopathy of the intrahepatic and extrahepatic biliary system, resulting in obstruction of bile flow and neonatal jaundice. Histopathological findings in liver biopsies include the expansion of the portal tracts, with edematous fibroplasia and bile ductular proliferation, with bile plugs in duct lumen. Lobular morphological features may include variable multinucleate giant cells, bilirubinostasis and hemopoiesis. The etiopathogenesis of biliary atresia is multifactorial and multiple pathomechanisms have been proposed. Experimental and clinical studies have suggested that viral infection initiates biliary epithelium destruction and release of antigens that trigger a Th1 immune response, which leads to further injury of the bile duct, resulting in inflammation and obstructive scarring of the biliary tree. It has also been postulated that biliary atresia is caused by a defect in the normal remodelling process. Genetic predisposition has also been proposed as a factor for the development of biliary atresia.
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Affiliation(s)
- Mukul Vij
- Senior Consultant Histopathologist, Department of Pathology, Dr Rela Institute & Medical Centre, Chennai, Tamil Nadu, India, 600044
| | - Mohamed Rela
- Institute of Liver Disease & Transplantation, Chairmen, Dr Rela Institute & Medical Centre, Chennai, Tamil Nadu, India, 600044
- Liver Transplant Unit, Kings College Hospital, London SE5 9RS, UK
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Rajagopalan R, Tsai EA, Grochowski CM, Kelly SM, Loomes KM, Spinner NB, Devoto M. Exome Sequencing in Individuals with Isolated Biliary Atresia. Sci Rep 2020; 10:2709. [PMID: 32066793 PMCID: PMC7026070 DOI: 10.1038/s41598-020-59379-4] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2019] [Accepted: 01/22/2020] [Indexed: 12/13/2022] Open
Abstract
Biliary atresia (BA) is a severe pediatric liver disease resulting in necroinflammatory obliteration of the extrahepatic biliary tree. BA presents within the first few months of life as either an isolated finding or with additional syndromic features. The etiology of isolated BA is unknown, with evidence for infectious, environmental, and genetic risk factors described. However, to date, there are no definitive causal genes identified for isolated BA in humans, and the question of whether single gene defects play a major role remains open. We performed exome-sequencing in 101 North American patients of European descent with isolated BA (including 30 parent-child trios) and considered several experimental designs to identify potentially deleterious protein-altering variants that may be involved in the disease. In a case-only analysis, we did not identify genes with variants shared among more than two probands, and burden tests of rare variants using a case-case control design did not yield significant results. In the trio analysis of 30 simplex families (patient and parent trios), we identified 66 de novo variants in 66 genes including potentially deleterious variants in STIP1 and REV1. STIP1 is a co-chaperone for the heat-shock protein, HSP90, and has been shown to have diverse functions in yeast, flies and mammals, including stress-responses. REV1 is known to be a key player in DNA repair pathway and to interact with HSP90. In conclusion, our results do not support the hypothesis that a simple genetic model is responsible for the majority of cases of isolated BA. Our finding of de novo variants in genes linked to evolutionarily conserved stress responses (STIP1 and REV1) suggests that exploration of how genetic susceptibility and environmental exposure may interact to cause BA is warranted.
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Affiliation(s)
- Ramakrishnan Rajagopalan
- Division of Genomic Diagnostics, Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, PA, USA
| | - Ellen A Tsai
- Division of Genomic Diagnostics, Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, PA, USA
- Genomics and Computational Biology Graduate Group, The University of Pennsylvania, Philadelphia, PA, USA
- Genetic Epidemiology Group, Department of Translational Biology, Biogen, Cambridge, MA, USA
| | - Christopher M Grochowski
- Division of Genomic Diagnostics, Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, PA, USA
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA
| | - Susan M Kelly
- Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Ann and Robert H. Lurie Children's Hospital of Chicago, Chicago, IL, USA
| | - Kathleen M Loomes
- Division of Gastroenterology, Hepatology and Nutrition, Children's Hospital of Philadelphia, Philadelphia, PA, USA
- Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Nancy B Spinner
- Division of Genomic Diagnostics, Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, PA, USA
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Marcella Devoto
- Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
- Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
- Department of Translational and Precision Medicine, University La Sapienza, Rome, Italy.
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Chung‐Davidson Y, Ren J, Yeh C, Bussy U, Huerta B, Davidson PJ, Whyard S, Li W. TGF-β Signaling Plays a Pivotal Role During Developmental Biliary Atresia in Sea Lamprey ( Petromyzon marinus). Hepatol Commun 2020; 4:219-234. [PMID: 32025607 PMCID: PMC6996360 DOI: 10.1002/hep4.1461] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/19/2019] [Accepted: 10/25/2019] [Indexed: 12/22/2022] Open
Abstract
Biliary atresia (BA) is a rare neonatal disease with unknown causes. Approximately 10% of BA cases develop in utero with other congenital defects that span a large spectrum of disease variations, including degeneration of the gall bladder and bile duct as well as malformation of the liver, intestines, and kidneys. Similar developmental alterations are manifested in a unique animal model, the sea lamprey (Petromyzon marinus), in which BA occurs naturally during metamorphosis. With the likelihood of conserved developmental mechanisms underlying organogenesis and degeneration, lamprey developmental BA may be a useful model to infer mechanisms underlying human embryonic BA. We reasoned that hepatobiliary transcriptomes regulate the transition between landmark stages of BA. Therefore, we examined sea lamprey hepatobiliary transcriptomes at four stages (M0, metamorphic stage 0 or larval stage, no BA; M2, metamorphic stage 2, onset of BA; M5, metamorphic stage 5, BA, and heightened hepatocyte proliferation and reorganization; and JV, juvenile, completion of BA) using messenger RNA sequencing and Kyoto Encyclopedia of Genes and Genomes pathway analyses. We found gene-expression patterns associated with the transition between these stages. In particular, transforming growth factor β (TGF-β), hedgehog, phosphatidylinositol-4,5-bisphosphate 3-kinase-Akt, Wnt, and mitogen-activated protein kinase pathways were involved during biliary degeneration. Furthermore, disrupting the TGF-β signaling pathway with antagonist or small interfering RNA treatments at the onset of BA delayed gall bladder and bile duct degeneration. Conclusion: Distinctive gene-expression patterns are associated with the degeneration of the biliary system during developmental BA. In addition, disrupting TGF-β signaling pathway at the onset of BA delayed biliary degeneration.
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Affiliation(s)
| | - Jianfeng Ren
- Key Laboratory of Exploration and Utilization of Aquatic Genetic ResourcesCollege of Fisheries and Life SciencesShanghai Ocean UniversityShanghaiChina
| | - Chu‐Yin Yeh
- College of Osteopathic MedicineMichigan State UniversityEast LansingMI
| | - Ugo Bussy
- Department of Fisheries and WildlifeMichigan State UniversityEast LansingMI
| | - Belinda Huerta
- Department of Fisheries and WildlifeMichigan State UniversityEast LansingMI
| | | | - Steven Whyard
- Department of Biological SciencesUniversity of ManitobaWinnipegMBCanada
| | - Weiming Li
- Department of Fisheries and WildlifeMichigan State UniversityEast LansingMI
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Lupo PJ, Mitchell LE, Jenkins MM. Genome-wide association studies of structural birth defects: A review and commentary. Birth Defects Res 2019; 111:1329-1342. [PMID: 31654503 DOI: 10.1002/bdr2.1606] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2019] [Revised: 09/21/2019] [Accepted: 10/02/2019] [Indexed: 12/14/2022]
Abstract
BACKGROUND While there is strong evidence that genetic risk factors play an important role in the etiologies of structural birth defects, compared to other diseases, there have been relatively few genome-wide association studies (GWAS) of these conditions. We reviewed the current landscape of GWAS conducted for birth defects, noting novel insights, and future directions. METHODS This article reviews the literature with regard to GWAS of structural birth defects. Key defects included in this review include oral clefts, congenital heart defects (CHDs), biliary atresia, pyloric stenosis, hypospadias, craniosynostosis, and clubfoot. Additionally, other issues related to GWAS are considered, including the assessment of polygenic risk scores and issues related to genetic ancestry, as well as utilizing genome-wide single nucleotide polymorphism array data to evaluate gene-environment interactions and Mendelian randomization. RESULTS For some birth defects, including oral clefts and CHDs, several novel susceptibility loci have been identified and replicated through GWAS, including 8q24 for oral clefts, DGKK for hypospadias, and 4p16 for CHDs. Relatively common birth defects for which there are currently no published GWAS include neural tube defects, anotia/microtia, anophthalmia/microphthalmia, gastroschisis, and omphalocele. CONCLUSIONS Overall, GWAS have been successful in identifying several novel susceptibility genes and genomic regions for structural birth defects. These findings have provided new insights into the etiologies of these phenotypes. However, GWAS have been underutilized for understanding the genetic etiologies of several birth defects.
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Affiliation(s)
- Philip J Lupo
- Department of Pediatrics, Section of Hematology-Oncology, Baylor College of Medicine, Houston, Texas
| | - Laura E Mitchell
- Department of Epidemiology, Human Genetics and Environmental Sciences, UTHealth School of Public Health, Houston, Texas
| | - Mary M Jenkins
- National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta, Georgia
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Abstract
PURPOSE OF REVIEW Biliary atresia is a poorly understood deadly disease. Genetic predisposition factors are suspected albeit not firmly established. This review summarizes recent evidence of genetic alterations in biliary atresia. RECENT FINDINGS Whole-genome association studies in biliary atresia patients identified four distinct predisposition loci with four different genes potentially involved in the disease occurrence. Variations in these genes were searched for, but none were found in patients with biliary atresia suggesting complex mechanisms. SUMMARY Despite decades since its description and decades of intensive researches, cause of biliary atresia disease remains enigmatic. The inheritance of biliary atresia is not Mendelian. Genetic predisposition factor is one of the explored fields to explain biliary atresia pathogenicity. Biliary atresia has been associated with several inborn syndromes, chromosome anomalies, and gene polymorphisms in specific populations. Four predisposition loci encompassing genes relevant to the disease have been identified, but no pathogenic variations were found in biliary atresia patients. Few reported cases of isolated biliary atresia manifestation in the context of known genetic diseases suggest coincidental findings. Alternatives to classic genetic alterations are proposed to explain genetic predisposition in biliary atresia including noncoding and epigenetic factors. Biliary atresia is most likely related to complex traits making its genetic exploration challenging.
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An improved and easy protocol for primary epithelial cell culture from atretic tissue in biliary atresia. Tissue Cell 2019; 56:83-89. [PMID: 30736909 DOI: 10.1016/j.tice.2019.01.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2018] [Revised: 01/03/2019] [Accepted: 01/04/2019] [Indexed: 02/07/2023]
Abstract
Biliary atresia (BA) is a lethal disease of infancy with obscure etiology. Insight into the pathogenesis of this disorder is limited by lack of availability of adequate epithelial tissue. Primary culture of human biliary epithelium may help to provide material for diagnostic and research purposes. However, culture of these cells from atretic tissue is a challenging task. We aimed to develop a reliable and easier protocol for culture of human biliary epithelial cells from excised atretic extrahepatic bile duct. An explant culture was performed using tissue obtained from 30 children with diseases of biliary tract. The culture showed florid cell growth in less than 3 weeks. Epithelial nature and biliary origin of cultured cells was confirmed using pancytokeratin and cytokeratin -7 antibodies. The protocol showed 100% success rate as cells could be cultured in all 30 patients. Moreover, the cells remained viable for a duration of over 3 months in most of the cases. This easier culture technique is likely to have an impact on the study of biliary cell pathophysiology, particularly in BA.
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50
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Abstract
Biliary atresia (BA) is the most common cause of pediatric end-stage liver disease and the etiology is poorly understood. There is no effective therapy for BA partly due to lack of human BA models. Towards developing in vitro human models of BA, disease-specific induced pluripotent stem cells (iPSCs) from 6 BA patients were generated using non-integrating episomal plasmids. In addition, to determine the functional significance of BA-susceptibility genes identified by genome-wide association studies (GWAS) in biliary development, a genome-editing approach was used to create iPSCs with defined mutations in these GWAS BA loci. Using the Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/Cas9 system, isogenic iPSCs deficient in BA-associated genes (GPC1 and ADD3) were created from healthy iPSCs. Both the BA patient-iPSCs and the knock out (KO) iPSCs were studied for their in vitro biliary differentiation potential. These BA-specific iPSCs demonstrated significantly decreased formation of ductal structures, decreased expression of biliary markers including CK7, EpCAM, SOX9, CK19, AE2, and CFTR and increased fibrosis markers such as alpha smooth muscle actin, Loxl2, and Collagen1 compared to controls. Both the patient- and the KO-iPSCs also showed increased yes-associated protein (YAP, a marker of bile duct proliferation/fibrosis). Collagen and YAP were reduced by treatment with the anti-fibrogenic drug pentoxifylline. In summary, these BA-specific human iPSCs showed deficiency in biliary differentiation along with increased fibrosis, the 2 key disease features of BA. These iPSCs can provide new human BA models for understanding the molecular basis of abnormal biliary development and opportunities to identify drugs that have therapeutic effects on BA.
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