Epistatic Association of CD14 and NOTCH2 Genetic Polymorphisms with Biliary Atresia in a Southern Chinese Population

Lin, Zefeng; Xie, Xiaoli; Lin, Huiting; Fu, Ming; Su, Liang; Tong, Yanlu; Chen, Hongjiao; Wang, Hezhen; Zhao, Jianhao; Xia, Huimin; Zhang, Yan; Zhang, Ruizhong

doi:10.1016/j.omtn.2018.10.006

“…According to previous reports, the miR-100 gene take part in the notch pathway and activates HES1 [ 30 ], indicating that it is an important regulatory factor in developmental disabilities [ 31 ] and the cellular growth cycle [ 32 , 33 ]. It is worth mentioning that the notch pathway was shown to regulate BA pathogenesis in our previous study [ 34 ]. In addition, the miR-100 gene is also involved in the inflammatory response.…”

Section: Discussionmentioning

confidence: 99%

MiR-100 rs1834306 A>G Increases Biliary Atresia Risk in Southern Han Chinese Children

Chang

¹

,

Liang

²

,

Chai

³

et al. 2023

BioMed Research International

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Background. Biliary atresia (BA) is a type of severe cholestatic childhood disease that may have a genetic component. miR-100 plays a key role in regulating cell apoptosis, proliferation, and inflammatory reactions. A single-nucleotide polymorphism in miR-100 has been proven to modulate susceptibility to various diseases. Methods. We conducted a case-control retrospective study to explore the correlation between miR-100 gene polymorphism (rs1834306 A>G) and biliary atresia susceptibility in 484 Chinese patients and 1445 matched control subjects. Results. Our results showed that rs1834306 A>G was correlated with a significantly increased risk for BA (GG vs. AA: adjusted odds ratio OR = 1.44 , 95 % confidence interval CI = 1.02 – 2.03 , p = 0.041 ; and GG vs. AA/AG: adjusted OR = 1.39 , 95 % CI = 1.02 – 1.89 , p = 0.036 ). Conclusions. Our results showed that the rs1834306 A>G polymorphism is associated with an increased risk for BA and contributes to BA susceptibility.

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“…58 Especially in ethnicities with apparently higher susceptibility for BA, like New Zealand Maori and Southern Chinese, genetic footprints were researched and have shown associated genetic polymorphisms. [59][60][61] Tian et al recently presented another important step to an in vitro human BA model, based on disease-specific induced pluripotent stem cells (iPSCs) and showing that BA-specific iPSCs result in defective biliary differentiation. 62 In the future, this result could potentially help to recapitulate key disease features from a patient's iPSCs.…”

Section: Discussionmentioning

confidence: 99%

Translational Research in Biliary Atresia: News from Mice and Men

Madadi-Sanjani

¹

,

Petersen

²

2019

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Biliary atresia (BA) is a fibro-obliterative cholangiopathy of unknown etiology. While Kasai portoenterostomy achieves temporary biliary drainage in some cases, BA remains the most common indication for liver transplantation during childhood. During the last few decades, observations on BA, like cholestatic diseases in animals and the introduction of different animal models for BA, have not achieved the anticipated results, and we are still not able to translate the basic research to the patient's bedside. This article presents a review of the literature on available BA animal models and gives a glimpse of future developments.

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“…These include Adducin 3 (ADD3) [42][43][44][45][46] , ADP-ribosylation factor 6 (ARF6) 48 , EGF Containing Fibulin Extracellular Matrix Protein 1 (EFEMP1) 49,50 , Glypican 1 (GPC1) 46,51,52 , NOTCH2 (with CD14 -epistatic) 53 , and JAG1 54 .…”

Section: Accepted Manuscriptmentioning

confidence: 99%

Genetic Contributions to Biliary Atresia: A Developmental Cholangiopathy

Hellen,

Karpen

2023

Semin Liver Dis

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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 a number of 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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“…Susceptible genes are selected according to the following criteria: (1) SNPs are significantly correlated with BA cohort; (2) It is verified by multiple cohorts or animal disease models; (3) its biological function is closely related to the four aspects described in our review. Some genes, such as IL18, CD14, NOTCH2 and so on, are only reported by one cohort are not in text but in Table 1 (34)(35)(36)(37)40). Genes that may be susceptible genes but have not yet been found BA are selected according to the following criteria: (1) Abnormal expression in BA specimens; (2) Demonstrated by animal disease models; (3) Their biological function is closely related to the four aspects described in our review.…”

Section: Genetic Factors In Bamentioning

confidence: 99%

Genetic Factors and Their Role in the Pathogenesis of Biliary Atresia

Wu

¹

,

Sun²

2022

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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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“…Simultaneous next-generation sequencing of multiple genes and whole exome or whole genome sequencing now enables rapid and affordable molecular diagnosis of many diseases that cannot be directly diagnosed from standard blood tests or liver biopsies [8]. Genetic variants in DD3, GPC1, CD14, EFEMP1, and NOTCH2 are associated with BA susceptibility [9][10][11][12][13]. Meanwhile, due to the important role of the immune microenvironment in the pathogenesis of BA, we proposed a scoring model of immune-related genes for early diagnosis.…”

Section: Introductionmentioning

confidence: 99%

A novel model based on immune-related genes for differentiating biliary atresia from other cholestatic diseases

Li

¹

,

Zheng

²

,

Zhang

³

et al. 2022

Pediatr Surg Int

2

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Based on a public gene expression database, this study established the immune-related genetic model that distinguished BA from other cholestasis diseases (DC) for the rst time. We explored the molecular mechanism of BA based on the gene model. MethodsThe BA microarray dataset GSE46960, containing BA, other cause of intrahepatic cholestasis than biliary atresia and normal liver gene expression data, was downloaded from the Gene Expression Omnibus (GEO) database. We performed a comprehensive bioinformatics analysis to establish and validate an immune-related gene model and subsequently identi ed hub genes as biomarkers associated with the molecular mechanisms of BA. To assess the model's performance for separating BA from other cholestasis diseases, we used receiver operating characteristic (ROC) curves and the area under the curve (AUC) of the ROC. Independent datasets GSE69948 and GSE122340 were used for the validation process. ResultsThe model was built using eight immune-related genes, including EDN1, HAMP, SAA1, SPP1, ANKRD1, MMP7, TACSTD2, and UCA1. In the GSE46960 and validation group, it presented excellent results, and the prediction accuracy of BA in comparison to other cholestasis diseases was good. Functional enrichment analysis revealed signi cant immunological differences between BA and other cholestatic diseases.Finally, we found that the TNFα-NF-κB pathway is associated with EDN1 gene expression and may explain brosis progression, which may become a new therapeutic target. ConclusionIn summary, we have successfully constructed an immune-related gene model that can distinguish BA from other cholestatic diseases, while identifying the hub gene. Our exploration of immune genes provides new clues for the early diagnosis, molecular mechanism, and clinical treatment of biliary atresia.

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Epistatic Association of CD14 and NOTCH2 Genetic Polymorphisms with Biliary Atresia in a Southern Chinese Population

Cited by 9 publications

References 33 publications

MiR-100 rs1834306 A>G Increases Biliary Atresia Risk in Southern Han Chinese Children

Translational Research in Biliary Atresia: News from Mice and Men

Genetic Contributions to Biliary Atresia: A Developmental Cholangiopathy

Genetic Factors and Their Role in the Pathogenesis of Biliary Atresia

A novel model based on immune-related genes for differentiating biliary atresia from other cholestatic diseases

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