Biliary atresia is associated with polygenic susceptibility in ciliogenesis and planar polarity effector genes

Glessner, Joseph T.; Ningappa, Mylarappa; Ngo, Kim A.; Zahid, Maliha; So, Juhoon; Higgs, Brandon W.; Sleiman, Patrick; Narayanan, Tejaswini; Ranganathan, Sarangarajan; March, Michael; Prasadan, Krishna; Vaccaro, Courtney; Reyes‐Múgica, Miguel; Velazquez, Jeremy J.; Salgado, Cláudia; Ebrahimkhani, Mo R.; Schmitt, Lori; Rajasundaram, Dhivyaa; Morgan, Paul; Pellegrino, Renata; Gittes, George K.; Liu, Dong; Wang, Xiang; Billings, Jonathan; Squires, Robert H.; Ashokkumar, Chethan; Sharif, Khalid; Kelly, Déirdre; Dhawan, Anil; Horslen, Simon; Lo, Cecilia; Shin, Donghun; Subramaniam, Shankar; Hákonarson, Hákon; Sindhi, Rakesh

doi:10.1016/j.jhep.2023.07.039

Cited by 10 publications

(3 citation statements)

References 60 publications

(48 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It is speculated that BAs are initiated by various factors such as virus infection 47 , toxins 48 and genetic defects 8 , suggesting the presence of the various subtypes even in the isolated BAs. A recent genome-wide association study (GWAS) of 811 human BA genome samples also supports the involvement of the multiple genes including SOX17 , to contribute to the onset and/or exacerbation of BA 49 . In this study, SOX17-low group showed a better prognosis after Kasai surgery, i.e., higher native liver survival rate and lower incidence of liver transplantation, together with no significant correlation of the SOX17-low group with the known prognostic factors such as BA types and patient’s age at Kasai surgery.…”

Section: Discussionmentioning

confidence: 86%

“…In this study, SOX17-low group showed a better prognosis after Kasai surgery, i.e., higher native liver survival rate and lower incidence of liver transplantation, together with no significant correlation of the SOX17-low group with the known prognostic factors such as BA types and patient’s age at Kasai surgery. Therefore, together with the GWAS data showing the significant association of SOX17 genes in human BA 49 , it is also possible that SOX17-low BA may be a potential subtype of human BA. The reason for the better prognosis after the Kasai surgery in this group may be explained by resecting the gallbladder-hepatic duct as a trigger of the BA and prevent the progression of liver damage after the surgery.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Impact of gallbladder hypoplasia on hilar hepatic ducts in biliary atresia

Miyazaki,

Takami,

Uemura

et al. 2024

Commun Med

View full text Add to dashboard Cite

Background Biliary atresia (BA) is an intractable disease of unknown cause that develops in the neonatal period. It causes jaundice and liver damage due to the destruction of extrahepatic biliary tracts,. We have found that heterozygous knockout mice of the SRY related HMG-box 17 (Sox17) gene, a master regulator of stem/progenitor cells in the gallbladder wall, exhibit a condition like BA. However, the precise contribution of hypoplastic gallbladder wall to the pathogenesis of hepatobiliary disease in Sox17 heterozygous embryos and human BA remains unclear. Methods We employed cholangiography and histological analyses in the mouse BA model. Furthermore, we conducted a retrospective analysis of human BA. Results We show that gallbladder wall hypoplasia causes abnormal multiple connections between the hilar hepatic bile ducts and the gallbladder-cystic duct in Sox17 heterozygous embryos. These multiple hilar extrahepatic ducts fuse with the developing intrahepatic duct walls and pull them out of the liver parenchyma, resulting in abnormal intrahepatic duct network and severe cholestasis. In human BA with gallbladder wall hypoplasia (i.e., abnormally reduced expression of SOX17), we also identify a strong association between reduced gallbladder width (a morphometric parameter indicating gallbladder wall hypoplasia) and severe liver injury at the time of the Kasai surgery, like the Sox17-mutant mouse model. Conclusions Together with the close correlation between gallbladder wall hypoplasia and liver damage in both mouse and human cases, these findings provide an insight into the critical role of SOX17-positive gallbladder walls in establishing functional bile duct networks in the hepatic hilus of neonates.

show abstract

Section: Discussionmentioning

confidence: 86%

Section: Discussionmentioning

confidence: 99%

Impact of gallbladder hypoplasia on hilar hepatic ducts in biliary atresia

Miyazaki,

Takami,

Uemura

et al. 2024

Commun Med

View full text Add to dashboard Cite

show abstract

“…46,47,[53][54][55] Hence, precise temporal and positional regulation of Hedgehog pathway activity appears to be necessary for proper biliary tree development, as well as for maintenance and repair of the biliary system in adulthood. Hedge-hog pathway dysregulation has been reported in biliary atresia, 50,56,57 primary biliary cholangitis (PBC), 58,59 and primary sclerosing cholangitis (PSC). 46 For example, the Hedgehog pathway was one of the leading (and most consistently induced) KEGG pathways revealed by GWAS (genomewide association study) analyses of two independent large human PBC datasets.…”

Section: Biliary Diseasementioning

confidence: 99%

Hedgehog Signaling: Implications in Liver Pathophysiology

Dutta,

Jun,

et al. 2023

Semin Liver Dis

View full text Add to dashboard Cite

The purpose of this review is to summarize current knowledge about the role of the Hedgehog signaling pathway in liver homeostasis and disease. Hedgehog is a morphogenic signaling pathway that is active in development. In most healthy tissues, pathway activity is restricted to stem cell and/or stromal cell compartments, where it enables stem cell self-renewal and tissue homeostasis. Aberrant over-activation of Hedgehog signaling occurs in many cancers, including hepatocellular and cholangio- carcinoma. The pathway is also activated transiently in stromal cells of injured tissues and orchestrates normal wound healing responses, including inflammation, vascular remodeling and fibrogenesis. In liver, sustained Hedgehog signaling in stromal cells plays a major role in the pathogenesis of cirrhosis. Hedgehog signaling was thought to be silenced in healthy hepatocytes. However, recent studies show that targeted disruption of the pathway in hepatocytes dysregulates lipid, cholesterol, and bile acid metabolism and promotes hepatic lipotoxicity, insulin resistance and senescence. Hepatocytes that lack Hedgehog activity also produce a secretome that activates Hedgehog signaling in cholangiocytes and neighboring stromal cells to induce inflammatory and fibrogenic wound healing responses that drive progressive fibrosis. In conclusion, Hedgehog signaling must be precisely controlled in adult liver cells in order to maintain liver health.

show abstract

A beneficial response of fetal wound healing gone bad in the bile duct: The overarching cause of biliary atresia?

Trampert,

Beuers

2024

Journal of Hepatology

View full text Add to dashboard Cite

Biliary atresia is associated with polygenic susceptibility in ciliogenesis and planar polarity effector genes

Cited by 10 publications

References 60 publications

Impact of gallbladder hypoplasia on hilar hepatic ducts in biliary atresia

Impact of gallbladder hypoplasia on hilar hepatic ducts in biliary atresia

Hedgehog Signaling: Implications in Liver Pathophysiology

A beneficial response of fetal wound healing gone bad in the bile duct: The overarching cause of biliary atresia?

Contact Info

Product

Resources

About