Genome-wide association study identifies a susceptibility locus for biliary atresia on 10q24.2

García-Barceló, María-Mercé; Yeung, Ming-Yiu; Miao, Xiaoping; Tang, Clara S.; Guo, Chao-Yu; So, Man-Ting; Ngan, Elly Sau-Wai; Lui, Vincent Chi-Hang; Chen, Yan; Liu, Xuelai; Hui, Kenneth-Jeremy W. S.; Li, Long; Guo, Weihong; Sun, Xin; Tou, Jinfa; Chan, Kin Wai; Wu, Xuan-Zhao; Song, You‐Qiang; Chan, Danny; Cheung, Kenneth M.C.; Chung, Patrick Ho Yu; Wong, Kenneth K.; Sham, Pak-Chung; Cherny, Stacey S.; Tam, Paul Kwong‐Hang

doi:10.1093/hmg/ddq196

Cited by 121 publications

(94 citation statements)

References 39 publications

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“…Analyses of gene synteny in this region showed that it was homologous to a region of human chromosome 10 (10q25.1; formerly 10q24.2) that was identified as a BA susceptibility locus in a GWAS of Han Chinese patients (Fig. 4E) (3). This association was confirmed in three independent studies of Chinese, Thai, and Caucasian BA patients (37–39).…”

Section: Resultsmentioning

confidence: 99%

“…Neither form of BA displays Mendelian inheritance, and most twin studies have shown nonconcordance, thus arguing against a single genetic determinant. Genome-wide association studies (GWAS) have led to identification of potential BA susceptibility loci on several different chromosomes, and a recent study suggested an association between BA risk and specific mitochondrial DNA haplogroups (3–6). Unfortunately, none of the affected genes within these regions have been identified.…”

Section: Introductionmentioning

confidence: 99%

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Identification of a plant isoflavonoid that causes biliary atresia

et al. 2015

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Biliary atresia (BA) is a rapidly progressive and destructive fibrotic disorder of unknown etiology affecting the extrahepatic biliary tree of neonates. Epidemiological studies suggest that an environmental factor, such as a virus or toxin, is the cause of the disease, although none have been definitively established. Several naturally occurring outbreaks of BA in Australian livestock have been associated with the ingestion of unusual plants by pregnant animals during drought conditions. We used a biliary secretion assay in zebrafish to isolate a previously undescribed isoflavonoid, biliatresone, from Dysphania species implicated in a recent BA outbreak. This compound caused selective destruction of the extrahepatic, but not intrahepatic, biliary system of larval zebrafish. A mutation that enhanced biliatresone toxicity mapped to a region of the zebrafish genome that has conserved synteny with an established human BA susceptibility locus. The toxin also caused loss of cilia in neonatal mouse extrahepatic cholangiocytes in culture and disrupted cell polarity and monolayer integrity in cholangiocyte spheroids. Together, these findings provide direct evidence that BA could be initiated by perinatal exposure to an environmental toxin.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Identification of a plant isoflavonoid that causes biliary atresia

et al. 2015

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“…64 Based on biological plausibility and bioinformatics assessment, 2 genes in this genomic region, X-prolyl aminopeptidase P1 ( XPNPEP1 ) and adducin 3 ( ADD3), may contribute to the pathogenesis of biliary atresia given that they are expressed in cholangiocytes and are known to be involved in the metabolism of inflammatory mediators. 64 A subsequent genome-wide association study from the United States has also implicated ADD3 as a possible predisposing factor in biliary atresia. 65 Genetic defects of XPNPEP1 could result in dysregulation of the inflammatory response in these patients, and mutation in ADD3 could lead to excessive deposition of actin and myosin, contributing to biliary fibrosis.…”

Section: Biliary Atresiamentioning

confidence: 99%

“…65 Genetic defects of XPNPEP1 could result in dysregulation of the inflammatory response in these patients, and mutation in ADD3 could lead to excessive deposition of actin and myosin, contributing to biliary fibrosis. 64 …”

Section: Biliary Atresiamentioning

confidence: 99%

The Cholangiopathies

Lazaridis

LaRusso

2015

Mayo Clinic Proceedings

171

170

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Cholangiocytes (ie, the epithelial cells that line the bile ducts) are an important subset of liver cells. They are actively involved in the modification of bile volume and composition, are activated by interactions with endogenous and exogenous stimuli (eg, microorganisms, drugs), and participate in liver injury and repair. The term cholangiopathies refers to a category of chronic liver diseases that share a central target: the cholangiocyte. The cholangiopathies account for substantial morbidity and mortality given their progressive nature, the challenges associated with clinical management, and the lack of effective medical therapies. Thus, cholangiopathies usually result in end-stage liver disease requiring liver transplant to extend survival. Approximately 16% of all liver transplants performed in the United States between 1988 and 2014 were for cholangiopathies. For all these reasons, cholangiopathies are an economic burden on patients, their families, and society. This review offers a concise summary of the biology of cholangiocytes and describes a conceptual framework for development of the cholangiopathies. We also present the recent progress made in understanding the pathogenesis of and how this knowledge has influenced therapies for the 6 common cholangiopathies—primary biliary cirrhosis, primary sclerosing cholangitis, cystic fibrosis involving the liver, biliary atresia, polycystic liver disease, and cholangiocarcinoma—because the latest scientific progress in the field concerns these conditions. We performed a search of the literature in PubMed for published papers using the following terms: cholangiocytes, biliary epithelia, cholestasis, cholangiopathy, and biliary disease. Studies had to be published in the past 5 years (from June 1, 2009, through May 31, 2014), and non-English studies were excluded.

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“…With regard to a gene mutation association, a recent study from China analyzed single-nucleotide polymorphisms (SNPs) and susceptibility genes in BA through genome-wide association studies (2). The results revealed a strong association of BA with the SNP rs17095355 on chromosome 10q24.…”

Section: Pathogenesismentioning

confidence: 99%

Biliary Atresia

Feldman

Mack

2015

J. pediatr. gastroenterol. nutr.

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Biliary atresia is a rare disease of unclear etiology, in which obstruction of the biliary tree causes severe cholestasis leading to cirrhosis and ultimately death if left untreated. Biliary atresia is the leading cause of neonatal cholestasis and the most frequent indication for pediatric liver transplantation. Any infant with persistent jaundice beyond 2 weeks of life needs to be evaluated for biliary atresia with fractionation of the bilirubin into conjugated and unconjugated portions. Early performance of a hepatoportoenterostomy in the first 45 days of life to restore bile flow and lessen further damage to the liver is thought to optimize outcome. Despite surgery, progressive liver scarring occurs, and 80% of patients with biliary atresia will require liver transplantation during childhood.

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Genome-wide association study identifies a susceptibility locus for biliary atresia on 10q24.2

Cited by 121 publications

References 39 publications

Identification of a plant isoflavonoid that causes biliary atresia

Identification of a plant isoflavonoid that causes biliary atresia

The Cholangiopathies

Biliary Atresia

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