Common genetic variants regulating ADD3 gene expression alter biliary atresia risk

Cheng, Gregory Yin Ming; Tang, Clara S.; Wong, Emily H. M.; Cheng, William; So, Man-Ting; Miao, Xiaoping; Zhang, Ruizhong; Cui, Long; Liu, Xuelai; Ngan, Elly Sau-Wai; Lui, Vincent Chi-Hang; Chung, Patrick Ho Yu; Chan, Iris Hiu-Shuen; Liu, Juncheng; Zhong, Wei; Xia, Huimin; Yu, Jian; Qiu, Xiu; Wu, Xuan-Zhao; Wang, Bin; Dong, Xiao; Tou, Jinfa; Huang, Liuming; Yi, Bin; Ren, Hongxia; Chan, Emily; Ye, Kenny; O’Reilly, Paul; Wong, Kenneth K.; Sham, Pak-Chung; Cherny, Stacey S.; Tam, Paul Kwong‐Hang; García-Barceló, María-Mercé

doi:10.1016/j.jhep.2013.07.021

Cited by 76 publications

(71 citation statements)

References 38 publications

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“…While this manuscript was under revision, a publication by Cheng et al also reported ADD3 as a likely candidate gene for BA. They found that the Chinese BA patients with the risk haplotype had significantly lower expression of ADD3 suggesting that the risk haplotype can contribute to BA by decreasing ADD3 expression (Cheng et al 2013). …”

Section: Discussionmentioning

confidence: 99%

Replication of a GWAS signal in a Caucasian population implicates ADD3 in susceptibility to biliary atresia

et al. 2013

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In the United States, biliary atresia (BA) is the most frequent indication for liver transplantation in pediatric patients. BA is a complex disease, with suspected environmental and genetic risk factors. A genome-wide association study in Chinese patients identified association to the 10q24.2 (hg18) genomic region. This signal was upstream of two genes, XPNPEP1 and ADD3, both expressed in intrahepatic bile ducts. We tested association to this region in 171 BA patients and 1,630 controls of European descent and found the strongest signal to be at rs7099604 (p = 2.5 × 10−3) in intron 1 of the ADD3 gene. Moreover, expression data suggest that ADD3, but not XPNPEP1, is differentially expressed in BA patients. The role of ADD3 in biliary development is unclear, but our findings suggest that this gene may be functionally relevant for the development of BA.

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Section: Discussionmentioning

confidence: 99%

Replication of a GWAS signal in a Caucasian population implicates ADD3 in susceptibility to biliary atresia

et al. 2013

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“…To ‘fine’ map the disease locus further, Cheng et al from the same investigator group genotyped 107 SNPs in this candidate 10q24.2 locus in 339 Han Chinese BA patients and 401 matched controls. The SNP rs17095355 achieved genome‐wide significance with a p‐value of 10 −10 .…”

Section: Summary Of Gwas Studies and Susceptibility Loci For Biliary mentioning

confidence: 99%

Genome‐wide association studies in biliary atresia

Ningappa

Min

Higgs

et al. 2015

WIREs Mechanisms of Disease

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Biliary atresia (BA) is a model complex disease resulting from interactions between multiple susceptibility loci and environmental factors. This perception is based on a heterogeneous phenotype extending beyond an absent extrahepatic bile duct to include gut and cardiovascular anomalies, and the association of BA with viral infections. Refractory jaundice and progression to cirrhosis shortly after birth can be fatal without surgical correction, and further suggests a pathogenesis during liver and bile duct development. Conclusive proof for a developmental origin would require documentation of disease progression in the perinatal or fetal liver, an impossible task for obvious reasons. We review three different sets of genome-wide association studies (GWAS) from three different cohorts of BA patients by three different groups of investigators, which address this knowledge gap. Knockdown of each susceptibility gene identified by GWAS in zebrafish embryos impairs excretion of bile from the liver, duplicating the characteristic diagnostic finding seen in affected children. This finding is associated with impaired intrahepatic biliary network formation in zebrafish morphants. Although distinct, these susceptibility genes share several functions including roles in mechanisms for organogenesis (glypican 1 or GPC1, and adenosine diphosphate ribosylation factor 6, or ARF6) or a greater expression in fetal liver than in adult liver (adducin 3 or ADD3). Together, these studies emphasize the importance of the human evidence, and present opportunities to map novel pathways which explain the phenotypic heterogeneity of BA.

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“…A genome-wide association study conducted in the Han Chinese population identified a potential susceptibility region for biliary atresia between the genes ADD3 and XPNPEP1 , chromosome10q25.1, and the association of one SNP with disease was replicated in independent Chinese and Thai samples [62,63]. More in-depth sequencing of a Han Chinese sample identified that a 5-SNP risk haplotype was associated with biliary atresia and the genotype correlated with reduced levels of ADD3 expression [64]. An attempt to replicate the association in a Caucasian cohort discovered a stronger signal in the first intron of ADD3 following SNP imputation, although the exact genotype at this SNP was not predictive of the degree of ADD3 expression.…”

Section: Proposed Genetic Etiologies Of Biliary Atresiamentioning

confidence: 99%

Genetic Contributors and Modifiers of Biliary Atresia

Mezina

Karpen²

2015

Dig Dis

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To date, the etiology and pathogenic underpinning of the progression of the most prevalent serious neonatal liver disease, biliary atresia, remains elusive. This disease presents as an aggressive form of neonatal cholestasis characterized by the destruction and obliteration of the extrahepatic bile ducts within the first few weeks of life and a rapid progression of biliary fibrosis, likely due to unremitting cholestasis and retention of biliary constituents including bile acids. In ∼5% of patients, biliary atresia is associated with laterality features, suggesting a genetic underpinning to a disease that begins soon after birth. However, biliary atresia does not occur within families and twins are discordant, indicating an absence of strict mendelian inheritance. Despite this, genes related to bile duct dysmorphogenesis/ciliopathies overlapping with features of biliary atresia in both humans and nonhuman model systems have been proposed. Taken together, strict genetic etiologies leading to a common pathway of a neonatal cholangiopathy resulting in biliary atresia remain elusive. Contributions from fibrogenesis- and inflammation-based studies suggest that early engagement of these pathways contributes to disease progression, but a recent double-blind study did not suggest any benefit from early use of corticosteroids. However, there are genetic contributions to the adaptation and response to cholangiopathies and cholestasis that may be present in certain populations that likely impact upon the response to hepatoportoenterostomy and subsequent biliary tract function. Studies utilizing next generation sequencing technologies (e.g., exome analysis) are ongoing in several laboratories around the world; they are expected to provide insights into genetic contributions to biliary atresia outcomes. Altogether, combinations of exome sequencing and large population studies are expected to reveal causative and modifying genes relevant to patients with biliary atresia as a means to provide therapeutic targets and potential opportunities for genetic screening.

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Common genetic variants regulating ADD3 gene expression alter biliary atresia risk

Cited by 76 publications

References 38 publications

Replication of a GWAS signal in a Caucasian population implicates ADD3 in susceptibility to biliary atresia

Replication of a GWAS signal in a Caucasian population implicates ADD3 in susceptibility to biliary atresia

Genome‐wide association studies in biliary atresia

Genetic Contributors and Modifiers of Biliary Atresia

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