Genome‐wide association studies in biliary atresia

Abstract

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.

Macrophage Migration Inhibitory Factor (MIF) Gene Promotor Polymorphism Is Associated with Increased Fibrosis in Biliary Atresia Patients, but Not with Disease Susceptibility

“…Another potential explanation is that the majority (15/18) of BA patients included in that study had liver transplantation at a relatively young age (8.4 ± 2.2 months) due to cholangitis or poor outcome of the surgery, suggesting another potential source of selection bias of more progressive BA (Arikan et al., ). Two relatively large genome‐wide association studies (GWAS) did not identify MIF promotor polymorphisms as susceptibility loci for BA (Cheng et al., ; Ningappa et al., ), which correlates with our results.…”

TGF‐β Signaling Plays a Pivotal Role During Developmental Biliary Atresia in Sea Lamprey (Petromyzon marinus)

“…For example, adducin 3, ADP ribosylation factor 6, ECM‐related genes, endothelial growth factor containing fibulin extracellular matrix protein 1, glypican 1, x‐prolyl aminopeptidase 1, and genes for several transcription factors are associated with both embryonic and perinatal BA. Working alone, these genetic variants may not be sufficient to cause BA and may involve other yet‐to‐be‐determined genes . With transcriptome KEGG analyses, we were able to identify additional signaling pathways involved in BA processes.…”

“…Several genome‐wide studies of single‐nucleotide polymorphisms or copy number variations and cDNA microarray studies in BA patients have associated few susceptible genes with this disease . For example, adducin 3, ADP ribosylation factor 6, ECM‐related genes, endothelial growth factor containing fibulin extracellular matrix protein 1, glypican 1, x‐prolyl aminopeptidase 1, and genes for several transcription factors are associated with both embryonic and perinatal BA.…”

Achondroplasia and Biliary Atresia: A Rare Association and Review of Literature

“…Genome association studies show that there are abnormalities in different susceptibility genes, which have roles in organogenesis, like glypican 1 (GPC1), adenosine diphosphate ribosylation factor 6 (ARF6), and adducin 3 (ADD3). [24][25][26][27][28] BA has been associated with abnormal notch signaling, missense mutations, or nodal cofactor cryptic (CFC1) mutations. 2,15,24,27,28 A recent report of two cases of BA showed an association of elevated serum levels FGF23 and hypophosphatemia, which returned to normal levels after liver transplant.…”