Association analysis and functional follow-up identified common variants of accounting for risk to biliary atresia.

Biliary atresia (BA) is a destructive, obliterative cholangiopathy characterized by progressive fibro-inflammatory disorder and obliteration of intra- and extrahepatic bile ducts. The () gene mutations have been found in some isolated BA cases. We aim to explore the association of common variants in with isolated BA risk in the Chinese Han population. We genotyped 31 tag single nucleotide polymorphisms covering the gene region in 333 BA patients and 1,665 healthy controls from the Chinese population, and performed case-control association analysis. The expression patterns of homologs were investigated in zebrafish embryos, and the roles of a and in biliary development were examined by morpholino knockdown in zebrafish. Single nucleotide polymorphisms rs6077861 [ = 1.74 × 10, odds ratio = 1.78, 95% confidence interval: 1.31-2.40] and rs3748478 ( = 5.77 × 10, odds ratio = 1.39, 95% confidence interval: 1.15-1.67) located in the intron region of showed significant associations with BA susceptibility. The homologs, and genes were expressed in the developing hepatobiliary duct of zebrafish, especially at 72 and 96 h postfertilization. Knockdown of both and led to poor biliary secretion, sparse intrahepatic bile duct network and smaller or no gallbladders compared with control embryos in the zebrafish model. Common genetic variants of were associated with BA susceptibility. Knockdown of homologs led to defective intrahepatic and extrahepatic bile ducts in zebrafish. These results suggest that might be implicated in the etiology of BA.