AUTHOR=Bai Mei-Rong , Pei Hao-Yue , Zhou Ying , Song Huan-Lei , Pan Wei-Hua , Gong Yi-Ming , Wu Wen-Jie , Yu Wen-Wen , Cui Meng-Meng , Gu Bei-Lin , Chu Xun , Cai Wei 

TITLE=Association analysis and functional follow-up identified common variants of JAG1 accounting for risk to biliary atresia

JOURNAL=Frontiers in Genetics

VOLUME=14

YEAR=2023

URL=https://www.frontiersin.org/journals/genetics/articles/10.3389/fgene.2023.1186882

DOI=10.3389/fgene.2023.1186882

ISSN=1664-8021

ABSTRACT=<p><bold>Background:</bold> Biliary atresia (BA) is a destructive, obliterative cholangiopathy characterized by progressive fibro-inflammatory disorder and obliteration of intra- and extrahepatic bile ducts. The <italic>Jagged1</italic> (<italic>JAG1</italic>) gene mutations have been found in some isolated BA cases. We aim to explore the association of common variants in <italic>JAG1</italic> with isolated BA risk in the Chinese Han population.</p><p><bold>Methods:</bold> We genotyped 31 tag single nucleotide polymorphisms covering the <italic>JAG1</italic> 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 <italic>JAG1</italic> homologs were investigated in zebrafish embryos, and the roles of <italic>jag1</italic>a and <italic>jag1b</italic> in biliary development were examined by morpholino knockdown in zebrafish.</p><p><bold>Results:</bold> Single nucleotide polymorphisms rs6077861 [<italic>P</italic><sub><italic>Allelic</italic></sub> = 1.74 × 10<sup>−4</sup>, odds ratio = 1.78, 95% confidence interval: 1.31–2.40] and rs3748478 (<italic>P</italic><sub><italic>Allelic</italic></sub> = 5.77 × 10<sup>−4</sup>, odds ratio = 1.39, 95% confidence interval: 1.15–1.67) located in the intron region of <italic>JAG1</italic> showed significant associations with BA susceptibility. The <italic>JAG1</italic> homologs, <italic>jag1a</italic> and <italic>jag1b</italic> genes were expressed in the developing hepatobiliary duct of zebrafish, especially at 72 and 96 h postfertilization. Knockdown of both <italic>jag1a</italic> and <italic>jag1b</italic> led to poor biliary secretion, sparse intrahepatic bile duct network and smaller or no gallbladders compared with control embryos in the zebrafish model.</p><p><bold>Conclusion:</bold> Common genetic variants of <italic>JAG1</italic> were associated with BA susceptibility. Knockdown of <italic>JAG1</italic> homologs led to defective intrahepatic and extrahepatic bile ducts in zebrafish. These results suggest that <italic>JAG1</italic> might be implicated in the etiology of BA.</p>