Association analysis and functional follow-up identified common variants of JAG1 accounting for risk to biliary atresia
Background: Biliary atresia (BA) is a destructive, obliterative cholangiopathy characterized by progressive fibro-inflammatory disorder and obliteration of intra- and extrahepatic bile ducts. The Jagged1 (JAG1) gene mutations have been found in some isolated BA cases. We aim to explore the associati...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2023-05-01
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| Series: | Frontiers in Genetics |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fgene.2023.1186882/full |
| _version_ | 1797826849034731520 |
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| author | Mei-Rong Bai Mei-Rong Bai Mei-Rong Bai Hao-Yue Pei Hao-Yue Pei Ying Zhou Huan-Lei Song Huan-Lei Song Wei-Hua Pan Yi-Ming Gong Wen-Jie Wu Wen-Wen Yu Wen-Wen Yu Meng-Meng Cui Meng-Meng Cui Bei-Lin Gu Bei-Lin Gu Xun Chu Xun Chu Xun Chu Wei Cai Wei Cai Wei Cai |
| author_facet | Mei-Rong Bai Mei-Rong Bai Mei-Rong Bai Hao-Yue Pei Hao-Yue Pei Ying Zhou Huan-Lei Song Huan-Lei Song Wei-Hua Pan Yi-Ming Gong Wen-Jie Wu Wen-Wen Yu Wen-Wen Yu Meng-Meng Cui Meng-Meng Cui Bei-Lin Gu Bei-Lin Gu Xun Chu Xun Chu Xun Chu Wei Cai Wei Cai Wei Cai |
| author_sort | Mei-Rong Bai |
| collection | DOAJ |
| description | Background: Biliary atresia (BA) is a destructive, obliterative cholangiopathy characterized by progressive fibro-inflammatory disorder and obliteration of intra- and extrahepatic bile ducts. The Jagged1 (JAG1) gene mutations have been found in some isolated BA cases. We aim to explore the association of common variants in JAG1 with isolated BA risk in the Chinese Han population.Methods: We genotyped 31 tag single nucleotide polymorphisms covering the JAG1 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 JAG1 homologs were investigated in zebrafish embryos, and the roles of jag1a and jag1b in biliary development were examined by morpholino knockdown in zebrafish.Results: Single nucleotide polymorphisms rs6077861 [PAllelic = 1.74 × 10−4, odds ratio = 1.78, 95% confidence interval: 1.31–2.40] and rs3748478 (PAllelic = 5.77 × 10−4, odds ratio = 1.39, 95% confidence interval: 1.15–1.67) located in the intron region of JAG1 showed significant associations with BA susceptibility. The JAG1 homologs, jag1a and jag1b genes were expressed in the developing hepatobiliary duct of zebrafish, especially at 72 and 96 h postfertilization. Knockdown of both jag1a and jag1b led to poor biliary secretion, sparse intrahepatic bile duct network and smaller or no gallbladders compared with control embryos in the zebrafish model.Conclusion: Common genetic variants of JAG1 were associated with BA susceptibility. Knockdown of JAG1 homologs led to defective intrahepatic and extrahepatic bile ducts in zebrafish. These results suggest that JAG1 might be implicated in the etiology of BA. |
| first_indexed | 2024-04-09T12:38:50Z |
| format | Article |
| id | doaj.art-8e5f9d9d679049929e2612145573659f |
| institution | Directory Open Access Journal |
| issn | 1664-8021 |
| language | English |
| last_indexed | 2024-04-09T12:38:50Z |
| publishDate | 2023-05-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Genetics |
| spelling | doaj.art-8e5f9d9d679049929e2612145573659f2023-05-15T05:07:18ZengFrontiers Media S.A.Frontiers in Genetics1664-80212023-05-011410.3389/fgene.2023.11868821186882Association analysis and functional follow-up identified common variants of JAG1 accounting for risk to biliary atresiaMei-Rong Bai0Mei-Rong Bai1Mei-Rong Bai2Hao-Yue Pei3Hao-Yue Pei4Ying Zhou5Huan-Lei Song6Huan-Lei Song7Wei-Hua Pan8Yi-Ming Gong9Wen-Jie Wu10Wen-Wen Yu11Wen-Wen Yu12Meng-Meng Cui13Meng-Meng Cui14Bei-Lin Gu15Bei-Lin Gu16Xun Chu17Xun Chu18Xun Chu19Wei Cai20Wei Cai21Wei Cai22Department of Pediatric Surgery, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, ChinaShanghai Institute of Pediatric Research, Shanghai, ChinaShanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, ChinaShanghai Institute of Pediatric Research, Shanghai, ChinaShanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, ChinaDepartment of Pediatric Surgery, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, ChinaShanghai Institute of Pediatric Research, Shanghai, ChinaShanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, ChinaDepartment of Pediatric Surgery, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, ChinaDepartment of Pediatric Surgery, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, ChinaDepartment of Pediatric Surgery, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, ChinaShanghai Institute of Pediatric Research, Shanghai, ChinaShanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, ChinaShanghai Institute of Pediatric Research, Shanghai, ChinaShanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, ChinaShanghai Institute of Pediatric Research, Shanghai, ChinaShanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, ChinaDepartment of Pediatric Surgery, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, ChinaShanghai Institute of Pediatric Research, Shanghai, ChinaShanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, ChinaDepartment of Pediatric Surgery, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, ChinaShanghai Institute of Pediatric Research, Shanghai, ChinaShanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, ChinaBackground: Biliary atresia (BA) is a destructive, obliterative cholangiopathy characterized by progressive fibro-inflammatory disorder and obliteration of intra- and extrahepatic bile ducts. The Jagged1 (JAG1) gene mutations have been found in some isolated BA cases. We aim to explore the association of common variants in JAG1 with isolated BA risk in the Chinese Han population.Methods: We genotyped 31 tag single nucleotide polymorphisms covering the JAG1 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 JAG1 homologs were investigated in zebrafish embryos, and the roles of jag1a and jag1b in biliary development were examined by morpholino knockdown in zebrafish.Results: Single nucleotide polymorphisms rs6077861 [PAllelic = 1.74 × 10−4, odds ratio = 1.78, 95% confidence interval: 1.31–2.40] and rs3748478 (PAllelic = 5.77 × 10−4, odds ratio = 1.39, 95% confidence interval: 1.15–1.67) located in the intron region of JAG1 showed significant associations with BA susceptibility. The JAG1 homologs, jag1a and jag1b genes were expressed in the developing hepatobiliary duct of zebrafish, especially at 72 and 96 h postfertilization. Knockdown of both jag1a and jag1b led to poor biliary secretion, sparse intrahepatic bile duct network and smaller or no gallbladders compared with control embryos in the zebrafish model.Conclusion: Common genetic variants of JAG1 were associated with BA susceptibility. Knockdown of JAG1 homologs led to defective intrahepatic and extrahepatic bile ducts in zebrafish. These results suggest that JAG1 might be implicated in the etiology of BA.https://www.frontiersin.org/articles/10.3389/fgene.2023.1186882/fullbiliary atresiaJAG1single nucleotide polymorphismszebrafishbile ducts |
| spellingShingle | Mei-Rong Bai Mei-Rong Bai Mei-Rong Bai Hao-Yue Pei Hao-Yue Pei Ying Zhou Huan-Lei Song Huan-Lei Song Wei-Hua Pan Yi-Ming Gong Wen-Jie Wu Wen-Wen Yu Wen-Wen Yu Meng-Meng Cui Meng-Meng Cui Bei-Lin Gu Bei-Lin Gu Xun Chu Xun Chu Xun Chu Wei Cai Wei Cai Wei Cai Association analysis and functional follow-up identified common variants of JAG1 accounting for risk to biliary atresia Frontiers in Genetics biliary atresia JAG1 single nucleotide polymorphisms zebrafish bile ducts |
| title | Association analysis and functional follow-up identified common variants of JAG1 accounting for risk to biliary atresia |
| title_full | Association analysis and functional follow-up identified common variants of JAG1 accounting for risk to biliary atresia |
| title_fullStr | Association analysis and functional follow-up identified common variants of JAG1 accounting for risk to biliary atresia |
| title_full_unstemmed | Association analysis and functional follow-up identified common variants of JAG1 accounting for risk to biliary atresia |
| title_short | Association analysis and functional follow-up identified common variants of JAG1 accounting for risk to biliary atresia |
| title_sort | association analysis and functional follow up identified common variants of jag1 accounting for risk to biliary atresia |
| topic | biliary atresia JAG1 single nucleotide polymorphisms zebrafish bile ducts |
| url | https://www.frontiersin.org/articles/10.3389/fgene.2023.1186882/full |
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