Genomics and Computational Biology Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
Division of Human Genetics, Department of Pediatrics, at The Children's Hospital of Philadelphia, and The Perelman School of Medicine at The University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
PLoS Genet. 2018 Aug 13;14(8):e1007532. doi: 10.1371/journal.pgen.1007532. eCollection 2018 Aug.
Biliary atresia (BA) is a rare pediatric cholangiopathy characterized by fibrosclerosing obliteration of the extrahepatic bile ducts, leading to cholestasis, fibrosis, cirrhosis, and eventual liver failure. The etiology of BA remains unknown, although environmental, inflammatory, infectious, and genetic risk factors have been proposed. We performed a genome-wide association study (GWAS) in a European-American cohort of 343 isolated BA patients and 1716 controls to identify genetic loci associated with BA. A second GWAS was performed in an independent European-American cohort of 156 patients with BA and other extrahepatic anomalies and 212 controls to confirm the identified candidate BA-associated SNPs. Meta-analysis revealed three genome-wide significant BA-associated SNPs on 2p16.1 (rs10865291, rs6761893, and rs727878; P < 5 ×10-8), located within the fifth intron of the EFEMP1 gene, which encodes a secreted extracellular protein implicated in extracellular matrix remodeling, cell proliferation, and organogenesis. RNA expression analysis showed an increase in EFEMP1 transcripts from human liver specimens isolated from patients with either BA or other cholestatic diseases when compared to normal control liver samples. Immunohistochemistry demonstrated that EFEMP1 is expressed in cholangiocytes and vascular smooth muscle cells in liver specimens from patients with BA and other cholestatic diseases, but it is absent from cholangiocytes in normal control liver samples. Efemp1 transcripts had higher expression in cholangiocytes and portal fibroblasts as compared with other cell types in normal rat liver. The identification of a novel BA-associated locus, and implication of EFEMP1 as a new BA candidate susceptibility gene, could provide new insights to understanding the mechanisms underlying this severe pediatric disorder.
先天性胆道闭锁（BA）是一种罕见的儿科胆管病，其特征为肝外胆管纤维硬化性闭塞，导致胆汁淤积、纤维化、肝硬化和最终肝功能衰竭。BA 的病因仍然未知，尽管已经提出了环境、炎症、感染和遗传危险因素。我们对 343 名孤立性 BA 患者和 1716 名对照的欧洲裔美国人队列进行了全基因组关联研究（GWAS），以确定与 BA 相关的遗传位点。在一个独立的欧洲裔美国人队列中，对 156 名患有 BA 和其他肝外异常的患者和 212 名对照进行了第二次 GWAS，以确认鉴定出的候选 BA 相关 SNP。荟萃分析揭示了 2p16.1 上与 BA 相关的三个全基因组显著 SNP（rs10865291、rs6761893 和 rs727878；P < 5 ×10-8），位于 EFEMP1 基因的第五内含子内，该基因编码一种分泌型细胞外蛋白，参与细胞外基质重塑、细胞增殖和器官发生。RNA 表达分析显示，与正常对照肝组织相比，来自 BA 或其他胆汁淤积性疾病患者的人肝组织中 EFEMP1 转录本增加。免疫组织化学显示，EFEMP1 在 BA 和其他胆汁淤积性疾病患者的肝组织中的胆管细胞和血管平滑肌细胞中表达，但在正常对照肝组织中的胆管细胞中不存在。与其他细胞类型相比，Efemp1 转录本在正常大鼠肝中的胆管细胞和门脉成纤维细胞中表达更高。一个新的 BA 相关位点的鉴定以及 EFEMP1 作为一个新的 BA 候选易感性基因的意义，可能为理解这种严重儿科疾病的机制提供新的见解。
