Genetic contributors and modifiers of biliary atresia.
Genetic contributors and modifiers of biliary atresia.
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DOI：
10.1159/000371694
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发表时间：
2015
期刊：
影响因子：
--
通讯作者：
Karpen SJ
中科院分区：
文献类型：
--
作者：
Mezina A;Karpen SJ
迄今为止，最常见的严重新生儿肝病胆道闭锁的病因和致病基础仍然难以捉摸。这种疾病表现为新生儿胆汁淤积的一种侵袭性形式，其特征是在生命的最初几周内肝外胆管被破坏和闭塞，以及胆汁纤维化的快速进展，这可能是由于持续的胆汁淤积和包括胆汁酸在内的胆汁成分的滞留所致。在大约 5% 的患者中，胆道闭锁与偏侧性特征相关，这表明这种疾病在出生后不久就开始存在遗传基础。然而，胆道闭锁不会发生在家庭内部，而且双胞胎的情况不一致，表明不存在严格的孟德尔遗传。尽管如此，在人类和非人类模型系统中，与胆管畸形发生/纤毛病相关的基因与胆道闭锁的特征重叠。总而言之，导致新生儿胆管病导致胆道闭锁的常见途径的严格遗传病因仍然难以捉摸。纤维发生和基于炎症的研究表明，这些途径的早期参与有助于疾病进展，但最近的一项双盲研究并未表明早期使用皮质类固醇有任何益处。然而，某些人群中可能存在对胆管病和胆汁淤积的适应和反应的遗传因素，这可能会影响对 HPE 的反应和随后的胆道功能。为了探索这些选择，我们对患有胆道闭锁的婴儿进行了全外显子组测序，这些研究提供了几个候选基因，其变异可能会影响疾病，其中包括非裔美国人中普遍存在的与疾病相关的 ABCB4 基因变异，该变异与较差的结果相关。总之，外显子组测序和大群体研究的结合有望揭示与胆道闭锁患者相关的致病基因和修饰基因，作为提供治疗靶点和潜在基因筛查机会的手段。
To date, the etiology and pathogenic underpinning of the progression of the most prevalent serious neonatal liver disease, biliary atresia, remains elusive. This disease presents as an aggressive form of neonatal cholestasis characterized by the destruction and obliteration of the extrahepatic bile ducts within the first few weeks of life, and rapid progression of biliary fibrosis, likely due to unremitting cholestasis and retention of biliary constituents including bile acids. In ~ 5% of patients, biliary atresia has is associated with laterality features, suggesting that a genetic underpinning to a disease that begins soon after birth. However, biliary atresia does not occur within families and twins are discordant, indicating an absence of strict Mendelian inheritance. Despite this, genes related to bile duct dysmorphogenesis/ciliopathies overlapping with features of biliary atresia in both humans and non-human model systems have been proposed. Taken together, strict genetic etiologies leading to a common pathway of a neonatal cholangiopathy resulting in biliary atresia remain elusive. Contributions from fibrogenesis and inflammation-based studies suggest that early engagement of these pathways contributes to disease progression, but a recent double-blind study did not suggest any benefit from early use of corticosteroids. However, there are genetic contributions to the adaptation and response to cholangiopathies and cholestasis that may be present in certain populations that likely impact upon the response to HPE and subsequent biliary tract function. To explore these options, we performed whole exome sequencing of infants with biliary atresia and these studies have provided several candidate genes whose variants likely impact upon disease, including a disease-associated variant of the ABCB4 gene prevalent in African-Americans that correlates with worse outcomes. All together, combinations of exome sequencing and large population studies are expected to reveal causative and modifying genes relevant to patients with biliary atresia as a means to provide therapeutic targets and potential opportunities for genetic screening.
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DOI：
10.1038/modpathol.2011.212
发表时间：
2012-05
期刊：
Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc
影响因子：
--
作者：
通讯作者：
--
影响因子：
5.1
作者：
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通讯作者：
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DOI：
10.1002/ajmg.1320430317
发表时间：
1992-06-01
期刊：
AMERICAN JOURNAL OF MEDICAL GENETICS
影响因子：
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作者：
GUNASEKARAN, TS;HASSALL, EG;YONG, SL
通讯作者：
YONG, SL
影响因子：
12.6
作者：
de Vries, Willemien;Homan-Van der Veen, Jenneke;Verkade, Henkjan J.
通讯作者：
Verkade, Henkjan J.
DOI：
10.1097/01.mpg.0000192247.55583.fa
发表时间：
2006-01-01
影响因子：
2.9
作者：
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通讯作者：
Aydogdu, S