Genetic factors of susceptibility and of severity in primary biliary cirrhosis
Genetic factors of susceptibility and of severity in primary biliary cirrhosis
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DOI：
10.1016/j.jhep.2008.07.027
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发表时间：
2008-12-01
影响因子：
25.7
通讯作者：
Barbu, Veronique
中科院分区：
文献类型：
--
作者：
Poupon, Raoul;Ping, Chen;Barbu, Veronique
背景/目的：原发性胆汁性肝硬化（PBC）的发病机制受遗传因素的影响，迄今为止尚不清楚。我们研究了参与免疫的候选基因序列多样性的影响，（CTLA-4和TNF α），胆汁形成（10个肝胆转运蛋白基因）和对胆汁淤积的适应性反应（三种核受体基因）对PBC的易感性和严重性的影响。在258例PBC患者和两个独立的286和269名健康对照组中，共鉴定和比较了42个Ht SNPs。结果：CTLA-4和TNF α基因的Ht单核苷酸多态性与PBC的易感性显著相关。熊去氧胆酸（UDCA）治疗下的肝病进展率与TNF α和SLC 4A 2/阴离子交换剂2（AE 2）基因的SNP显著相关。多因素考克斯回归分析，包括临床和生化参数显示，SLC 4A 2/AE 2变异是一个独立的预后factor.Conclusions：这些数据点的免疫系统的基因编码调节剂在PBC的易感性的主要作用。他们还证明，TNF α和SLC 4A 2/AE 2的等位基因变异对UDCA治疗下PBC的演变特征具有显著影响。(C)2008年欧洲肝脏研究协会。Elsevier B. V.出版，保留所有权利。
Background/Aims: In primary biliary cirrhosis (PBC), pathogenesis is influenced by genetic factors that remain poorly elucidated up to now. We investigated the impact of sequence diversity in candidate genes involved in immunity (CTLA-4 and TNF alpha), in bile formation (10 hepatobiliary transporter genes) and in the adaptative response to cholestasis (three nuclear receptor genes) on the susceptibility and severity of PBC.Methods: A total of 42 Ht SNPs were identified and compared in 258 PBC patients and two independent groups of 286 and 269 healthy controls. All participants were white continental individuals with French ancestry.Results: Ht SNPs of CTLA-4 and TNF alpha genes were significantly associated with susceptibility to PBC. The progression rate of liver disease under ursodeoxycholic acid (UDCA) therapy was significantly linked to SNPs of TNF alpha and SLC4A2/anion exchanger 2 (AE2) genes. A multivariate Cox regression analysis including clinical and biochemical parameters showed that SLC4A2/AE2 variant was an independent prognostic factor.Conclusions: These data point to a primary role of genes encoding regulators of the immune system in the susceptibility to PBC. They also demonstrate that allelic variations in TNF alpha and SLC4A2/AE2 have a significant impact on the evolutive profile of PBC under UDCA therapy. (C) 2008 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.