Liver disease in pediatric patients with cystic fibrosis is associated with glutathione S-transferase P1 polymorphism
Liver disease in pediatric patients with cystic fibrosis is associated with glutathione S-transferase P1 polymorphism
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DOI：
10.1053/jhep.2002.35534
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发表时间：
2002-10-01
期刊：
影响因子：
13.5
通讯作者：
Clement, A
中科院分区：
文献类型：
--
作者：
Henrion-Caude, A;Flamant, C;Clement, A
囊性纤维化（CF）患者的肝脏疾病是不稳定的，尚未明确与任何特定的风险因素相关。虽然囊性纤维化跨膜传导调节因子（CFTR）的表达仅限于肝脏中的胆管上皮，但最近的研究结果表明，CFTR调节还原型谷胱甘肽（GSH）转运，CFTR功能障碍导致抗氧化防御失衡。在肝脏解毒酶中，谷胱甘肽S-转移酶（GST）在抗氧化应激的保护中起着关键作用。由于氧化损伤有助于肝脏疾病的发展，我们假设GST超家族的2个成员，GSTM 1和GSTP 1，它们在胆管上皮中表达，可能会影响CF患者的肝脏状态。在106名CF儿童（平均年龄11.5岁）中评估了GSTM 1和GSTP 1基因多态性的潜在影响。聚合酶链反应/限制性片段长度多态性分析发现，肝硬化CF患者GSTP 1-Ile（105）/Ile（105）基因型频率显著高于非肝硬化CF患者（P <0.03）。在年龄最小的患者中，6岁，GSTP 1-Ile（105）/Ile（105）基因型与其他GSTP 1基因型相比，肝脏疾病风险增加8倍（P = .002）。GSTM 1基因型和肝脏状态之间没有相关性。总之，GSTP 1-Ile（105）编码等位基因与CF的肝功能障碍有关。这种多态性的鉴定可能具有预后价值，并提示肝脏疾病风险增加的CF患者的早期治疗。
Liver disease in patients with cystic fibrosis (CF) is inconstant and has not yet been clearly related to any specific risk factor. While the expression of cystic fibrosis transmembrane conductance regulator (CFTR) is restricted to the biliary epithelium in the liver, recent findings indicate that CFTR modulates reduced glutathione (GSH) transport and that CFTR dysfunction creates an imbalance in the antioxidant defense. Among liver detoxifying enzymes, the glutathione S-transferases (GSTs) play a key role in the protection against oxidative stress. Because oxidative injury contributes to the development of liver disease, we hypothesized that 2 members of the GST superfamily, GSTM1 and GSTP1, which are expressed in the biliary epithelium, could influence the hepatic status in patients with CF. The potential impact of GSTM1 and GSTP1 gene polymorphisms was assessed in 106 children with CF (mean age, 11.5 years). Based on polymerase chain reaction/restriction fragment length polymorphism analysis, we found that the frequency of GSTP1-Ile(105)/Ile(105) genotype was significantly higher in patients with CF with liver disease than in those without (P < .03). Among the youngest patients, aged 6 years, GSTP1-Ile(105)/Ile(105) genotype was associated with a 8-fold increase in the risk of liver disease compared with other GSTP1 genotypes (P = .002). No association between the GSTM1 genotype and liver status was documented. In conclusion, GSTP1-Ile(105)-encoding allele contributes to hepatic dysfunction in CF. Identification of this polymorphism may have prognostic value and prompt early treatment in patients with CF with an increased risk of liver disease.