首页> 外文期刊>Annals of Internal Medicine >Variations in the Promoter Region of the Glutaminase Gene and the Development of Hepatic Encephalopathy in Patients With Cirrhosis: A Cohort StudyManuel Romero-Gómez, María Jover, José A. Del Campo, José L. Royo, Elena Hoyas, José J. Galán, Carmina Montoliu, Eugenia Baccaro, Mónica Guevara, Juan Córdoba, Germán Soriano, José M. Navarro, Carmen Martínez-Sierra, Lourdes Grande, Antonio Galindo, Emilia Mira, Santos Mañes, and Agustín Ruiz
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Variations in the Promoter Region of the Glutaminase Gene and the Development of Hepatic Encephalopathy in Patients With Cirrhosis: A Cohort StudyManuel Romero-Gómez, María Jover, José A. Del Campo, José L. Royo, Elena Hoyas, José J. Galán, Carmina Montoliu, Eugenia Baccaro, Mónica Guevara, Juan Córdoba, Germán Soriano, José M. Navarro, Carmen Martínez-Sierra, Lourdes Grande, Antonio Galindo, Emilia Mira, Santos Mañes, and Agustín Ruiz

机译:肝硬化患者谷氨酰胺酶基因启动子区域的变化与肝性脑病的发展:一项队列研究:曼努埃尔·罗梅罗·戈麦斯,玛丽亚·乔佛,何塞·德尔·坎波,何塞·罗伊,艾琳娜·霍亚斯,何塞·J·加兰,卡米纳蒙托留,尤金尼亚·巴卡罗,莫妮卡·格瓦拉,胡安·科尔多瓦,热尔曼·索里亚诺,何塞·纳瓦罗,卡门·马丁内斯·塞拉,卢尔德·格兰德,安东尼奥·加林多,艾米莉亚·米拉,桑托斯·马涅斯和阿古斯丁·鲁伊斯

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Background: Hepatic encephalopathy is a major complication ofncirrhosis and is associated with a poor prognosis.nObjective: To identify mutations in the gene sequence for glutam-ninase in humans that could be responsible for the development ofnhepatic encephalopathy in patients with cirrhosis.nDesign: Cohort study.nSetting: Outpatient clinics in 6 Spanish hospitals.nPatients: 109 consecutive patients with cirrhosis in the estimationncohort, 177 patients in the validation cohort, and 107 healthyncontrol participants.nMeasurements: Patients were followed every 3 or 6 months untilnthe development of hepatic encephalopathy or liver transplantation,ndeath, or the end of the study.nResults: The genetic analyses showed that glutaminase TACC andnCACC haplotypes were linked to the risk for overt hepatic enceph-nalopathy. Mutation scanning of the glutaminase gene identified ansection in the promoter region where base pairs were repeated (anmicrosatellite). Over a mean follow-up of 29.6 months, hepaticnencephalopathy occurred in 28 patients (25.7%) in the estimationcohort. Multivariable Cox models were used to determine the fol-nlowing independent predictors: Child–Turcotte–Pugh stage (hazardnratio [HR], 1.6 [95% CI, 1.29 to 1.98]; P u0001 0.001), minimal hepaticnencephalopathy (HR, 3.17 [CI, 1.42 to 7.09]; P u0001 0.006), andnhaving 2 long alleles of the microsatellite (HR, 3.12 [CI, 1.39 ton7.02]; P u0001 0.006). The association between 2 long alleles of thenmicrosatellite and overt hepatic encephalopathy was confirmed in anvalidation cohort (HR, 2.1 [CI, 1.17 to 3.79]; P u0001 0.012). Func-ntional studies showed higher luciferase activity in cells transfectednwith the long form of the microsatellite, which suggests that thenlong microsatellite enhances glutaminase transcriptional activity.nLimitation: Other genes and allelic variants might be involved innthe clinical expression of hepatic encephalopathy.nConclusion: This study identifies a genetic factor that is associatednwith development of hepatic encephalopathy in patients withncirrhosis.nPrimary Funding Source: Instituto de Salud Carlos III, SpanishnMinistry of Health.
机译:背景:肝性脑病是肝硬化的主要并发症,且预后较差。n目的:鉴定人类中谷氨酰胺酶基因序列的突变,该突变可能与肝硬化患者肝性脑病的发展有关。nDesign:队列研究设置:西班牙6所医院的门诊诊所患者:患者估计为109例连续性肝硬化患者,验证队列为177例患者,健康对照者为107例n测量:患者每3或6个月随访一次,直到肝性脑病或肝病发展结果,遗传分析表明,谷氨酰胺酶TACC和nCACC单倍型与明显的肝性脑病相关。谷氨酰胺酶基因的突变扫描鉴定了在启动子区域中的一个区域,在该区域中重复了碱基对(微卫星)。在平均29.6个月的随访中,估计队列中有28例患者(25.7%)发生了肝性脑病。多变量Cox模型用于确定以下独立预测因素:Child–Turcotte–Pugh阶段(危险比[HR],1.6 [95%CI,1.29至1.98]; P u0001 0.001),最小型肝性脑病(HR,3.17 [CI] ,1.42至7.09]; P u0001 0.006),并且具有2个微卫星长等位基因(HR,3.12 [CI,1.39ton7.02]; P u0001 0.006)。在验证队列中证实了微卫星的2个长等位基因与明显的肝性脑病之间的关联(HR,2.1 [CI,1.17至3.79]; P u0001 0.012)。功能研究表明,用长形微卫星转染的细胞具有更高的荧光素酶活性,这表明长形微卫星可增强谷氨酰胺酶的转录活性。限制:其他基因和等位基因变异可能参与肝性脑病的临床表达。一种与肝硬化患者肝性脑病的发展有关的遗传因素。n原始资金来源:西班牙卫生部Salud Carlos III研究所。

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