Genetic Susceptibility Factors in Porphyria Cutanea Tarda (PCT)

迟发性皮肤卟啉症 (PCT) 的遗传易感因素

基本信息

批准号：
7905421
负责人：
KARL ELMO ANDERSON
金额：
$ 4.78万
依托单位：
UNIVERSITY OF TEXAS MED BR GALVESTON
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-08-01 至 2010-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7905421
关键词：
Affect Alcohol consumption Alcohols Animals CYP1A1 gene CYP1A2 gene CYP2E1 gene Case-Control Studies Cell Culture System Cell Culture Techniques Clinical Clinical Investigator Clinical Research Communities Cytochrome P450 DNA Databases Development Diagnosis Digestive System Disorders Disease Disease susceptibility Enrollment Enzymes Estrogens Frequencies Funding Future GSTM1 gene GSTT1 gene Generations Genetic Genetic Polymorphism Genetic Predisposition to Disease Genotype Glutathione S-Transferase Grant HIV Hepatic Hepatitis C Hepatocyte Hospitals Human Individual Inherited Investigation Iron Iron Overload Knowledge Laboratories Lead Leadership Liver Liver diseases Logistic Regressions Lymphocyte Matched Group Metabolism Modeling Mutation Oxidative Stress Patients Phase Phenotype Photosensitivity Play Population Porphyria Cutanea Tarda Porphyrins Predisposition Process Recording of previous events Relapse Research Research Personnel Resources Risk Factors Role Sampling Skin Smoking Testing Texas Time Translating Uroporphyrinogen Decarboxylase Work base clinical phenotype decarboxylase inhibitor gulf coast innovation novel patient population programs repository research clinical testing response treatment response working group

项目摘要

DESCRIPTION (provided by applicant): Porphyria cutanea tarda (PCT) is due to the inhibition of a specific hepatic enzyme, uroporphyrinogen decarboxylase (UROD), which leads to marked porphyrin accumulation in the liver. The disease develops in some individuals who are predisposed by certain environmental and inherited susceptibility factors, and is manifested by skin photosensitivity and liver damage. Susceptibility factors include hepatitis C, alcohol use, smoking, iron overload, HIV, estrogens and an inherited partial deficiency of UROD. Why PCT develops in only a few individuals with these susceptibility factors, many of which are relatively common, is not known, and additional influences.- most likely additional inherited differences - remain to be identified. PCT itself causes liver damage, and genetic factors that promote its development may play a role in other liver diseases, such as those induced by hepatitis C and alcohol. We will investigate the novel hypothesis, based on previous work in laboratory models, and limited human studies, that polymorphisms in phase I and phase II enzymes, such as cytochrome P450 enzymes (CYPs) and glutathione transferases (GSTs) may contribute to developing PCT. Their substrates and products may influence oxidative stress in hepatocytes, and hepatic CYPs play a role in generating a specific UROD inhibitor. At least 120 patients with well- documented PCT and matched controls will participate in a case-control study and be phenotyped in detail, including characterization of known susceptibility factors. Hospital controls will be matched 1:1 and community controls 2:1 with PCT patients. DNA samples will be prepared from patients and controls and genotyped for specific CYP1A1, CYP1A2, CYP2E1, GSTM1 and GSTT1 polymorphisms, and the results analyzed as related to phenotype (e.g. presence or absence of PCT, clinical features, known susceptibility factors, treatment response and history of relapse). DNA samples and lymphocytes from these patients and matched controls, and information regarding clinical phenotype (including known susceptibility factors) will be stored as a repository for future, multi-center studies of additional genetic influences on the development of PCT. We will utilize resources of the UTMB General Clinical Research Center and the Texas Gulf Coast Digestive Diseases Center. This study and projects which follow will lead to a better understanding of PCT and also contribute to knowledge about how agents such as alcohol and hepatitis C interact with genetic factors in causing human liver diseases.

描述（由申请人提供）：斑岩cutanea tarda（PCT）是由于抑制了特定的肝酶，尿中核蛋白原脱羧酶（UROD），这导致肝素在肝脏中的堆积显着。该疾病在某些受某些环境和遗传易感性因素易感的人中发展，并由皮肤光敏性和肝脏损害表现出来。易感因素包括肝炎，酒精使用，吸烟，铁超载，艾滋病毒，雌激素和遗传性局部缺乏。为什么只有少数具有这些敏感性因素（其中许多相对普遍）的人出现PCT，尚不清楚和其他影响。-最有可能的其他继承差异 - 仍然有待鉴定。 PCT本身会导致肝脏损害，促进其发育的遗传因素可能在其他肝病中起作用，例如丙型肝炎和酒精引起的疾病。我们将基于实验室模型的先前工作以及人类研究有限的新假设，即I阶段和II期酶的多态性（例如细胞色素P450酶（CYPS）（CYPS）和谷胱甘肽转移酶（GST）可能有助于发展PCT。它们的底物和产物可能会影响肝细胞中的氧化应激，并且肝CYP在产生特定的UROD抑制剂中起作用。至少有120名有据可查的PCT和匹配对照的患者将参加一项病例对照研究，并进行详细表型，包括表征已知的敏感性因子。医院控制将以1：1匹配，社区控制2：1与PCT患者。 DNA样品将从患者和对照组中制备，并针对特异性CYP1A1，CYP1A2，CYP2E1，GSTM1和GSTT1多态性进行基因分型，并且与表型相关的结果（例如，PCT的存在或不存在，临床特征，已知的临床特征，已知的敏锐性因素，治疗方法，治疗响应和相关历史）。这些患者的DNA样品和淋巴细胞以及匹配的对照组以及有关临床表型（包括已知敏感性因子）的信息将存储为未来的存储库，用于未来的多中心研究，研究了对PCT发展的额外遗传影响。我们将利用UTMB一般临床研究中心和得克萨斯州墨西哥湾沿岸消化疾病中心的资源。这项研究和随后的项目将使PCT更好地了解PCT，并有助于了解诸如酒精和乙型肝炎等药物在引起人肝病时如何与遗传因素相互作用。