Genetic Susceptibility Factors in Porphyria Cutanea Tarda (PCT)

描述（由申请人提供）：迟发性皮肤卟啉症（PCT）是由于一种特定的肝酶，尿卟啉原脱羧酶（UROD）的抑制，导致肝脏中显著的卟啉积累。该病发生在某些易受环境和遗传易感性因素影响的个体中，表现为皮肤光敏性和肝损伤。易感因素包括丙型肝炎、饮酒、吸烟、铁超载、艾滋病毒、雌激素和遗传性部分缺乏症。为什么PCT只在少数具有这些易感因素的个体中发展，其中许多是相对常见的，尚不清楚，以及其他影响。-很可能是额外的遗传差异-仍有待确定。PCT本身会导致肝损伤，促进其发展的遗传因素可能在其他肝脏疾病中发挥作用，例如由丙型肝炎和酒精引起的疾病。基于实验室模型和有限的人类研究，我们将研究一种新的假设，即I期和II期酶(如细胞色素P450酶（CYPs）和谷胱甘肽转移酶（GSTs）的多态性可能有助于PCT的发展，它们的底物和产物可能影响肝细胞的氧化应激，肝脏CYPs在产生特异性UROD抑制剂中发挥作用。至少120例有充分记录的PCT患者和匹配的对照将参加病例对照研究，并详细分型，包括已知易感因素的表征。医院对照与PCT患者的比例为1:1，社区对照为2:1。将从患者和对照组中制备DNA样本，并对特定的CYP1A1、CYP1A2、CYP2E1、GSTM1和GSTT1多态性进行基因分型，并分析结果与表型（例如是否存在PCT、临床特征、已知易感因素、治疗反应和复发史）的相关性。我们将利用UTMB综合临床研究中心和德克萨斯海湾沿岸消化疾病中心的资源，将这些患者和匹配对照的DNA样本和淋巴细胞以及有关临床表型（包括已知易感因素）的信息存储为未来多中心研究其他遗传影响PCT发展的信息库。这项研究和随后的项目将有助于更好地了解PCT，并有助于了解酒精和丙型肝炎等病原体如何与遗传因素相互作用，从而导致人类肝脏疾病。

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.