Hereditary Hemochromatosis and Telomere Length

描述（由申请人提供）：遗传性血色素沉着症是一种铁代谢紊乱，导致铁超载，并可发展为致命的并发症，如终末期肝功能衰竭、原发性肝细胞癌和充血性心力衰竭。基因突变已被确定与血色素沉着症相关，尽管许多具有这些突变的个体并未表现出血色素沉着症的迹象。因此，确定与这些基因相互作用的与血色素沉着病结果相关的因素是很重要的。端粒长度是表征生物衰老的一种新型生物标志物。目前尚不清楚血色素沉着症基因和铁超载如何与端粒长度相关。本研究的目的是：1)确定白细胞端粒长度与血色素沉着病相关结局的关系；2)检验端粒长度与血色素沉着病基因型和表型指标的关系；3)分析生活方式和临床护理对端粒长度和血色素沉着病结局的影响。我们建议对血色素沉着症和铁超载筛查（继承人）研究公共使用数据集进行分析。我们将对存储样本的端粒长度进行新的分析，并将其与本研究的其他现有数据合并。在这个为期两年的项目中，我们将研究治疗和生活方式变量对这些个体端粒长度和血色素沉着病相关结果的影响，以了解哪些变量对衰老和发病风险起缓冲作用。我们将研究继承人研究综合临床检查中包括的4组，这将使我们能够检查血色素沉着病基因型和铁超载表型表达的影响。第一组将是HFE基因阳性且铁升高（血清铁蛋白（SF）升高和转移饱和度（TS）升高）表型阳性的个体。第二组是HFE基因阴性且表型阳性的个体。第三组是HFE基因阳性且铁升高表型阴性的个体。最后一组将是HFE基因阴性和高铁表型阴性的个体。研究对象总数为1157人。虽然HH患者发生各种临床疾病的风险增加，但尚不清楚HH是否与白细胞端粒长度相关，以及某些治疗和生活方式活动是否可以缓冲这种关系。这项研究的创新之处在于，累积应激和疾病的遗传易感性都表现在端粒长度上。本研究将通过研究可能加速或减缓生物衰老过程和相应疾病发展的因素，扩展先前对血色素沉着症和铁超载患者加速衰老和发病率的认识。该项目对使用表型标记进行早期检测和筛查以及依从性治疗和健康生活方式具有潜在意义。

DESCRIPTION (provided by applicant): Hereditary hemochromatosis is a disorder of iron metabolism that leads to iron overload and can progress to fatal complications such as terminal hepatic failure, primary hepatocellular carcinoma, and congestive heart failure. Gene mutations have been identified that are associated with hemochromatosis, although many individuals with these mutations do not display signs of hemochromatosis. Therefore, it is important to determine factors interacting with these genes that are associated with hemochromatosis outcomes. Telomere length is a novel biomarker that represents biological aging. It is unclear how hemochromatosis genes and iron overload relates to telomere length. The aims of the study are to 1) Determine the relationship between leukocyte telomere length and hemochromatosis related outcomes, 2) Examine the relationship between telomere length and genotype and phenotype indicators for hemochromatosis, and 3) Analyze the impact of lifestyle and clinical care on telomere length and hemochromatosis outcomes. We propose to conduct an analysis of the Hemochromatosis and Iron Overload Screening (HEIRS) Study public use data set. We will conduct new analyses of telomere length from stored samples and merge that with other existing data from this study. During this two-year project, we will examine the impact of treatment and lifestyle variables on telomere length and hemochromatosis related outcomes among these individuals to see which variables act as buffers to aging and morbidity risk. We will study 4 groups included in the HEIRS Study Comprehensive Clinical Exam which will allow us to examine both the impact of hemochromatosis genotype and phenotypic expression of iron overload. The first group will be individuals who are HFE gene positive and are phenotype positive for elevated iron (elevated serum ferritin (SF) and elevated transferring saturation (TS)). The second group will be individuals who are HFE gene negative and are phenotype positive. The third group will be individuals who are HFE gene positive and are phenotype negative for elevated iron. The final group will be individuals who are HFE gene negative and are phenotype negative for elevated iron. The total number of subjects to be studied will be 1,157. Although there is an increased risk of development of a variety of clinical conditions in patients with HH, it is not known whether HH is associated with leukocyte telomere length and whether certain treatment and lifestyle activities can buffer the relationship. This study is innovative in that the cumulative stress and heritable predispositions for disease are represented in telomere length. This study will extend previous knowledge of accelerated aging and morbidity among individuals with hemochromatosis and iron overload by examining factors that may accelerate or slow the biological aging process and corresponding development of disease. This project has potential implications for early detection and screening using phenotypic markers as well as compliance with treatment and a healthy lifestyle.