GENE-METAL INTERACTIONS AND PARKINSON'S DISEASE

帕金森氏病（PD）是一种相对常见的，使人衰弱的神经退行性疾病，病因不明。最近对双胞胎中PD一致性的研究表明，50岁以后经历的PD（即，> 90%的PD）在病因学上很大程度上必须是环境因素，或者是尚未发现的基因与环境相互作用的结果。在少数但高度提示性的研究中，暴露于金属，特别是铅，与PD的发生相关。尚未使用最先进的生物标记技术对这一主题进行流行病学研究，以测量金属接触和积累。此外，有理由相信基因-金属相互作用可能会大大增加PD的风险。特别是，一些证据表明，增加铅暴露与铁代谢的改变相互作用，导致PD。鉴于铁代谢在很大程度上依赖于遗传因素，改变铁代谢的突变可能与PD相关。在本申请中，我们的研究团队将利用充分描述的、高度积极的和地理上方便的PD患者和潜在对照人群、用于测量金属暴露的生物标志物的最先进方法、聚合酶链反应（PCR）测定、农药暴露评估以及经验丰富的研究者团队来进行新的病例对照研究。在这项研究中，我们将评估年龄> 50岁的PD患者以及按年龄、性别、种族和地理区域匹配的对照组。我们将检验几个假设，其中主要的两个假设是：（1）在病例和对照组中，骨铅水平较高与PD病例的可能性较高相关;（2）骨铅的影响在至少有一个C282 Y或H63 d血色素沉着症（HFE）基因突变的个体中最高。我们还将探讨几个附属的假设有关的关系PD的锰和铜的水平在脚趾甲和农药暴露，评估自我报告的历史和工作历史与工作暴露矩阵。

Parkinson's disease (PD) is a relatively common, debilitating neurodegenerative disorder of uncertain etiology. Recent studies of PD concordance in twins indicate that PD experienced after the age of 50 years (i.e., > 90 % of PD) must be either largely environmental in etiology, or the result of still undiscovered gene-environment interactions. Exposure to metals, particularly lead, has been associated with the development of PD in a few but highly-suggestive studies. This topic has not yet been studied epidemiologically using state-of-the-art biological marker techniques for measuring metals exposure and accumulation. In addition, there is reason to believe that gene-metal interactions may greatly increase the risk of PD. In particular, some evidence suggests that increased exposure to lead interacts with the altered iron metabolism cause PD. Given that iron metabolism is dependent to as large degree on genetic factors, mutations that alter iron metabolism may be associated with PD. In this application, our research team will take advantage of well- described, highly motivated and geographically convenient populations of PD patients and potential controls, state-of-the-art methods for measuring biological markers of metals exposure, polymerase chain reaction (PCR) assays, assessment of pesticide exposure, and a highly- experienced team of investigators to conduct a new case control study. In this study, we will evaluate PD patients > 50 years old as well as controls matched by age, gender, ethnicity, and geographic region. We will test several hypothesis, the main two of which will be that (1) among the cases and controls, higher levels of lead in bone are associated with a higher odds of being a PD cases; and (2) the effect of bone lead will be highest in individuals with at least one copy of the C282Y or H63d hemochromatosis (HFE) gene mutation. We will also explore several subsidiary hypothesis related to the relationship of PD to levels of manganese and copper in toenails and to pesticide exposures, assessed by self-reported history and by linking job histories with a job- exposure matrix.