GENE-METAL INTERACTIONS AND PARKINSON'S DISEASE

帕金森氏病（PD）是一种病因不明的相对常见的、使人衰弱的神经退行性疾病。最近对双胞胎PD一致性的研究表明，50岁以后发生的PD（约占PD的90%）在很大程度上要么是环境病因，要么是尚未发现的基因-环境相互作用的结果。暴露于金属，特别是铅，已经与PD的发展在一些但高度启发性的研究。这个主题还没有使用最先进的生物标记技术来测量金属暴露和积累进行流行病学研究。此外，有理由相信基因-金属相互作用可能会大大增加帕金森病的风险。特别是，一些证据表明，铅暴露增加与铁代谢改变相互作用导致帕金森病。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有关。在此应用中，我们的研究团队将利用描述良好，积极性高，地理位置方便的PD患者和潜在对照人群，最先进的测量金属暴露生物标志物的方法，聚合酶链反应（PCR）测定，农药暴露评估，以及经验丰富的调查团队来进行新的病例对照研究。在这项研究中，我们将评估年龄在50岁至50岁之间的PD患者以及与年龄、性别、种族和地理区域相匹配的对照组。我们将检验几个假设，其中主要的两个假设是：(1)在病例和对照中，骨骼中较高的铅水平与PD病例的较高几率相关；(2)至少有一个拷贝C282Y或H63d血色素沉着症（HFE）基因突变的个体，骨铅的影响最大。我们还将探讨与PD与脚趾甲中锰和铜水平以及农药暴露相关的几个辅助假设，通过自我报告的病史和将工作史与工作暴露矩阵联系起来进行评估。

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.