Environmental Epidemiology of Essential Tremor

描述（由申请人提供）：特发性震颤（ET）是人类最常见的震颤原因，但其病因尚不清楚。环境毒物可能是其病因之一。这些因素被认为在其他神经退行性疾病中发挥重要作用，但它们在ET中的作用受到的关注较少。在过去的4年（2000-2004年）中，我们研究了251例ET病例和300例对照中的3种推定毒物：铅、-碳碱生物碱（bca；有害生物碱和有害生物碱）和有机氯农药（ocr）。Harmane和hammine是主要关注的神经毒素，因为ET的唯一实验模型涉及对实验动物施用bca。我们的数据表明，血液中有害生物碱和有害生物碱的浓度与ET风险增加密切相关。我们在未来4年的首要目标是推进我们对bca的研究。我们计划将样本扩大到900名受试者（450例ET病例和450例匹配对照）。这个建议的样本量比其他病例对照研究（每组使用10-15个受试者）的样本量要大得多，并且将提供一个独特的机会来检验我们的假设。在目的1中，我们将探讨高血BCA浓度的机制（在病例或对照中）。较高的血BCA浓度是否与BCA代谢能力的遗传差异有关（即参与BCA代谢的基因多态性，CYP1A2和n -乙酰转移酶2，Aim 1A）？用肉类问卷（Aim 1B）评估较高的血液有害物质浓度是否由于当前饮食暴露较多？遗传和饮食因素是否相互作用影响血液中有害物质的浓度（Aim 1C）？在Aim 2中，我们将进一步探讨疾病状态（ET与对照组）与这些遗传和饮食因素之间的关系。ET的风险最终与这些遗传因素（Aim 2A）、饮食因素（Aim 2B）或这些因素的相互作用（Aim 2C）有关吗？我们假设饮食暴露和遗传多态性将与血液BCA浓度和疾病状态相关。在ET的病因学中，环境/毒性因素可能是该病在人群中发病率的重要原因。识别和了解这些有毒物质是预防这种只有有限治疗选择的疾病的第一步。

DESCRIPTION (provided by applicant): Essential tremor (ET) is the most common cause of tremor in humans yet its etiology remains unclear. Environmental toxicants may contribute to its etiology. Such factors are thought to play an important role in other neurodegenerative diseases, but their role in ET has received less attention. During the last 4 years (2000-2004), we studied 3 putative toxicants: lead, beta carboline alkaloids (BCAs; harmane and harmine) and organochlorine pesticides (OCRs) in 251 ET cases and 300 controls. Harmane and harmine were the neurotoxins of primary interest because the only experimental model for ET involves the administration of BCAs to laboratory animals. Our data indicates that blood concentrations of harmane and harmine are strongly associated with an increased risk of ET. Our overarching aim over the next 4 years is to carry our study of the BCAs forward. We plan to expand our sample to 900 subjects (450 ET cases and 450 matched controls). This proposed sample size is much larger than that used in other case-control studies (which have used 10-15 subjects in each group), and will provide a unique opportunity to test our hypotheses. In Aim 1, we will explore the mechanisms (in either cases or controls) that underlie a higher blood BCA concentration. Are higher blood BCA concentrations associated with genetic differences in ability to metabolize BCAs (i.e., polymorphisms in genes that are involved in BCA metabolism, CYP1A2 and N-acetyltransferase 2, Aim 1A)? Are higher blood harmane concentrations due to greater current dietary exposure, assessed with a meat questionnaire (Aim 1B)? Do genetic and dietary factors interact in their influences on blood harmane concentrations (Aim 1C)? In Aim 2, we will further explore the association between disease status (ET vs. controls) and these genetic and dietary factors. Is the risk of ET ultimately associated with these genetic factors (Aim 2A), dietary factors (Aim 2B), or the interaction of these factors (Aim 2C)? We hypothesize that dietary exposure and genetic polymorphisms will be associated both with blood BCA concentrations and with disease status. An environmental/toxic component to the etiology of ET may account for a significant proportion of the incidence of this disease in the population. Identification and understanding these toxicants is the first step in preventing a disease with only limited treatment options.