MOLECULAR EPIDEMIOLOGY OF PARKINSON'S DISEASE

帕金森病的分子流行病学

基本信息

批准号：
6607657
负责人：
DEMETRIUS MICHAEL MARAGANORE
金额：
$ 84.04万
依托单位：
MAYO CLINIC ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2000
资助国家：
美国
起止时间：
2000-09-30 至 2005-06-30
项目状态：
已结题

项目摘要

Parkinson's disease (PD) is a common and disabling condition in the expanding elderly population of the US and worldwide. Its etiology remains unknown and both genetic and environmental factors have been suspected. The long-term goal of the proposed studies is to clarify the etiology of PD and to identify means to prevent it. Specifically, we will study the association of PD with susceptibility genes previously found associated with novelty seeking behavior, substance use (tobacco, alcohol, and caffeine), and anxiety and depressive disorders. The hypotheses tested derive directly from our current work and preliminary findings. We will employ the case-unaffected sibling control study design and analyses will use a generalization of the sibling transmission disequilibrium test, or S-TDT. In total, nine candidate susceptibility genes will be considered, of which only five have undergone limited study for PD. The candidate susceptibility genes include three detoxification genes, three dopaminergic genes, and three serotonergic genes. We will include 800 cases of PD referred to the Mayo Clinic from a 120-mile radius or from a 5-state region during approximately a 10- year period. We will also include their eligible siblings age 40 years or above, projecting that blood DNA samples will be available for 563 affected probands or siblings and 1,180 unaffected siblings stratified in 521 informative sibships. Sibships with multiple affected or unaffected siblings will be included. PD cases will undergo a clinical assessment and blood sampling, and provide family information through a face-to-face interview followed by a written mail-in form. All living siblings ages 40 and above will be screened for PD using a validated telephone instrument. Subjects screening negative for PD will provide DNA with mail-in blood sampling kits only. Persons screening positive will be clinically assessed at the Mayo Clinic or at home, and blood DNA samples will be directly obtained. Genotyping will be performed using polymerase chain reaction methods and will be blinded to affected or unaffected status. The study will avoid population stratification bias by using sibling controls. The candidate susceptibility genes selected for primary analyses relate to personality traits, substance use, and psychiatric diseases that we have found associated with PD. The selection of these genes represents a major paradigm shift. We will also establish a large DNA bank for rapid and efficient testing of new genetic hypothesis for PD. This application is submitted in response to RFA ES- 00-002 ('The Role of the Environment in Parkinson's Disease"). We specifically address the RFA's objectives of evaluating endogenous (including biomarkers) and exogenous (including dietary and lifestyle) susceptibility factors for PD using molecular epidemiology tools.

帕金森病 (PD) 是美国和全球不断增长的老年人口中的一种常见致残性疾病。其病因仍不清楚，并且怀疑遗传和环境因素。拟议研究的长期目标是阐明帕金森病的病因并确定预防方法。具体来说，我们将研究帕金森病与先前发现的与寻求新奇行为、物质使用（烟草、酒精和咖啡因）以及焦虑和抑郁症相关的易感基因的关联。测试的假设直接来自我们当前的工作和初步发现。我们将采用未受影响的兄弟姐妹对照研究设计，并使用兄弟姐妹传递不平衡检验（S-TDT）的推广进行分析。总共将考虑 9 个候选易感基因，其中只有 5 个经过了有限的 PD 研究。候选易感基因包括三个解毒基因、三个多巴胺能基因和三个血清素能基因。我们将纳入大约 10 年内从 120 英里半径或 5 个州地区转诊至 Mayo Clinic 的 800 例 PD 病例。我们还将包括他们年龄在 40 岁或以上的符合条件的兄弟姐妹，预计将提供 563 名受影响的先证者或兄弟姐妹以及 1,180 名未受影响的兄弟姐妹的血液 DNA 样本，这些兄弟姐妹分层在 521 个信息丰富的同胞中。具有多个受影响或未受影响的兄弟姐妹的兄弟姐妹将包括在内。 PD 病例将接受临床评估和血液采样，并通过面对面访谈和书面邮寄表格提供家庭信息。所有年龄在 40 岁及以上的在世兄弟姐妹都将使用经过验证的电话仪器进行 PD 筛查。 PD 筛查呈阴性的受试者将仅通过邮寄血液采样套件提供 DNA。筛查呈阳性的人员将在梅奥诊所或家中接受临床评估，并直接获取血液 DNA 样本。基因分型将使用聚合酶链反应方法进行，并且对受影响或未受影响的状态不知情。该研究将通过使用兄弟姐妹对照来避免群体分层偏差。选择用于初步分析的候选易感性基因与我们发现与 PD 相关的人格特征、物质使用和精神疾病有关。这些基因的选择代表了重大的范式转变。我们还将建立一个大型 DNA 库，用于快速有效地测试 PD 的新遗传假说。本申请是为了响应 RFA ES-00-002（“环境在帕金森病中的作用”）而提交的。我们特别针对 RFA 评估内源性（包括生物标志物）和外源性（包括饮食和生活方式）易感性因素的目标PD 使用分子流行病学工具。