Parkinson's Diseases Susceptibility Genes and Pesticides

帕金森病易感基因和农药

• 批准号: 8220763
• 负责人: Beate R Ritz
• 金额: $ 63.82万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-02-01 至 2015-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8220763
• 关键词: Address; Age; Aging; Agriculture; Air; Alzheimer' s Disease; Behavioral; Boston; Brain Diseases; Caffeine; California; Case-Control Studies; Clinical Trials; Communities; Complex; Computer Simulation; County; DNA; Data; Disease; Disease susceptibility; Enrollment; Environment; Environmental Exposure; Environmental Wind; Exposure to; Farming environment; Funding; Future; Gene Mutation; Genes; Genetic; Genetic Variation; Geographic Information Systems; Grant; HTRA2 gene; Haplotypes; Height; Home environment; Human; Inherited; Interview; Investigation; Knowledge; LRRK2 gene; Laws; Life Style; Maps; Measurement; Medical History; Modeling; Movement Disorders; Names; National Institute of Environmental Health Sciences; Neurologist; Neurons; Occupational; PARK2 gene; PARK6 gene; PARK8 gene; Parkinson Disease; Participant; Patients; Pesticides; Phenotype; Pilot Projects; Population; Population Control; Population Study; Predisposition; Prevention; Public Policy; Quality of life; Recruitment Activity; Registries; Regulation; Reporting; Research; Resources; Risk; Risk Factors; Rural; Sample Size; Sampling; Smoking; Soil; Specialist; Speed; Subgroup; Susceptibility Gene; Testing; Therapeutic; Time; Toxic Environmental Substances; Toxin; UCHL1 gene; Universities; Variant; Vulnerable Populations; Water; Water Pollution; Work; alpha synuclein; base; cost; data sharing; disability; disease diagnosis; disorder risk; gene interaction; genetic variant; improved; innovation; land use; novel; parkin gene/protein; parkinson' s disease registry; pesticide exposure; pesticide interaction; public health relevance; rural area; therapeutic development; tool; toxicant interaction; validation studies

DESCRIPTION (provided by applicant): We propose expanding our existing Parkinson's disease, Environment and Genes (PEG) study population to further investigate the contributions of specific agricultural pesticides alone and in combination with biologically relevant genes that increase susceptibility to Parkinson's disease (PD). With prior funding, we have already enrolled 363 movement disorder specialist-confirmed idiopathic PD patients and, by the end of 2010, have enrolled 910 population controls from a heavily pesticide exposed population in three rural counties of California's Central Valley. All PEG study participants provide a biologic sample, complete a risk factor interview that includes detailed pesticide/farm work exposure assessments, and provide lifetime residential and occupational addresses that are combined with California state mandated commercial pesticide use reports in our sophisticated geographic information system (GIS) computer model to estimate ambient pesticide exposure over time. Our specific aims in this application are (1) Establish the largest case-control study of well characterized incident Parkinson's disease in the US with unprecedented pesticide exposure assessment by recruiting 500 additional movement disorder specialist-confirmed incident cases of PD utilizing the California PD Registry - a unique and time-limited resource for PD research given that the financial situation of the state of California jeopardizes future state funding to continue this effort and the 2,600 patients already identified are aging and progressing rapidly with regard to disease state; (2) Create a novel, comprehensive tool to assess pesticide exposures by incorporating data on wind speed, direction, and atmospheric mixing heights, farm boundaries, and soil composition and groundwater flow; and expand and validate our existing GIS-based computer model of pesticide exposure by incorporating occupational addresses, in addition to residential addresses, to estimate exposure to commercial pesticides and validating our model using Dept of Pesticide Regulation and CA Air Resource Board water and air measurements; and (3) Investigate novel gene-pesticide interactions for recognized PD risk genes (PARK1/PARK4 SNCA, PARK2 parkin, PARK5 UCHL1, PARK6 PINK, PARK8 LRRK2, and PARK13 HTRA2). While the PEG study has provided important and groundbreaking first results on pesticide and pesticide-gene interactions in PD in humans, this application provides the opportunity to increase our sample size and therefore our statistical power to evaluate the impact of less commonly used pesticides, combinations of pesticides, less frequent genetic mutations, and GxE interactions with one of the best pesticide exposure assessment models in a well defined and extensively phenotyped case population. Improving our understanding of environmental toxins, the genetic variation, and their impact on idiopathic PD will improve prevention efforts, advance therapeutic developments, and inform public policy on pesticide regulation. PUBLIC HEALTH RELEVANCE: Parkinson's disease (PD) is, after Alzheimer disease, the second most common brain disorder causing disability and loss of quality of life in more than 1% of all people over age 60 and costing the nation approximately 23 billion US Dollars annually. We do not know the causes of PD but research suggests that there are many, likely occurring over a long period of time, and probably requiring a combination of factors such as environmental exposure to toxins, genetic or hereditary factors, and gene-toxicants interactions during aging. By advancing our understanding of environmental toxins, genetic variation, and their impact on idiopathic PD scientific research can inform public policy on pesticide regulation, improve prevention efforts aimed at eliminating detrimental exposures, and advance therapeutic investigations.

描述（由申请人提供）：我们建议扩大现有的帕金森病、环境和基因 (PEG) 研究群体，以进一步研究特定农业农药单独使用以及与增加帕金森病 (PD) 易感性的生物学相关基因相结合的贡献。通过先前的资助，我们已经招募了 363 名运动障碍专家确诊的特发性帕金森病患者，到 2010 年底，我们已经招募了来自加州中央山谷三个农村县的 910 名来自严重农药暴露人群的对照人群。所有 PEG 研究参与者都提供生物样本，完成风险因素访谈，其中包括详细的农药/农场工作暴露评估，并提供终生居住和职业地址，这些地址与我们复杂的地理信息系统 (GIS) 中加利福尼亚州规定的商业农药使用报告相结合）计算机模型来估计环境农药随时间的暴露情况。我们在此应用中的具体目标是 (1) 通过利用加州帕金森病登记处招募 500 个额外的运动障碍专家确认的帕金森病病例，通过前所未有的农药暴露评估，建立美国最大的帕金森病病例对照研究 -鉴于加利福尼亚州的财政状况危及未来继续开展这项工作的州资金，并且已确定的 2,600 名患者正在老龄化，并且疾病状况正在迅速进展，因此这是 PD 研究的独特且有时限的资源； (2) 创建一种新颖的综合工具，通过纳入风速、风向、大气混合高度、农场边界、土壤成分和地下水流量等数据来评估农药暴露情况；扩展和验证我们现有的基于 GIS 的农药暴露计算机模型，除了住宅地址之外，还纳入职业地址，以估计商业农药的暴露量，并使用农药监管部和加州空气资源委员会的水和空气测量来验证我们的模型； (3) 研究已知的 PD 风险基因（PARK1/PARK4 SNCA、PARK2 parkin、PARK5 UCHL1、PARK6 PINK、PARK8 LRRK2 和 PARK13 HTRA2）的新基因-农药相互作用。虽然 PEG 研究提供了有关人类 PD 中农药和农药基因相互作用的重要且开创性的初步结果，但该应用提供了增加样本量的机会，从而提高了我们评估不常用农药、农药组合的影响的统计能力。农药、较少发生的基因突变以及 GxE 与定义明确且广泛表型的病例群体中最好的农药暴露评估模型之一的相互作用。提高我们对环境毒素、遗传变异及其对特发性帕金森病影响的了解，将改善预防工作，推动治疗发展，并为农药监管公共政策提供信息。 公共健康相关性：帕金森病 (PD) 是仅次于阿尔茨海默病的第二大常见脑部疾病，导致超过 1% 的 60 岁以上人群残疾和生活质量下降，每年给国家造成约 230 亿美元的损失。我们不知道帕金森病的病因，但研究表明，帕金森病的病因有很多，可能会在很长一段时间内发生，并且可能需要多种因素的结合，例如环境毒素暴露、遗传或遗传因素以及基因毒物相互作用。老化。通过加深我们对环境毒素、遗传变异及其对特发性帕金森病的影响的了解，科学研究可以为农药监管的公共政策提供信息，改善旨在消除有害接触的预防工作，并推进治疗研究。