Urate as a Predictor of Parkinson's Disease Risk and Progression

尿酸盐作为帕金森病风险和进展的预测因子

基本信息

批准号：
8244353
负责人：
ALBERTO ASCHERIO
金额：
$ 69.49万
依托单位：
HARVARD SCHOOL OF PUBLIC HEALTH
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-04-15 至 2014-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8244353
关键词：
Affect Age Alcohol consumption Aliquot Anti-Inflammatory Agents Anti-inflammatory Antioxidants Biological Markers Blood Blood specimen Body mass index Caffeine Cells Cessation of life Cheek structure Cholesterol Chronic Clinical Clinical Investigator Code Cohort Analysis Collaborations Consumption DNA Data Data Analyses Databases Development Diagnosis Diet Dietary Factors Disease Progression Drug usage Enrollment Enzymes Epidemiologic Studies Epidemiologist Epidemiology Excretory function Exposure to Female Ferritin Foxes Gender Gene Mutation Genes Genetic Determinism Genetic Markers Genetic Polymorphism Genetic Research Genetic Variation Genome Genomics Genotype Glucose Transporter Haplotypes Health Health Professional High Density Lipoprotein Cholesterol Hormone replacement therapy Human Hypertension Hypoxanthines Individual Intake Investigation LDL Cholesterol Lipoproteins Laboratories Lead Measures Mediating Metabolic Metabolic Pathway Metabolism Mutation Names National Heart, Lung, and Blood Institute National Institute of Neurological Disorders and Stroke Nerve Degeneration Nested Case-Control Study Nurses&apos Health Study Organic Anion Transporters Outcome Oxidative Stress Parkinson Disease Parkinsonian Disorders Participant Pathway interactions Patients Pesticides Pharmaceutical Preparations Physical activity Physiological Plasma Population Study Prevention approach Principal Investigator Progressive Disease Purines Recording of previous events Reporting Research Research Personnel Resources Risk Risk Factors SNCA gene Sampling Screening procedure Serum Single Nucleotide Polymorphism Smoking Symptoms Tail Therapeutic Thiazide Diuretics Tocopherols UCHL1 gene United States National Institutes of Health Urate Uric Acid Vitamins Woman Xanthine Dehydrogenase Xanthines alpha synuclein cancer prevention candidate selection cigarette smoking cohort deprenyl design disorder risk follow-up genome wide association study genome-wide indexing interest leucine-rich repeat kinase 2 men mortality neuroimaging non-genetic novel novel strategies promoter prospective protective effect purine purine metabolism randomized trial research study tau Proteins ubiquitin C-terminal hydrolase urate transporter

项目摘要

DESCRIPTION (provided by principal investigator): Urate, the end product of purine metabolism, at physiological concentrations is an effective antioxidant and may provide a natural defense against the development of Parkinson's disease (PD). In previous studies, healthy individuals with higher blood levels of urate were found to have a reduced risk of developing PD. Further, we found that higher blood urate levels in patients recently diagnosed with PD predict a favorable (slower) rate of disease progression, assessed by both clinical and neuroimaging measures. These studies suggest that urate may serve as a robust predictor of the neurodegeneration that leads to PD and its progression, and, because urate and its metabolic pathways are particularly amenable to pharmacological and dietary manipulations, have a potential therapeutic significance. It remains to be established, however, whether this association reflects a neuroprotective effect of urate or its metabolic precursors, or whether it is explained by a still unidentified common factor/confounder. Further, whereas a strong inverse association between blood urate and both PD risk and progression has been established in men, results in women are uncertain, because few women were included in previous studies. Primary purpose of the proposed investigation is to conduct a systematic and in depth analysis of how blood urate and its determinants, including genetic variations in the urate pathway, affect both PD UriskU and UprogressionU in men and women. The investigation will comprise two main components. One is a nested case-control study including 1,492 incident cases of PD (685 women) and 3,316 matched controls to examine: 1) whether blood levels of urate predict risk of PD independently from known or suspected risk factors for PD and from genetic and non-genetic determinants of uricemia, and 2) whether mutations in genes involved in urate metabolism are associated with blood levels of urate and PD risk. The second is a cohort analysis among participants in two previously conducted large randomized trial in patients with early PD. We will examine: 1) whether the previously reported strong inverse associations between serum urate and PD progression are independent of genetic mutations affecting urate metabolism, and 2) whether these genetic mutations predict blood or CSF levels of urate, or PD progression. The combination of an epidemiological (disease risk) and clinical (disease progression) outcome is a novel aspect of this application, which is made possible by a close collaboration between PD epidemiologists and clinical investigators. PUBLIC HEALTH RELEVANCE We propose to examine whether blood levels of urate (uric acid) and genetic mutations that affects the formation of urate or its excretion predict the risk of developing Parkinson's disease or the progression of symptoms among patients with Parkinson's disease. Parkinson's disease is a chronic progressive disease for which there is no cure. Preliminary results suggest that blood urate could exert a protective effect. Because blood levels of urate can be modified with existing drugs, the proposed project could lead to novel approaches to the prevention and treatment of Parkinson's disease.

描述（由主要研究者提供）：尿酸盐，嘌呤代谢的最终产物，以生理浓度是一种有效的抗氧化剂，可以自然防御帕金森氏病（PD）的发展。在先前的研究中，发现尿酸血液水平较高的健康个体患有PD的风险降低。此外，我们发现，最近被诊断为PD的患者的血液水平较高，可以预测通过临床和神经成像措施评估的疾病进展率（较慢）。这些研究表明，尿酸盐可以作为导致PD及其进展的神经变性的强大预测指标，并且由于尿酸盐及其代谢途径特别适合药理和饮食操纵，因此具有潜在的治疗意义。但是，该关联是否反映了尿酸盐的神经保护作用或其代谢前体，还是由仍然未识别的共同因素/混杂因素来解释，这尚待确定。此外，尽管在男性中已经建立了血液与PD风险和进展之间的牢固的反相关性，但女性的结果却尚不确定，因为以前的研究中很少有女性。拟议的研究的主要目的是对血液尿酸盐及其决定因素（包括尿酸途径的遗传变异）如何影响男性和女性的PD Urisku和Uprogessionu，对血液尿酸盐及其决定因素（包括遗传变异）进行深入分析。调查将包括两个主要组成部分。一个是一项嵌套的病例对照研究，其中包括1,492例PD事件（685名女性）和3,316个匹配的对照，以检查：1）尿酸盐血液水平是否可以独立于PD的PD风险，从已知或怀疑的PD危险因素中，对尿素和尿液中的遗传和非遗传性决定因素和非遗传性的遗传和非遗传确定性以及毒液中的毒素含量是否相关。第二个是对早期PD患者的两名先前进行大型随机试验的参与者的队列分析。我们将检查：1）先前报道的血清尿酸盐和PD进展之间的强逆相关是否独立于影响尿酸代谢的遗传突变，以及2）这些遗传突变是否预测了尿酸盐的血液或CSF水平或PD进展。流行病学（疾病风险）和临床（疾病进展）结果的结合是该应用的一个新方面，PD流行病学家与临床研究者之间的紧密合作使其成为可能。我们建议的公共卫生相关性旨在检查尿酸的血液水平（尿酸）和影响尿酸盐形成或其排泄物的基因突变是否会预测患帕金森氏病的风险或帕金森氏病患者中症状的进展。帕金森氏病是一种无法治愈的慢性进行性疾病。初步结果表明，血尿酸可能发挥保护作用。由于可以用现有药物来改变尿酸盐的血液水平，因此拟议的项目可能会导致预防和治疗帕金森氏病的新方法。