Sunlight Exposure & Vitamin D Metabolic Gene Variations in Parkinson's Disease

阳光照射

• 批准号: 7740121
• 负责人: Beate R Ritz
• 金额: $ 7.7万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7740121
• 关键词: Adult; Affect; Affinity; Age; Antioxidants; Binding; Biological; Biological Process; Blood Circulation; Brain; California; Candidate Disease Gene; Carrier Proteins; Case-Control Studies; Cessation of life; Colon; Complex; DNA; Data; Denmark; Disease; Education; Environment; Environmental Risk Factor; Enzymes; Etiology; Exposure to; Funding; Future; GC gene; Gender; Genes; Genetic Models; Genetic Polymorphism; Genetic Variation; Genotype; Geographic Information Systems; Goals; Haplotypes; Human; Human Genetics; Hypothalamic structure; Immune; Individual; Laboratory Study; Logistic Regressions; Malignant Neoplasms; Measures; Metabolic; Metabolism; Mixed Function Oxygenases; Modeling; Motivation; Multiple Sclerosis; Nerve Degeneration; Neurodegenerative Disorders; Neuroprotective Agents; Oxidative Stress; Parkinson Disease; Pathogenesis; Pathway interactions; Pattern; Physiological; Population; Population Control; Production; Prostate; Protein Binding; Race; Receptor Gene; Recommendation; Recording of previous events; Research; Resources; Risk; Role; Sampling; Skin Pigmentation; Smoking; Source; Substantia nigra structure; Sun Exposure; System; Testing; Toxin; UV Radiation Exposure; United States; Variant; Vitamin D; Vitamin D-Binding Protein; Vitamin D3 Receptor; base; case control; disorder prevention; disorder risk; dopaminergic neuron; gene environment interaction; geographic difference; malignant breast neoplasm; neuron loss; novel; pesticide exposure; public health relevance; response

DESCRIPTION (provided by applicant): Parkinson's disease (PD), a debilitating neurodegenerative disorder characterized by the progressive death of dopaminergic neurons in the substantia nigra, is increasingly recognized as having a complex multi-factorial etiology. Vitamin D, which is produced in the body principally in response to sunlight exposure, influences numerous biological processes, and has been investigated for its potential role in diseases such as multiple sclerosis (as an immune modulator), and some cancers (as an anti-oxidant). Evidence from a number of laboratory studies demonstrates that vitamin D acts as a neuroprotective agent in toxin-induced and genetic models of PD, and studies in humans suggest geographic differences in PD rates exist with north-south gradients. Whether inadequate sunlight exposure leading to deficient production of vitamin D is associated with PD, however, has not been adequately investigated to date in human populations. The goal of the proposed research is to generate pilot data investigating a potential novel mechanism of pathogenesis for sporadic PD; specifically, we will examine the hypothesis that long-term low levels of vitamin D either through inadequate sunlight exposure or alterations in metabolic genes that influence physiological vitamin D levels increase the risk of PD. We will utilize the unique existing resource created by our group at UCLA over the past decade in the NIEHS-funded Parkinson Environment Gene (PEG) study (368 cases, 401 population controls). In the PEG study, we have 1) access to a sophisticated and validated GIS model of UV exposure which we will apply to residential history of PEG subjects to generate individual estimates of cumulative lifetime and average annual UV radiation exposure, and 2) stored DNA samples with which we will assess polymorphisms and haplotype patterns in vitamin D pathway genes. We will test associations between long- term UV exposure measures and PD using multivariable logistic regression models adjusted for potential confounding factors such as age, race, gender, education, smoking, dietary sources of vitamin D, skin pigmentation and pesticide exposure. Similarly, we will examine whether genetic variations presumed to result in different physiological vitamin D activity in genes critical to the vitamin D pathway (VDR, GC, CYP27A1, CYP27B1 and CYP24A1) increase the risk of PD. We will also preliminarily investigate gene-gene and gene- environment interactions to assess whether the estimated effects of sunlight exposure and hence circulating vitamin D metabolite levels on PD are modified by variants in the above genes, as well as whether the selected genes interact with each other to increase or decrease PD risk. The proposed research will thus explore a novel mechanism in the etiology of PD and generate pilot data that - if successful - we plan to replicate in a larger Danish sample (4000 cases and controls) with comparatively less sun exposure than the PEG Central California population. PUBLIC HEALTH RELEVANCE: Parkinson's disease (PD) is a debilitating neurodegenerative disorder that affects approximately 55,000 adults in the US each year. Environmental factors, human genetic variation, and gene-environment interactions likely contribute to PD. We will explore a novel hypothesis that long-term low levels of vitamin D either through inadequate sunlight exposure or alterations in genes that influence vitamin D levels increase the risk of PD. If successful, this research could have important implications for future recommendations in PD prevention.

描述（由申请人提供）：帕金森氏病（PD）是一种衰弱的神经退行性疾病，其特征在于，以多巴胺能神经元在Nigra中进行性死亡，越来越多地被认为具有复杂的多因素病因。维生素D主要是为了响应阳光暴露而在体内产生的，它影响了许多生物学过程，并已因其在多发性硬化症（作为免疫调节剂）和一些癌症（作为抗氧化剂）等疾病中的潜在作用而进行了研究。许多实验室研究的证据表明，维生素D在毒素诱导的PD和遗传模型中充当神经保护剂，对人类的研究表明，南北梯度的PD速率上存在地理差异。然而，迄今为止，在人类种群中，尚未对阳光暴露不足导致维生素D不足与PD产生不足有关。拟议的研究的目的是生成试验数据，研究零星PD的潜在新型发病机理。具体而言，我们将研究以下假设：长期低水平的维生素D要么通过阳光不足或影响生理维生素D水平的代谢基因的改变会增加PD的风险。在过去十年中，我们将利用我们小组在NIEHS资助的帕金森环境基因（PEG）研究中创建的独特现有资源（368例，401个人口控制）。在PEG研究中，我们有1）获得了复杂且经过验证的紫外线暴露模型，我们将适用于PEG受试者的住宅历史，以产生累积的寿命和平均年度UV辐射暴露的个别估计，以及2）储存的DNA样品，我们将通过这些样本进行多态性和单型型模式在vitamin d path中的基因。我们将使用多变量的逻辑回归模型在长期的紫外线暴露措施和PD之间进行关联，并针对潜在的混杂因素进行调整，例如年龄，种族，性别，教育，吸烟，维生素D的饮食来源，皮肤色素沉着和农药暴露。同样，我们将研究是否假定遗传变异会导致对维生素D途径至关重要的基因（VDR，GC，CYP27A1，CYP27A1，CYP27B1和CYP24A1）的不同生理维生素D活性增加了PD的风险。我们还将初步研究基因基因和基因环境相互作用，以评估阳光暴露的估计影响以及循环维生素D代谢物水平是否通过上述基因中的变体来改变PD，以及所选基因是否相互作用相互作用以增加或降低PD风险。因此，拟议的研究将探索PD病因的新型机制，并生成试验数据，如果成功的话，我们计划在较大的丹麦样本（4000例病例和对照组）中复制，而太阳暴露的阳光比PEG Central California人群较少。公共卫生相关性：帕金森氏病（PD）是一种令人衰弱的神经退行性疾病，每年影响美国约55,000名成年人。环境因素，人遗传变异和基因环境相互作用可能导致PD。我们将探讨一个新的假设，即长期通过阳光暴露不足或影响维生素D水平的基因改变的长期维生素D会增加PD的风险。如果成功，这项研究可能对预防PD的未来建议具有重要意义。