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）：帕金森病（PD）是一种使人衰弱的神经退行性疾病，其特征是黑质中多巴胺能神经元进行性死亡，人们越来越认识到其具有复杂的多因素病因。维生素 D 主要是在阳光照射下在体内产生的，它会影响许多生物过程，并且已对其在多发性硬化症（作为免疫调节剂）和某些癌症（作为抗肿瘤药物）等疾病中的潜在作用进行了研究。氧化剂）。多项实验室研究的证据表明，维生素 D 在毒素诱导的 PD 模型和遗传模型中发挥着神经保护剂的作用，对人类的研究表明，PD 发生率存在南北梯度的地理差异。然而，迄今为止，尚未在人群中充分研究阳光照射不足导致维生素 D 生成不足是否与 PD 相关。拟议研究的目标是生成试点数据，调查散发性帕金森病发病机制的潜在新机制；具体来说，我们将检验以下假设：由于阳光照射不足或影响生理维生素 D 水平的代谢基因改变而导致维生素 D 水平长期偏低，会增加患 PD 的风险。我们将利用我们在加州大学洛杉矶分校的团队在过去十年中在 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 个病例，401 个群体对照）。在 PEG 研究中，我们可以 1) 访问复杂且经过验证的紫外线暴露 GIS 模型，我们将将该模型应用于 PEG 受试者的居住历史，以生成累积寿命和平均每年紫外线辐射暴露的个人估计值，以及 2) 存储的 DNA 样本我们将用它来评估维生素 D 途径基因的多态性和单倍型模式。我们将使用多变量逻辑回归模型来测试长期紫外线暴露测量与帕金森病之间的关联，并根据年龄、种族、性别、教育程度、吸烟、维生素 D 膳食来源、皮肤色素沉着和农药暴露等潜在混杂因素进行调整。同样，我们将检查对维生素 D 途径至关重要的基因（VDR、GC、CYP27A1、CYP27B1 和 CYP24A1）中可能导致不同生理维生素 D 活性的遗传变异是否会增加 PD 风险。我们还将初步研究基因-基因和基因-环境相互作用，以评估阳光照射的估计影响以及循环维生素 D 代谢水平对帕金森病的影响是否会因上述基因的变异而改变，以及所选基因是否与每个基因相互作用其他增加或减少帕金森病风险的措施。因此，拟议的研究将探索 PD 病因学中的一种新机制，并生成试点数据，如果成功，我们计划在更大的丹麦样本（4000 例病例和对照）中进行复制，且与 PEG 中部加州人群相比，阳光照射相对较少。公共健康相关性：帕金森病 (PD) 是一种使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、人类遗传变异以及基因与环境的相互作用可能导致帕金森病。我们将探索一个新的假设，即由于阳光照射不足或影响维生素 D 水平的基因改变而导致长期低水平的维生素 D 会增加患 PD 的风险。如果成功，这项研究可能会对未来帕金森病预防的建议产生重要影响。