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

描述(申请人提供)：帕金森病(PD)是一种衰弱的神经退行性疾病，其特征是黑质中多巴胺能神经元的进行性死亡，越来越多的人认识到帕金森病的病因是复杂的多因素。维生素D主要是在阳光照射下在体内产生的，它影响着许多生物过程，并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被研究。来自许多实验室研究的证据表明，维生素D在毒素诱导的帕金森病和遗传模型中起到了神经保护剂的作用，而对人类的研究表明，帕金森病发病率存在南北梯度的地理差异。然而，阳光暴露不足导致维生素D产生不足是否与帕金森病有关，到目前为止，还没有在人类人群中进行充分的研究。这项拟议研究的目标是产生初步数据，调查散发性帕金森病潜在的新发病机制；具体地说，我们将检验长期低水平的维生素D暴露或影响生理维生素D水平的代谢基因变化会增加帕金森病风险的假说。我们将利用加州大学洛杉矶分校我们的团队在过去十年中创造的独特的现有资源，在NIEHS资助的帕金森环境基因(PEG)研究中(368例，401人口对照)。在聚乙二醇组的研究中，我们有1)一个复杂和有效的紫外线暴露的地理信息系统模型，我们将把它应用于聚乙二醇组受试者的居住史，以产生累积寿命和年平均紫外线辐射暴露的个人估计，以及2)储存的DNA样本，我们将用它来评估维生素D途径基因的多态和单倍型模式。我们将使用多变量Logistic回归模型检验长期紫外线暴露措施与帕金森病的相关性，这些模型对潜在的混杂因素进行了调整，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。类似地，我们将研究可能导致维生素D途径关键基因(VDR、GC、CYP27A1、CYP27B1和CYP24A1)中不同生理维生素D活性的基因变异是否会增加帕金森病的风险。我们还将初步调查基因-基因和基因-环境的相互作用，以评估阳光照射和循环维生素D代谢产物水平对帕金森病的估计影响是否被上述基因的变异所改变，以及所选基因是否相互作用，以增加或降低帕金森病的风险。因此，这项拟议的研究将探索帕金森病病因学的新机制，并产生试点数据--如果成功的话--我们计划在更大的丹麦样本(4000例病例和对照)中复制，其日照暴露比聚乙二醇加州中部人口相对较少。公共卫生相关性：帕金森氏病(PD)是一种衰弱的神经退行性疾病，每年在美国约有55,000名成年人受到影响。环境因素、人类遗传变异和基因-环境相互作用可能是导致帕金森病的原因。我们将探索一种新的假设，即长期低水平的维生素D，无论是由于阳光暴露不足，还是影响维生素D水平的基因改变，都会增加帕金森病的风险。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。

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.