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

描述（由申请人提供）：帕金森病（PD）是一种以黑质多巴胺能神经元进行性死亡为特征的衰弱性神经退行性疾病，越来越多的人认为其具有复杂的多因素病因。维生素D主要是人体在阳光照射下产生的，影响许多生物过程，并已被研究其在多发性硬化症（作为免疫调节剂）和某些癌症（作为抗氧化剂）等疾病中的潜在作用。来自许多实验室研究的证据表明，维生素D在毒素诱导的和遗传的帕金森病模型中起神经保护剂的作用，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，日光照射不足导致维生素D生成不足是否与帕金森病有关，迄今尚未在人群中进行充分调查。提出的研究目标是产生试点数据，调查散发性帕金森病的潜在新机制；具体来说，我们将检验长期维生素D水平低的假设，无论是由于阳光照射不足，还是由于影响生理维生素D水平的代谢基因的改变，都会增加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）研究中创造的独特现有资源（368例，401例人口对照）。在PEG研究中，我们有1)获得一个复杂且经过验证的紫外线暴露GIS模型，我们将将其应用于PEG受试者的居住历史，以产生累积寿命和平均年紫外线辐射暴露的个人估计，2)存储的DNA样本，我们将评估维生素D途径基因的多态性和单倍型模式。我们将使用多变量logistic回归模型来检验长期紫外线照射措施与帕金森病之间的关系，该模型校正了潜在的混杂因素，如年龄、种族、性别、教育程度、吸烟、维生素D的饮食来源、皮肤色素沉着和农药暴露。同样，我们将研究在维生素D通路关键基因（VDR、GC、CYP27A1、CYP27B1和CYP24A1）中导致不同生理维生素D活性的遗传变异是否会增加PD的风险。我们还将初步研究基因-基因和基因-环境的相互作用，以评估上述基因的变异是否改变了阳光照射和循环维生素D代谢物水平对帕金森病的影响，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，拟议的研究将探索PD病因学的新机制，并产生试点数据，如果成功，我们计划在更大的丹麦样本（4000例和对照）中复制，与PEG加利福尼亚中部人群相比，阳光照射较少。公共卫生相关性：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、人类遗传变异和基因与环境的相互作用都可能导致帕金森病。我们将探索一个新的假设，即长期低水平的维生素D，无论是由于阳光照射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，这项研究可能对未来PD预防的建议具有重要意义。

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.