Molecular Epidemiology of Parkinson's Disease

描述(由申请人提供)：这是一个竞争性的继续申请ES10751的资助，题为“帕金森氏病的分子流行病学”。帕金森病(PD)发病机制中的关键步骤可能包括可溶性α-突触核蛋白及其聚集和纤化。这些事件被蛋白质降解和纤维隔离所减弱。连锁衍生基因α-突触核蛋白(SNCA)、泛素羧基末端水解酶L1(UCHL1)、微管相关蛋白tau(MAPT)和Parkin(PRKN)可能通过它们在这一发病途径中的作用而导致PD易感性。我们推测，这四个基因的功能变异性及其联合作用改变了帕金森病严重程度的结果，年龄、性别和环境因素也对易感性和结果有影响。我们建议延长我们的赠款ES10751，具体目标如下：1.完善连锁易感基因与帕金森病之间的关联。人类、灵长类和啮齿动物的跨物种序列保护将用于突出SNCA、UCHL1、MAPT和PRKN基因座中的功能结构域。其他变异，包括单核苷酸多态(SNPs)，将在这些区域内被识别(Vista或“vSNPs”)。连锁不平衡将用于识别单倍型标记变体(“ht-SNPs”)。将在扩大的梅奥样本中进行以家庭为基础的和病例对照关联分析，该样本包括1500对匹配的帕金森病病例和未受影响的兄弟姐妹或无关的人口对照。A2.研究这些基因的相互作用，以及它们与环境和性别相关因素的相互作用。使用目标1的数据，我们将使用递归划分和条件Logistic回归方法来研究SNCA、UCHL1、MAPT和PRKN对PD的联合影响。我们还将确定这些基因如何与环境风险因素相互作用，包括杀虫剂、烟草、咖啡和酒精。此外，我们将评估性别和内源性或外源性雌激素如何改变女性的这些相互作用。A3.研究影响帕金森病预后的遗传因素。在已建立的1,000名Mayo PD患者队列中，我们将进行纵向评估并进行生存和回归分析，以确定SNCA、UCHL1、MAPT和PRKN基因的多态性是否与疾病严重程度的结果相关。特别是，我们将考虑死亡、养老院安置、痴呆症事件以及Hoehn和Yahr分期。我们还将考虑日常生活能力、治疗并发症和生活质量。前两个目标将加深我们对神经保护治疗的分子靶点的理解，第三个目标将预测其疗效。我们的发现将有助于疾病的早期发现(生物标志物)和初级预防策略。他们还将加快新疗法的开发，降低研发成本，并确定最有可能受益的患者亚群。

DESCRIPTION (provided by applicant): This is a competing continuation application for the grant ES10751 entitled "Molecular Epidemiology of Parkinson's Disease". Key steps in the pathogenesis of Parkinson's disease (PD) may include increased soluble alpha-synuclein and its aggregation and fibrillization. These events are attenuated by protein degradation and fibril sequestration. The linkage-derived genes alpha-synuclein (SNCA), ubiquitin carboxy-terminal hydrolase L1 (UCHL1), microtubule-associated protein tau (MAPT), and parkin (PRKN) confer PD susceptibility, possibly via their effects on this pathogenesis pathway. We postulate that functional variability in these four genes and their joint effects modify PD severity outcomes, and that age, gender, and environmental factors also contribute to susceptibility and outcomes. We propose renewal of our grant ES10751 with the following 3 specific aims: A1. To refine the association between linkage-derived susceptibility genes and PD. Human, primate, and rodent cross-species sequence conservation will be used to highlight functional domains within the SNCA, UCHL1, MAPT, and PRKN loci. Additional variants, including single nucleotide polymorphisms (SNPs), will be identified within these regions (VISTA or "vSNPs"). Linkage disequilibrium will be used to identify haplotype-tagging variants ("ht-SNPs"). Family-based and case-control association analyses will be performed in an expanded Mayo sample of 1,500 matched pairs of PD cases and unaffected siblings or unrelated population controls. A2. To study interactions of these genes, and their interactions with environmental and gender-related factors. Using data from aim 1, we will apply recursive partitioning and conditional logistic regression approaches to investigate the joint effects of SNCA, UCHL1, MAPT, and PRKN on PD. We will also determine how these genes interact with environmental risk factors including pesticides, tobacco, coffee, and alcohol. In addition, we will assess how gender and endogenous or exogenous estrogen modify these interactions in women. A3. To study genetic factors influencing PD outcomes. In an established cohort of 1,000 Mayo PD patients, we will perform longitudinal assessments and conduct survival and regression analyses to determine whether polymorphism in the SNCA, UCHL1, MAPT, and PRKN genes correlates with disease severity outcomes. In particular, we will consider death, nursing home placement, incident dementia, and Hoehn and Yahr stage. We will also consider activities of daily living, complications of therapy, and quality of life. The first two aims will refine our understanding of molecular targets for neuroprotective therapies, and the third aim will predict their efficacy. Our findings will contribute to early disease detection (biomarkers) and primary prevention strategies. They will also accelerate the development of new treatments, reduce research and development costs, and identify subgroups of patients most likely to benefit.