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，授予ES 10751题为“帕金森病的分子流行病学”。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维化的增加。这些事件通过蛋白质降解和原纤维螯合而减弱。连锁衍生基因α-突触核蛋白（SNCA），泛素羧基末端水解酶L1（UCHL 1），微管相关蛋白tau（MAPT）和parkin（PRKN）赋予PD易感性，可能通过其对该发病途径的影响。我们假设这四个基因的功能变异性及其联合作用改变了PD的严重程度结果，年龄、性别和环境因素也有助于易感性和结果。我们建议更新我们的补助金ES 10751，具体目标如下：A1。进一步明确连锁易感基因与PD的关系。人类、灵长类动物和啮齿类动物跨物种序列保守性将用于突出SNCA、UCHL 1、MAPT和PRKN基因座内的功能结构域。将在这些区域（VISTA或“vSNP”）内鉴定包括单核苷酸多态性（SNP）的其他变体。连锁不平衡将用于鉴定单倍型标记变体（“ht-SNP”）。将在1，500对PD病例和未受影响同胞或无关人群对照的匹配对的扩展马约样本中进行基于家族和病例对照的关联分析。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，我们将应用递归分割和条件Logistic回归方法来研究SNCA，UCHL 1，MAPT和PRKN对PD的联合作用。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PD结局的遗传因素。在一个包含1,000名马约PD患者的既定队列中，我们将进行纵向评估，并进行生存和回归分析，以确定SNCA、UCHL 1、MAPT和PRKN基因的多态性是否与疾病严重程度结局相关。特别是，我们将考虑死亡，养老院安置，事件痴呆症，和Hoehn和Yahr阶段。我们还将考虑日常生活活动，治疗并发症和生活质量。前两个目标将完善我们对神经保护疗法的分子靶点的理解，第三个目标将预测其疗效。我们的研究结果将有助于早期疾病检测（生物标志物）和一级预防策略。它们还将加速新疗法的开发，降低研发成本，并确定最有可能受益的患者亚组。

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.