Gene-Environment Interactions and Stroke Susceptibility

中风是美国第三大死亡原因， 经常与长期残疾有关。易卒中型 自发性高血压大鼠（SHRSP），这是由选择性 从自发性高血压大鼠（SHR）中繁殖，代表了一种合适的 高血压相关中风的模型。中风的发生受以下因素的影响 多基因和环境因素的复杂相互作用。的作用 饮食中的钠和钾在调节中风发作方面的作用 在人类和动物模型中都有很好的记录。在SHRSP中， 钠和低钾会加速中风的发展。在 相比之下，大量摄入钾可以显著预防中风 即使血压水平保持不变。我们有 应用基因表达谱分析策略，使用寡核苷酸 微阵列，以确定基因和基因通路牵连的发展 中风的几率。因为基因表达谱是独特的， 全面反映了一个定义集的复杂和动态的相互作用 基因与环境的关系，基因表达变化的表征 在不同的近交系大鼠品系中， 中风的遗传倾向将为研究中风的机制提供线索， 控制中风易感基因与饮食的相互作用 已知影响疾病进程的因素。拟议的申请将 重点是确定与饮食盐相互作用的中风易感基因 摄入量影响SHRSP卒中事件的起始， 男性大脑皮质区基因表达谱 SHRSPs和SHR暴露于常规饮食与卒中允许饮食。我们将 然后识别这些表达候选基因中的遗传变异， 作为一组选定的生物学/位置候选基因。我们将评估 在F2中，遗传变异与中风潜伏期的共分离 SHRSP × SHR亲本杂交的后代。此外，我们将研究是否 候选基因中的遗传变异与 F2中的中风潜伏期被饮食因素改变。我们将最终 评价已建立的卒中因果关系范例的潜在相关性 在人类疾病的实验模型中。具体来说，我们将描述 10个基因的人类同源物内或附近的序列变异 并确定这些基因的变异是否与 在大样本人群中， 参与社区动脉粥样硬化风险（ARIC）研究。我们将 还鉴定和表征了一组选定的 中风候选人基因，并测试这些基因中的变异是否 与ARIC样本中发生中风的风险相关。

Stroke is the third leading cause of death in the United States and is frequently associated with long-term disability. The stroke-prone spontaneously hypertensive rat (SHRSP), which was developed by selective breeding from the spontaneously hypertensive rat (SHR), represents a suitable model of hypertension-associated stroke. Stroke occurrence is influenced by the complex interaction of multiple genes and environmental factors. The role of dietary sodium and potassium in modulating the onset of stroke has been well documented both in humans and animal models. In the SHRSP, diet high in sodium and low in potassium accelerates the development of stroke. In contrast, a high intake of potassium markedly protects against stroke occurrence, even though blood pressure levels remain unchanged. We have applied a gene expression profiling strategy using oligonucleotide micro-arrays to identify genes and gene pathways implicated in the development of stroke in this animal model. Because gene expression profiles uniquely and comprehensively reflect the complex and dynamic interaction of a defined set of genes with the environment, characterization of gene expression changes induced by dietary perturbations among inbred rat strains differing in their genetic propensity to develop stroke will provide clues on the mechanisms governing the interaction of stroke susceptibility genes with the dietary factors known to influence the disease process. The proposed application will focus on identifying stroke-susceptibility genes interacting with dietary salt intake to influence the initiation of stroke events in the SHRSP by comparing the gene expression profiles in the cortical regions of the brain of male SHRSPs and SHRs exposed to a regular vs. stroke- permissive diet. We will then identify genetic variants in these expressional candidate genes, as well as a panel of selected biological/positional candidate genes. We will assess the cosegregation of the genetic variants with stroke latency in the F2 progeny of SHRSP x SHR parental crosses. In addition, we will examine whether the relationship between genetic variants in candidate genes and variation in stroke latency in the F2 is modified by dietary factors. We will finally evaluate the potential relevance of a paradigm of stroke causation established in an experimental model to human disease. Specifically, we will characterize sequence variation within or near the human homologue of ten genes identified in this proposal and determine whether variation in these genes is associated with stroke incidence in a large population-based sample of individuals participating in the Atherosclerosis Risk in Communities (ARIC) study. We will also identify and characterize DNA variation in a panel of selected stroke-candidate human genes and test whether variation in these genes is associated with risk of developing a stroke in the ARIC sample.