Genetic Modulation of Sickle Cell Anemia

描述(由申请人提供)：基因-表型相关性研究可能提供重要的预后信息，并指导遗传病的治疗决策。镰状细胞性贫血是孟德尔式的典型单基因疾病，其表型是出了名的异质性。这种多样性很可能是由许多修饰基因的作用和相互作用造成的。候选疾病调控基因可能调控氧化生物学、一氧化氮代谢、血管功能、炎症和细胞-细胞相互作用。我们的新观察将候选基因的多态与非裔美国人镰状细胞性贫血的表型联系起来，并由父母拨款资助，需要扩展到另一个人群并得到证实。巴西巴伊亚州的萨尔瓦多为验证性和其他研究提供了一个理想的地点。该地区居住着大量的镰状细胞病患者，临床和研究基础设施可以重新集中在遗传关联研究上。这项工作将使我们更接近于将我们的观察结果应用于预测和治疗，同时在萨尔瓦多建设现代基因研究的能力。我们的主要目标是：1)开发一个镰状细胞病患者登记、数据库和来自巴西萨尔瓦多·巴伊亚的镰状细胞病患者DNA样本库。2)巴伊亚州巴西患者候选基因的单核苷酸多态(SNPs)基因分型。这些结果将与我们在非裔美国人中的发现进行比较，以提供地理上不同人群中调节基因的相似性和差异性的信息。3)培训巴西调查人员使用最先进的大型复杂数据集分析方法，同时继续改进在预测有用的互动网络中使用多态的方法。我们的研究结果还将使巴西研究人员做好准备，与我们合作建立一个新的NIH镰状细胞病临床研究网络。

DESCRIPTION (provided by applicant): Genotype-phenotype association studies may provide important prognostic information and guide therapeutic decision making in genetic disease. The phenotype of sickle cell anemia, a prototypic Mendelian single gene disorder, is notoriously heterogeneous. The diversity is likely to result from the actions and interactions of many modifying genes. Candidate disease modulating genes may regulate oxidative biology, nitric oxide metabolism, vascular function, inflammation and cell-cell interaction. Our novel observations linking polymorphisms in candidate genes with phenotypes of sickle cell anemia in African Americans and funded by the parent grant need to be expanded to another population and confirmed. Salvador, Bahia, Brazil provides an ideal site for confirmatory and additional studies. A large number of sickle cell disease patients reside in the area and a clinical and research infrastructure exists that can be refocused on genetic association studies. This work will move us closer toward applying our observations prognostically and therapeutically, while building the capacity for modern genetic studies in Salvador. Our prime objectives are: 1) developing a sickle cell disease patient registry, database and DNA sample repository of sickle cell disease patients from Salvador Bahia, Brazil. 2) genotyping single nucleotide polymorphisms (SNPs) in candidate genes in Brazilian patients in Bahia. These results will be compared with our findings in African Americans providing information on the similarities and differences in modulating genes in geographically distinct populations. 3) training Brazilian investigators in state-of-the-art methods of analysis of large complex data sets while continuing to refine methods for using polymorphisms in prognostically useful interactive networks. Our results will also prepare Brazilian investigators to collaborate with us in a new NIH Sickle Cell Disease Clinical Research Network.