Genetic Modulation of Sickle Cell Anemia

描述（由申请人提供）：基因型-表型关联研究可以提供重要的预后信息并指导遗传病的治疗决策。镰状细胞性贫血是一种典型的孟德尔单基因疾病，其表型是众所周知的异质性。这种多样性可能是许多修饰基因的作用和相互作用的结果。候选疾病调节基因可能调节氧化生物学、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多态性与非裔美国人镰状细胞性贫血表型联系起来，并由父母资助，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进一步的验证性研究提供了理想的地点。大量镰状细胞病患者居住在该地区，现有的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应用于预测和治疗，同时在萨尔瓦多建立现代基因研究的能力。我们的主要目标是：1)建立巴西萨尔瓦多巴伊亚州镰状细胞病患者的登记、数据库和DNA样本库。2)巴伊亚州巴西患者候选基因的单核苷酸多态性（snp）基因分型。这些结果将与我们在非裔美国人身上的发现进行比较，从而提供在地理上不同的人群中调节基因的异同信息。3)培训巴西调查人员使用最先进的方法分析大型复杂数据集，同时继续改进在预测有用的交互网络中使用多态性的方法。我们的研究结果还将为巴西研究人员与我们在新的NIH镰状细胞病临床研究网络中合作做好准备。

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.