Genetic Modulation of Sickle Cell Anemia

描述（由申请人提供）：基因型-表型关联研究可提供重要的预后信息，并指导遗传性疾病的治疗决策。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。这种多样性可能是由许多修饰基因的作用和相互作用造成的。候选疾病调节基因可以调节氧化生物学、一氧化氮代谢、血管功能、炎症和细胞-细胞相互作用。我们的新观察结果将候选基因的多态性与非裔美国人的镰状细胞贫血表型联系起来，并由父母资助，需要扩展到另一个人群并得到证实。萨尔瓦多（巴伊亚，巴西）是进行确证性和额外研究的理想地点。大量的镰状细胞病患者居住在该地区，并且存在可以重新关注遗传关联研究的临床和研究基础设施。这项工作将使我们更接近于将我们的观察结果应用于诊断和治疗，同时建立萨尔瓦多现代遗传研究的能力。我们的主要目标是：1）开发来自巴西巴伊亚的萨尔瓦多的镰状细胞病患者的镰状细胞病患者登记处、数据库和DNA样品储存库。2)对巴伊亚巴西患者候选基因的单核苷酸多态性（SNP）进行基因分型。这些结果将与我们在非洲裔美国人中的发现进行比较，以提供有关地理上不同人群中调节基因的相似性和差异性的信息。3)培训巴西研究人员掌握大型复杂数据集分析的最先进方法，同时继续改进在实用的交互式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合作建立一个新的NIH镰状细胞病临床研究网络做好准备。

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.