Genetic Dissection of Sickle Cell Anemia Phenotypes

镰状细胞性贫血表型的基因剖析

• 批准号: 6911936
• 负责人: PAOLA SEBASTIANI
• 金额: $ 16.15万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-06-01 至 2007-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6911936
• 关键词: computer simulation; gene expression; genetic susceptibility; genotype; model design /development; phenotype; polymerase chain reaction; sickle cell anemia; single nucleotide polymorphism

DESCRIPTION (provided by applicant): Sickle cell anemia is a paradigmatic single gene disorder caused by homozygosity for a unique mutation on the beta-globin locus producing the abnormal sickle hemoglobin (HbS). Phenotypically, sickle cell anemia is a complex disease with different clinical courses ranging from early childhood mortality to virtually unrecognized conditions. Damaged red cells initiate hemolysis, vaso-occlusion and the vascular pathology of sickle cell disease. Vaso-occlusion injures vital tissues causing pain and impairing function. Death is premature and life can be oppressive. Supported by the NIH/NHLBI R01 HL68970 "Genetic modulation of sickle cell anemia", in 2001 Dr Steinberg initiated a genome scan study to understand the genetic basis of the major sickle cell anemia phenotypes. This study has led so far to the discovery of several genes that are associated with individual phenotypes of sickle cell anemia, and more than one phenotype appears to be associated with the same genetic variants. These findings support the hypotheses that clinical heterogeneity in sickle cell disease, as in other "single gene" Mendelian disorders, must be caused by the genetic variability in genes that influence the occurrence of defined phenotypes. This variability may be also modulated by other clinical conditions, and some of the sub-phenotypes of sickle cell anemia may have common genetics bases. To model these relationships and to allow ultimately the use of these discoveries as prognostic and therapeutic models, we are developing new computational methods for learning about simultaneous gene-phenotypes associations based on multivariate dependency models. In this project, we propose to use these new modeling techniques for the simultaneous discovery of the genetic basis of several sickle cell anemia phenotypes, and to use the discovered associations for prognosis of the risk of complications in sickle cell anemia patients.

描述（由申请人提供）：镰状细胞性贫血是一种典型的单基因疾病，由β-珠蛋白基因座上独特突变的纯合性引起，产生异常镰状血红蛋白（HbS）。镰状细胞性贫血是一种复杂的疾病，从幼儿死亡到几乎未被认识的疾病，临床病程各不相同。受损的红细胞引发溶血、血管闭塞和镰状细胞病的血管病理学。血管闭塞损伤重要组织，引起疼痛和功能损害。死亡是过早的，生活可能是压迫性的。在NIH/NHLBI R 01 HL 68970“镰状细胞贫血的遗传调节”的支持下，Steinberg博士于2001年启动了一项基因组扫描研究，以了解主要镰状细胞贫血表型的遗传基础。这项研究迄今为止已经发现了与镰状细胞贫血个体表型相关的几个基因，并且不止一种表型似乎与相同的遗传变异相关。这些研究结果支持了镰状细胞病的临床异质性的假设，在其他“单基因”孟德尔疾病，必须由基因的遗传变异性，影响确定的表型的发生。这种变异性也可能受到其他临床条件的调节，并且镰状细胞性贫血的一些亚表型可能具有共同的遗传学基础。为了模拟这些关系，并最终允许使用这些发现作为预后和治疗模型，我们正在开发新的计算方法，用于学习基于多变量依赖模型的同时基因-表型关联。在这个项目中，我们建议使用这些新的建模技术，同时发现几种镰状细胞贫血表型的遗传基础，并使用发现的关联来预测镰状细胞贫血患者并发症的风险。