Pleiotropic and epistatic effects in sickle cell anemia

描述（由申请人提供）： 镰状细胞性贫血（SCA）是典型的单基因疾病，但镰状细胞性贫血（SCA） 突变不足以定义表型。多效性作用 影响并发症。其次，SCA表现出强烈的个体间 变异性，这可能是上位基因的影响，因为 严重程度主要决定因素的遗传力在以下方面表现出高度一致性： 单卵双胞胎（89%）。该项目的目的是定义 镰状细胞介导的血管闭塞中的上位性/多效性基因 不同的器官，建立在我们多年的遗传学研究基础上， 这一问题在小鼠和人的病理生理学。我们将参与 镰状细胞介导的血管闭塞相关基因的检测 模型，在镰状细胞介导的基因检测 镰状细胞性贫血患者的血管闭塞， 镰状细胞血管闭塞和血管增生过程相关基因 镰状细胞性视网膜和脉络膜血管并发症 贫血，我们以前的工作已经定义为一个特例。的 实验设计如下：方法1： 镰状转基因小鼠等动物模型-+ RNA -+表达芯片-> 选择相对于对照-+的高表达基因和低表达基因 BLAST -->将分析所选人类基因的潜在上位性 通过SNP阵列和测序来定义多态性， 适当定义的人类镰状细胞性贫血DNA样本。方法2：在 没有动物模型的并发症，但基于人类的候选基因 病理生理学数据、SNP和测序分析将在 镰状细胞性贫血患者与镰状细胞性贫血患者 贫血患者没有它。当然，适当匹配的年龄组将 选择以确保控制中不再可能出现并发症 组将在动物模型中跟踪这两种方法定义的基因 当可用时（KO或过表达），或产生用于进一步确认。 该提案的成员在视网膜、血管和视网膜病变方面具有特殊的专业知识， 问题和统计分析。我们的机构已经建立了 转基因小鼠、微循环制剂、造血和 患者随访，以及经验丰富的SNP、测序和CHIP 表达设施。

DESCRIPTION (provided by applicant): Sickle cell anemia (SCA) is the paradigmatic monogenic disease, but the sickle mutation is not sufficient to define the phenotype. Pleiotropic effects influence complications. Secondly, SCA exhibits an intense inter-individual variability, which is likely to be the effect of epistatic genes, since heritability of major determinants of severity exhibit high concordance in monozygote twins (89%). The aim of this project is to define the epistatic/pleiotropic genes involved in sickle-cell mediated vaso-occlusion in different organs, building on our years of working on the genetics and pathophysiology of this problem in mice and men. We will engage in the detection of genes involved in sickle cell-mediated vaso-occlusion in animal models, in the detection of genes involved in sickle cell-mediated vaso-occlusion in patients with sickle cell anemia and in the detection of genes involved in vaso-occlusive and vaso-proliferative processes in sickle cell retina and choroid and in cerebrovascular complications in sickle cell anemia, which our previous work has defined as a special case. The experimental design is the following: Approach 1: Appropriate tissues in sickle transgenic mice and other animal models -+ RNA -+ expression chips -> select the higher express genes and the lower expressing genes vs control -+ BLAST --> the selected human genes will be analyzed for potential epistatic effects by SNP arrays and by sequencing to define polymorphism in appropriately defined human sickle cell anemia DNA samples. Approach 2: In the complications without animal models, but candidate genes based on human pathophysiological data, SNPs and sequencing analyzes will be performed in sickle cell anemia patients with a particular complication vs sickle cell anemia patients without it. Of course, appropriate matching age groups will be selected to assure that the complication is no longer possible in the control group. Genes defined by these two approaches will be followed in animal models when available (KO or over expression, or generated for further confirmation. Members of this proposal have special expertise in retinal, cerebro-vascular problems and statistical analysis. Our institution has well established expertise in transgenic mice, microcirculatory preparations, hemopoiesis and patient follow-up, as a well as experienced SNP, sequencing and CHIP expression facilities.