Genetic Diversity of Sickle Cell Anemia

描述(由申请人提供)： 镰状细胞性贫血是一种毁灭性的疾病，主要影响非裔美国人。我们的目标是捕捉可能导致这种疾病臭名昭著的异质性临床过程的基因多样性，并利用这些信息开发预测性网络模型，使我们能够预测其严重血管病变并发症的可能性，以及哪些患者最有可能出现早期死亡。与血管病变在镰状细胞疾病发病机制中的重要性一致，候选基因关联研究和全基因组关联研究的初步分析已经在调节血管对损伤的增殖反应的典型途径中发现了遗传多态，如转化生长因子-β/骨形态发生蛋白途径。此外，使用疾病严重程度的综合估计作为表型，发现了重要的幸存者基因变异，这些变异似乎是正常的非镰状细胞疾病衰老过程的调节器。再一次，这些多态标记了调节血管功能的基因。为了实现我们的目标，我们组建了一个由成熟的研究人员组成的新联盟，以及当代最大的患者数据库和生物样本库，以及必要的实验室和分析能力。这个小组包括Mark Gladwin、Marilyn Telen和Martin Steinberg，他们与Clinton Baldwin在我们的高通量遗传学实验室合作，以及Paola Sebastiani，他领导贝叶斯网络建模工作。利用我们已有的资源，我们将直接检查五个主要亚型的基因型-表型关系。这些结果不仅有可能改变镰状细胞场，而且还提供了对炎症、氧化和溶血应激的基本血管反应的独特和普遍的见解。我们认为，镰状细胞病代表了血管应激的“熔炉”，它尖锐地识别了可能广泛调控的遗传变异：1)全身和肺血管系统的增殖性血管反应；2)血管对衰老的反应；3)红细胞固有的溶血倾向；4)控制HBF的产生。进一步的基因分型将使我们能够验证我们先前在镰状细胞性贫血中的基因-表型关联。对有希望的候选基因进行重新测序将使我们能够发现更多的多态性，也许可以揭示功能变异。然而，仅仅发现遗传变异是不够的；随着我们捕捉到与这种疾病的选定亚型相关的遗传异质性，我们将开发预测有用的网络模型。 公共卫生相关声明： 在镰状细胞性贫血中，患者有非常不同的临床表现和生存时间。这很可能受到许多其他基因的影响，这些基因影响血管功能和镰刀状红细胞的寿命。我们将发现影响这些过程的遗传变异，并使用新的方法来模拟遗传变异之间的相互作用，这些遗传变异可以用来预测并发症的发展，如肺动脉高压、红细胞寿命和死亡率。

DESCRIPTION (provided by applicant): Sickle cell anemia is a devastating disease affecting primarily African Americans. Our goals are to capture the genetic diversity that is likely to underlie the notoriously heterogeneous clinical course of this disease, and with this information, develop predictive network models that will allow us to foretell the likelihood of its severe vasculopathic complications and which patients might be most likely to have early mortality. Consistent with the importance of vasculopathic complications in the pathogenesis of sickle cell disease, candidate gene association studies and preliminary analysis of genome-wide association studies have identified genetic polymorphisms in canonical pathways regulating proliferative vascular responses to injury, like the TGF-¿/BMP pathway. Furthermore, using an integrated estimate of disease severity as a phenotype, important survivor gene variants that appear to be modulators of the normal, non-sickle cell disease, aging process were found. Once again, these polymorphisms mark genes regulating vascular function. To accomplish our goals we have assembled a new consortium of established investigators and the largest contemporary patient databases and biological sample repository along with the necessary laboratory and analytical capabilities. This group includes Mark Gladwin, Marilyn Telen, and Martin Steinberg, working with Clinton Baldwin in our high throughput genetics laboratory and Paola Sebastiani who leads the effort in Bayesian network modeling. With our established resources, we will directly examine genotype-phenotype relationships focusing on five major sub-phenotypes. The results have the potential to transform not only the sickle cell field, but also provide unique and generalizable insights into the fundamental vascular responses to inflammatory, oxidative and hemolytic stress. We propose that sickle cell disease represents a "crucible" of vascular stress that sharply identifies genetic variants that may broadly regulate: 1) proliferative vascular responses in the systemic and pulmonary vasculature; 2) vascular responses to aging; 3) the intrinsic propensity of red cells to hemolyze; 4) the control of HbF production. Further genotyping will allow us to validate our prior genotype-phenotype associations in sickle cell anemia. Resequencing promising candidate genes will to allow us to discover additional polymorphisms perhaps revealing functional variants. However, finding genetic variation alone is insufficient; as we capture the genetic heterogeneity associated with selected sub-phenotypes of this disease, we will develop predictive network models that will be prognostically useful. Public Health Relevance Statement: In sickle cell anemia, patients have very different clinical manifestations and lengths of survival. It is likely that this is influenced by many other genes that affect vascular function and sickle red cell lifespan. We will discover genetic variants that influence these processes and use novel methods to model interactions among genetic variants that can be used to predict the development of complications like pulmonary hypertension, red cell lifespan and mortality.