Genetic Diversity of Sickle Cell Anemia

镰状细胞性贫血的遗传多样性

• 批准号: 7848005
• 负责人: Martin H. Steinberg
• 金额: $ 179.67万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7848005
• 关键词: Affect; African American; Age; Aging; Aging-Related Process; Biological; Biological databases; Blood Vessels; Candidate Disease Gene; Cessation of life; Chronic; Clinical; Clinical Course of Disease; Custom; DNA Resequencing; Data; Development; Disease; Doppler Echocardiography; Erythrocytes; Future; Genes; Genetic; Genetic Heterogeneity; Genetic Polymorphism; Genetic Variation; Genotype; Goals; Heart Ventricle; Hemolysis; Hemolytic Anemia; Heterogeneity; Hormones; Individual; Inflammatory; Laboratories; Lead; Leg; Length; Link; Longevity; Lung; Methods; Modeling; National Heart, Lung, and Blood Institute; Outcome; Pathogenesis; Pathway interactions; Patients; Phenotype; Plasma; Population Study; Priapism; Process; Production; Pulmonary Hypertension; Recruitment Activity; Regulation; Relative (related person); Research Personnel; Resources; Rheology; Risk; Sampling; Screening procedure; Severities; Severity of illness; Sickle Cell; Sickle Cell Anemia; Sickle vasoocclusion; Single Nucleotide Polymorphism; Stress; Survivors; Thalassemia; Ulcer; United States National Institutes of Health; Validation; Variant; Vascular Diseases; Walking; Work; base; computer based statistical methods; density; disease phenotype; follow-up; genetic variant; genome wide association study; insight; interest; mortality; network models; novel; patient population; pressure; prognostic; public health relevance; repository; response; response to injury; sickling; sildenafil; trait; validation studies

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.

描述（由申请人提供）： 镰状细胞性贫血是一种主要影响非洲裔美国人的毁灭性疾病。我们的目标是捕捉可能成为这种疾病臭名昭著的异质性临床过程基础的遗传多样性，并利用这些信息开发预测网络模型，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早期死亡。与血管病变并发症在镰状细胞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确定了调节对损伤的增殖性血管反应的典型途径（如TGF-β/BMP途径）中的遗传多态性。此外，使用疾病严重程度的综合评估作为表型，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病衰老过程的调节剂，这些多态性再次标志着调节血管功能的基因。为了实现我们的目标，我们已经组建了一个新的财团，由已建立的研究人员和最大的当代患者数据库和生物样本储存库沿着必要的实验室和分析能力。这个小组包括Mark Gladwin、Marilyn Telen和Martin Steinberg，他们与我们的高通量遗传学实验室的Clinton Baldwin以及领导贝叶斯网络建模工作的保拉阿提亚尼一起工作。利用我们现有的资源，我们将直接研究基因型-表型关系，重点是五个主要的亚表型。这些结果不仅有可能改变镰状细胞领域，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可推广的见解。我们提出镰状细胞病代表了血管应激的“坩埚”，其可明确识别可广泛调节以下的遗传变异：1）全身和肺血管系统中的增殖性血管反应; 2）血管对老化的反应; 3）红细胞溶血的内在倾向; 4）HbF产生的控制。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型-表型关联。重新测序有希望的候选基因将使我们能够发现更多的多态性，可能揭示功能变异。然而，仅仅发现遗传变异是不够的;当我们捕获与这种疾病的选定亚表型相关的遗传异质性时，我们将开发出预测性网络模型，这将是非常有用的。 公共卫生相关性声明： 在镰状细胞贫血中，患者具有非常不同的临床表现和存活时间。这很可能受到许多其他影响血管功能和镰状红细胞寿命的基因的影响。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，这些遗传变异可用于预测肺动脉高压，红细胞寿命和死亡率等并发症的发展。