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裔美国人的毁灭性疾病，我们的目标是捕获可能构成这种疾病众所周知的异质性临床病程的遗传多样性，并利用这些信息开发预测网络模型，使我们能够预测未来的情况。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，这与血管病变并发症在镰状细胞病发病机制中的重要性、候选基因关联研究和全基因组关联的初步分析一致。研究已经确定了调节增殖性血管对损伤反应的经典途径中的遗传多态性，例如 TGF-¿此外，使用疾病严重程度的综合估计作为表型，发现了似乎是正常非镰状细胞疾病和衰老过程调节剂的重要幸存者基因变异，这些多态性标记了调节血管的基因。为了实现我们的目标，我们组建了一个由成熟的研究人员和最大的当代患者数据库和生物样本库以及必要的实验室和分析能力组成的新联盟，该团队包括与克林顿合作的马克·格拉德温（Mark Gladwin）、玛丽莲·泰伦（Marilyn Telen）和马丁·斯坦伯格（Martin Steinberg）。我们的高通量遗传学实验室的鲍德温（Baldwin）和领导贝叶斯网络建模工作的保拉·塞巴斯蒂亚尼（Paola Sebastiani）利用我们现有的资源，将直接检查五种主要亚表型的基因型-表型关系。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普遍的见解，我们认为镰状细胞病代表了血管应激的“严酷考验”，可以敏锐地识别血管应激。可能广泛调节：1）全身和肺血管系统的增殖血管反应；2）血管对衰老的反应；3）红细胞溶血的内在倾向；4）HbF产生的控制将使我们能够进一步进行基因分型。验证我们先前在镰状细胞性贫血中的基因型-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可能揭示功能变异的其他多态性。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，我们将开发对预后有用的预测网络模型。 公共卫生相关声明： 在镰状细胞性贫血中，患者的临床表现和生存时间可能会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。模拟遗传变异之间的相互作用，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。