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; 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）： 镰状细胞贫血是一种毁灭性疾病，主要影响非洲裔美国人。我们的目标是捕获遗传多样性，这可能是该疾病的臭名昭著的异质临床过程的基础，并且通过这些信息，开发了预测性网络模型，使我们能够预言其严重的血管性并发症的可能性，哪些患者可能最有可能早期死亡。与血管性并发症在镰状细胞疾病的发病机理中的重要性相一致，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在规范的遗传多态性的遗传性多态性，这些途径可以调节对损伤的血管反应的增殖，例如TGF-€e /bmp Pathway。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，非滴答细胞疾病的调节剂的重要冲浪者基因变体，发现了衰老过程。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，我们组建了一个新的研究人员的联盟，当代最大的患者数据库和生物样品存储库以及必要的实验室和分析能力。该小组包括马克·格拉德温（Mark Gladwin），玛丽莲·泰伦（Marilyn Telen）和马丁·斯坦伯格（Martin Steinberg），与克林顿·鲍德温（Clinton Baldwin）合作，在我们的高吞吐量遗传学实验室和Paola Sebastiani中，他们领导了贝叶斯网络建模的努力。凭借我们既定的资源，我们将直接研究以五种主要子表型为重点的基因型 - 表型关系。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见解。我们建议镰状细胞疾病代表一种血管胁迫的“坩埚”，急剧识别可能广泛调节的遗传变异：1）全身性和肺血管中的增殖血管反应； 2）对衰老的血管反应； 3）红细胞溶解的内在倾向； 4）HBF生产的控制。进一步的基因分型将使我们能够验证镰状细胞贫血中先前的基因型 - 表型关联。重新定制承诺候选基因将使我们发现可能揭示功能变异的其他多态性。但是，仅找到遗传变异是不够的。当我们捕获与该疾病选定的亚表格相关的遗传异质性时，我们将开发预测性网络模型，这些模型将非常有用。 公共卫生相关性声明： 在镰状细胞贫血中，患者的临床表现非常不同，生存期长度。这可能受到影响血管功能和镰状细胞寿命的许多其他基因的影响。我们将发现影响这些过程的遗传变异，并使用新颖的方法来建模遗传变异的相互作用，这些变体可用于预测并发症的发展，例如肺动脉高压，红细胞寿命和死亡率。