Whole Genome Sequence Analysis of Genetic Factors for Stroke, Hypertension, and Fetal Hemoglobin in Sickle Cell Disease

镰状细胞病中风、高血压和胎儿血红蛋白遗传因素的全基因组序列分析

• 批准号: 9229121
• 负责人: GRIER P PAGE
• 金额: $ 12.18万
• 依托单位: RESEARCH TRIANGLE INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-02-01 至 2019-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9229121
• 关键词: ANXA2 gene; Adult; Adverse effects; Affect; Alloimmunization; Bioinformatics; Blood Pressure; Brazil; Candidate Disease Gene; Child; Childhood; Chronic Kidney Failure; Clinical; Clinical Data; Comorbidity; Complex; Control Locus; Data; Diastolic blood pressure; Disease; Factor Analysis; Fetal Hemoglobin; Funding; Gene Targeting; Generations; Genes; Genetic; Genetic Determinism; Genetic Variation; Genetic study; Genotype; Goals; Grant; HIV Infections; Hemoglobin; Hemoglobin concentration result; Heterogeneity; Homozygote; Hypertension; Individual; Ischemic Stroke; Joints; Lead; Leg Ulcer; Longevity; Maintenance; Measures; Medical; Medicine; Mendelian disorder; Methods; Michigan; Mining; Morbidity - disease rate; Mutation; National Heart, Lung, and Blood Institute; Odds Ratio; Parents; Pathway interactions; Patients; Phenotype; Population; Predisposing Factor; Priapism; Pulmonary Hypertension; Quality of life; Regulation; Reporting; Research Personnel; Resource Informatics; Resources; Risk; Risk Factors; Sample Size; Secondary to; Sequence Analysis; Sickle Cell; Sickle Cell Anemia; Stroke; TGFBR3 gene; Testing; The Sun; Trans-Omics for Precision Medicine; Transfusion; United States; Universities; Variant; Work; acute chest syndrome; cohort; cost; data resource; exome sequencing; experience; genetic analysis; genetic variant; genome sequencing; genome wide association study; genome-wide; genome-wide analysis; hemoglobin B; high risk; improved; inter-individual variation; mortality; novel; programs; response; success; trait; whole genome; working group

Project Summary/Abstract Sickle cell disease (SCD) is caused by only a few mutations in the β-hemoglobin gene (HBB). Individuals with the same mutation can have clinically quite different diseases, from mild with few clinical complications to severe complications such as stroke, leg ulceration, pulmonary hypertension, priapism, and acute chest syndrome. We propose to identify functional genetic variation that leads to the heterogeneity of SCD including ischemic stroke, hypertension, and elevated fetal hemoglobin in a cohort of 2,056 SCD patients from the REDS-III Brazilian SCD cohort. This deeply phenotyped cohort is undergoing whole genome sequencing (WGS) under the auspices of the NHLBI TOPMed program. The TOPMed program provides funding for WGS at the Baylor Genome Sequencing Center and genotype calling will be performed at Dr. Abecasis' lab at University of Michigan, but does not provide resources for analyses that combine WGS with clinical and end point data. The WGS data in this cohort provides a valuable opportunity to understand the genetics of the many comorbid conditions that bedevil SCD patients. This R21 is building on the work on the REDS-III study, which collected the Brazilian cohort between October 2013 and May 2015 to study aspects of transfusion such as determinants of response to transfusion, HIV infection, and alloimmunization. All the phenotypes to be studied here—ischemic stroke, blood pressure, and HbF levels—are secondary to the primary end points. We propose to study the genetics of ischemic stroke in HbSS/HbSB0 patients using whole genome, burden, pathway, and bioinformatics approaches with guidance from previous SCD stroke candidate gene and non- SCD genome-wide studies. We will further study the genetics of blood pressure and hypertension by focusing on all the known complex and Mendelian blood pressure loci (around 250). Finally, building on previous successful genome-wide studies of fetal hemoglobin levels, we will replicate reported findings and conduct genome-wide studies. The team pursuing this opportunity are all REDS-III investigators and pull together the WGS and bioinformatics expertise of Drs. Page (leader of the REDS-III bioinformatics and statistical genetics team), Sun, and Guo; and the disease and medical experience of Drs. Busch (transfusion medicine), Custer (U.S. PI of the Brazilian cohort; transfusion medicine), Shannon (SCD expert), Sabinio (Brazilian PI of the Brazilian co-cohort), and Rich (senior statistical geneticist) to understand and interpret these valuable resources data. They will also work with the TOPMed sickle cell phenotyping working group and other TOPMed investigators.

项目摘要/摘要 镰状细胞疾病（SCD）仅是由β-血红蛋白基因（HBB）中的几个突变引起的。有个人 相同的突变在临床上可能完全不同，从几乎没有临床并发症的轻度到 严重的并发症，例如中风，腿部溃疡，肺动脉高压，priapism和急性胸部 综合征。我们建议确定导致SCD异质性的功能遗传变异 来自2,056例SCD患者的缺血性中风，高血压和胎儿血红蛋白升高 红色III巴西SCD队列。这种深厚的表型队列正在进行整个基因组测序 （WGS）在NHLBI顶级程序的主持下。顶级计划为WGS提供资金 在Baylor基因组测序中心和基因型调用将在Abecasis博士的实验室进行 密歇根大学，但不提供将WG与临床和结束的分析提供资源 点数据。该队列中的WGS数据提供了一个宝贵的机会来了解 许多合并症的疾病，这些疾病是SCD患者。 R21正在基于Reds-III研究的工作，该研究在10月之间收集了巴西队列 2013年和2015年5月研究输血的各个方面，例如对输血的反应决定者 感染和同种免疫。在此处研究的所有表型 - 流行中风，血压和 HBF水平 - 是主要终点的继发。 我们建议使用整个基因组，伯恩，Burnen， 途径和生物信息学在先前的SCD中风候选基因和非 - SCD全基因组研究。我们将通过聚焦进一步研究血压和高血压的遗传学 在所有已知的复合体和孟德尔血压区域（约250个）上。最后，建立在以前的基础上 成功的胎儿血红蛋白水平的全基因组研究，我们将复制报道的发现并进行 全基因组研究。 追求这个机会的团队都是红色III调查人员，并将WGS和生物信息学结合在一起 博士的专业知识。 Page（红色III生物信息学和统计遗传学团队的负责人），Sun和Guo；和 Drs的疾病和医疗经验。布希（输血医学），卡斯特（巴西美国的PI 队列；输血医学），香农（SCD专家），Sabinio（巴西PI的巴西共同托管）和 Rich（高级统计遗传学家）了解和解释这些有价值的资源数据。他们也会 与顶级的镰状细胞表型工作组和其他最佳研究人员一起工作。