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.

项目概要/摘要 镰状细胞病 (SCD) 仅由 β-血红蛋白基因 (HBB) 的少数突变引起。 相同的突变可能导致临床上截然不同的疾病，从轻微的、很少有临床并发症到 严重并发症，如中风、腿部溃疡、肺动脉高压、阴茎异常勃起和急性胸闷 我们建议识别导致 SCD 异质性的功能性遗传变异，包括 来自美国 2,056 名 SCD 患者的队列显示缺血性中风、高血压和胎儿血红蛋白升高 REDS-III 巴西 SCD 队列 这个深度表型队列正在进行全基因组测序。 (WGS) 在 NHLBI TOPMed 计划的支持下 TOPMed 计划为 WGS 提供资金。 在贝勒基因组测序中心进行，基因型识别将在 Abecasis 博士的实验室进行 密歇根大学，但不提供将 WGS 与临床和最终结果相结合的分析资源 该队列中的点数据为了解该群体的遗传学提供了宝贵的机会。 许多合并症困扰着 SCD 患者。 该 R21 建立在 REDS-III 研究的基础上，该研究收集了 10 月间的巴西队列数据 2013 年和 2015 年 5 月研究输血的各个方面，例如输血反应的决定因素、艾滋病毒 这里要研究的所有表型——缺血性中风、血压和 HbF 水平——对于主要终点而言是次要的。 我们建议利用全基因组、负荷、 途径和生物信息学方法，以先前的 SCD 中风候选基因和非 我们将重点关注SCD全基因组研究，进一步研究血压和高血压的遗传学。 最后，建立在之前的基础上。 胎儿血红蛋白水平的成功全基因组研究，我们将复制报告的结果并进行 全基因组研究。 寻求这个机会的团队都是 REDS-III 的研究人员，并将全基因组测序和生物信息学结合在一起 Page 博士（REDS-III 生物信息学和统计遗传学团队的负责人）、Sun 和郭博士的专业知识； Busch 博士（输血医学）、Custer（巴西美国 PI）的疾病和医疗经验 队列；输血医学）、Shannon（SCD 专家）、Sabinio（巴西队列的巴西 PI）和 Rich（高级统计遗传学家）也将理解和解释这些宝贵的资源数据。 与 TOPMed 镰状细胞表型分析工作组和其他 TOPMed 研究人员合作。