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

项目总结/摘要 镰状细胞病（SCD）是由β-血红蛋白基因（HBB）中的少数突变引起的。人士 同样的突变在临床上可能导致完全不同的疾病，从轻微的临床并发症到 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部 综合征我们建议确定导致SCD异质性的功能性遗传变异，包括 缺血性卒中、高血压和胎儿血红蛋白升高的研究， REDS-III巴西SCD队列。这一深度表型化的队列正在进行全基因组测序 (WGS)在NHLBI TOPMed计划的赞助下。TOPMed计划为WGS提供资金 在贝勒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，但不提供用于将联合收割机WGS与临床和终末期相结合的分析的资源。 点数据该队列的WGS数据为了解该人群的遗传学提供了宝贵的机会 许多困扰SCD患者的合并症。 这项R21研究是建立在REDS-III研究的基础上的，该研究收集了10月至12月期间的巴西队列。 2013年和2015年5月，研究输血的各个方面，如输血反应的决定因素、艾滋病毒 感染和同种免疫。这里要研究的所有表型-缺血性中风，血压， HbF水平是次要的主要终点。 我们建议使用全基因组，负荷， 途径和生物信息学方法，以先前SCD卒中候选基因和非SCD卒中候选基因为指导， SCD全基因组研究。我们将进一步研究血压和高血压的遗传学， 所有已知的复杂和孟德尔血压位点（约250个）。最后，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，我们将复制报告的结果，并进行 全基因组研究 追求这个机会的团队都是REDS-III研究人员，他们将WGS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负责人）、Sun博士和Guo博士的专业知识;和 Busch（输血医学）、卡斯特（巴西的美国PI） 队列;输血医学），Shannon（SCD专家），Sabinio（巴西联合队列的巴西PI），和 丰富的（高级统计遗传学家）理解和解释这些宝贵的资源数据。他们还将 与TOPMed镰状细胞表型工作组和其他TOPMed研究者合作。

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.