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

项目摘要/摘要 镰状细胞病是由β-血红蛋白基因(HBb)的少数突变引起的。具有以下特征的个人 相同的突变可能会导致临床上完全不同的疾病，从轻微的、几乎没有临床并发症到 严重并发症，如中风、腿部溃疡、肺动脉高压、异常勃起和急性胸部 综合症。我们建议识别导致SCD异质性的功能性遗传变异，包括 来自中国的2056名SCD患者中的缺血性中风、高血压和胎儿血红蛋白升高 REDS-III巴西SCD队列。这个表型很深的队列正在进行全基因组测序 (WGS)，由NHLBI TOPMed计划赞助。TOPMed计划为WGS提供资金 在贝勒基因组测序中心，基因分型将在阿贝卡斯博士的实验室进行，网址为 密歇根大学，但不提供将WGS与临床和END相结合的分析资源 点数据。这个队列中的WGS数据提供了一个宝贵的机会来了解 许多并存的疾病困扰着SCD患者。 这款R21是在REDS-III研究的基础上进行的，该研究收集了10月间的巴西队列 2013年和2015年5月，研究输血方面，如输血反应的决定因素，艾滋病毒 感染和同种异体免疫。所有要在这里研究的表型--缺血性中风、血压和 HBF水平-相对于主要终点而言是次要的。 我们建议用全基因组、BREAD、HbSB0研究HbSS/HbSB0患者缺血性中风的遗传学。 途径，以及在先前SCD卒中候选基因和非SCD的指导下的生物信息学方法 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基因座(约250)上。最后，在以前的基础上 成功地对胎儿血红蛋白水平进行全基因组研究，我们将复制已报道的结果并进行 全基因组研究。 寻求这一机会的团队都是REDS-III调查人员，并将WGS和生物信息学结合在一起 佩奇博士(REDS-III生物信息学和统计遗传学小组组长)、孙博士和郭博士的专业知识； 巴西的布希博士(输血医学)、卡斯特博士(美国的皮尔)的疾病和医疗经验 队列；输血医学)，Shannon(SCD专家)，Sabinio(巴西队列中的巴西PI)，以及 里奇(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调查人员合作。

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.