Systematic Investigation of Blacks with Stroke - Genomics (SIBS-Genomics) Study

黑人中风的系统调查 - 基因组学 (SIBS-Genomics) 研究

• 批准号: 9980719
• 负责人: BRUCE OVBIAGELE
• 金额: $ 42.46万
• 依托单位: COLLEGE OF MEDICINE, UNIVERSITY OF IBADAN
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-15 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9980719
• 关键词: 12q24; Africa; African; African American; Age; Age of Onset; American; Arteries; Atherosclerosis; Biological Process; CDKN2A gene; Candidate Disease Gene; Cause of Death; Cessation of life; Clinical; Communities; Complement; Complex; Computer software; Coupled; Custom; Data; Data Set; Dementia; Development; Diagnosis; Diagnostic; Disease; Education; Environmental Risk Factor; Ethnic Origin; European; Funding; Future; Gene Frequency; Genetic; Genetic Annotation; Genetic Determinism; Genetic Risk; Genome; Genomics; Goals; HDAC9 gene; Heritability; Heterogeneity; Hypertension; Interleukin-6; Intervention; Investigation; Ischemic Stroke; Lacunar Infarctions; Legal patent; Linkage Disequilibrium; Maps; Measures; Meta-Analysis; Microvascular Dysfunction; Minor; Molecular; National Institute of Neurological Disorders and Stroke; Pathogenesis; Pathway interactions; Phenotype; Population; Prevalence; Prevention; Prevention strategy; Process; Relative Risks; Reporting; Research; Research Personnel; Resolution; Risk Factors; SERPINI2 gene; Sampling; Stroke; Structure; Translating; Translations; United States National Institutes of Health; Untranslated RNA; Validation; Variant; cardiometabolism; case control; causal variant; data format; design; disability; genetic variant; genome sequencing; genome wide association study; genome-wide; genomic locus; improved; novel; outcome forecast; prognostic tool; recruit; sex; stroke outcome; stroke risk; targeted biomarker; tool; whole genome

Stroke is the second leading cause of death globally. Ischemic stroke which accounts for up to 90% of strokes in the USA, is the clinical culmination of several complex and interacting biological processes, initiated by various genetic and environmental factors, thereby making ready analyses of its underlying mechanisms a challenge. Substantial amount of genetic risk for stroke remain unexplained. Moreover, genetic variants previously associated with stroke in African and European Americans could not be translated into clinical use because they have not been validated and functionally annotated. A better understanding of these unique factors is imperative for the formation of successful tailor-made interventions to mitigate this colossal burden. Due to its higher stroke heritability and resolution for fine mapping, the continental African population holds the aces to advancing stroke genomics but has never been included in stroke GWAS studies. The overall goal of SIBS-Genomics, is to discover, validate and functionally characterize novel genetic variants associated with ischemic stroke in people of African ancestry. SIBS Genomics will leverage several NIH-funded initiatives in the US and Africa led by SIBS Genomics investigators including REGARDS, SiGN, COMPASS, MEPI, THRIVES (U01NS079179), PINGS (NS094033) and the NINDS-funded Stroke Investigative Research and Educational Network (SIREN U54HG007479), the largest study of stroke in people of African ancestry. Indeed SIBS Genomics promises to substantially advance the global effort to discover the novel genetic loci for ischemic stroke thereby facilitating the understanding of the corresponding molecular mechanisms of ischemic stroke for numerous reasons: a) use of accurately phenotyped subjects with comprehensive covariate dataset (special stroke phenotyping software with patent developed in SIREN), b) use of a novel NIH-funded most effective chip for dense genome-wide association study in African ancestry, c) an unexplored population with substantially higher heritability and racial predilection of stroke; and higher resolution for fine-mapping due to its low linkage disequilibrium. d) and processing of samples for future whole genome sequencing and transomics analyses. The goal of SIBS Genomics will be accomplished using a novel multi-stage approach in a concise network of leading global content experts. Validation and functional annotation of genetic variants previously reported in Americans will be performed using data from continental Africans. Furthermore, discovery of novel variants will be sought in continental Africans and validated in African Americans (71% of whom migrated from West Africa); while Americans of diverse ancestries will be included in trans-ancestry meta-analyses. Overall, new clues on the molecular mechanisms of stroke will open new array of targeted biomarkers (for prediction, diagnosis, prognosis), and interventions (neuroprotective, treatment, prevention) for stroke. This unique transomics study will translate to efficient solutions for controlling the burden of stroke in American populations, especially African Americans in whom the burden remains disproportionately high.

中风是全球第二大死亡原因。缺血性中风占90% 美国的中风是几个复杂且相互作用的生物过程的临床高潮，由 各种遗传和环境因素，从而对其潜在机制进行分析 挑战。大量中风的遗传风险仍然无法解释。此外，基因变异 以前与非洲裔和欧洲裔美国人中风相关的药物无法转化为临床应用 因为它们尚未经过验证和功能注释。更好地了解这些独特因素 制定成功的定制干预措施以减轻这一巨大负担至关重要。 由于其较高的中风遗传力和精细绘图分辨率，非洲大陆人口 拥有推进中风基因组学的王牌，但从未被纳入中风 GWAS 研究中。整体 SIBS-Genomics 的目标是发现、验证和功能表征相关的新型遗传变异 非洲血统的人患有缺血性中风。 SIBS Genomics 将利用 NIH 资助的多项举措 由 SIBS Genomics 调查人员领导的美国和非洲，包括 REGARDS、SiGN、COMPASS、MEPI、THRIVES (U01NS079179)、PINGS (NS094033) 和 NINDS 资助的中风调查研究和教育 网络 (SIREN U54HG007479)，最大的非洲裔中风研究。事实上 SIBS 基因组学 有望大幅推进全球发现缺血性中风新基因位点的努力 促进对缺血性中风相应分子机制的理解 原因：a）使用具有全面协变量数据集的准确表型受试者（特殊中风 具有 SIREN 开发专利的表型分析软件），b）使用 NIH 资助的新型最有效芯片进行密集 非洲血统的全基因组关联研究，c）一个未经探索的人群，其 中风的遗传性和种族偏好；由于其低连接，精细映射的分辨率更高 不平衡。 d) 和处理样本以用于未来的全基因组测序和转组学分析。 SIBS Genomics 的目标将在简洁的网络中使用新颖的多阶段方法来实现 全球领先的内容专家。先前报道的遗传变异的验证和功能注释 美国人将使用非洲大陆人的数据进行测试。此外，新变体的发现将 在非洲大陆人中寻求并在非裔美国人中得到验证（其中 71% 来自西非移民）；尽管 不同血统的美国人将被纳入跨血统荟萃分析中。总体而言，新的线索 中风的分子机制将开辟一系列新的靶向生物标志物（用于预测、诊断、预后）， 以及中风​​的干预措施（神经保护、治疗、预防）。这项独特的转组学研究将转化为 控制美国人群，尤其是非洲裔美国人的中风负担的有效解决方案 他们的负担仍然过重。