Sequence analysis of hematological traits in African Americans

非裔美国人血液学特征的序列分析

• 批准号: 9176217
• 负责人: Ethan Mather Lange
• 金额: $ 79.79万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-01 至 2016-08-02
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9176217
• 关键词: Affect; African American; Alleles; American; Architecture; Binding; Biological Assay; Biology; Blood; Blood Cell Count; Blood Cells; CRISPR/Cas technology; Cardiovascular Diseases; Cardiovascular system; Cell Lineage; Cell physiology; Chronic Disease; Clinical; Clinical Treatment; Code; Collaborations; Collection; Complex; Computer Simulation; Data; Data Set; Disease; Elements; Enhancers; Ethnic Origin; European; Gene Expression; Gene Expression Regulation; Genes; Genetic; Genetic Enhancer Element; Genetic study; Genome engineering; Genomics; Genotype; Goals; Guide RNA; Heart; Hematological Disease; Hematopoiesis; Hematopoietic stem cells; Human; Immune System Diseases; Jackson Heart Study; Lead; Lung; Lung diseases; Maps; Measures; Meta-Analysis; Methodology; Minority; National Heart, Lung, and Blood Institute; Nucleic Acid Regulatory Sequences; Participant; Pathway interactions; Pattern; Phase; Phenotype; Plague; Population; Population Sizes; Production; Quantitative Genetics; Recording of previous events; Regulatory Element; Role; Sampling; Sequence Analysis; Signal Transduction; Staging; Stroke; Therapeutic; Trans-Omics for Precision Medicine; Translating; Untranslated RNA; Validation; Variant; Women' s Health; Work; base; bead chip; blood-based biomarker; cardiovascular disorder risk; cell type; clinical practice; cohort; design; disease diagnosis; epigenetic profiling; epigenomics; exome; exome sequencing; gene function; genetic association; genetic risk factor; genetic variant; genome editing; genome sequencing; genome wide association study; genome-wide; genomic variation; health disparity; improved; innovation; novel; novel therapeutics; programs; promoter; rare variant; regional difference; success; trait; transcription factor; transcriptomics; whole genome

Circulating blood cell counts represent important intermediate phenotypes for a variety of cardiovascular, pulmonary, hematologic, and immunologic diseases. These traits differ by ethnicity and studying the genetics of these quantitative blood traits in African Americans (AAs) may reveal new biologic pathways that ultimately contribute to our understanding both of biology of blood cell production and of the relationship of blood counts with CVD and other chronic diseases that disproportionately impact AAs. Genome-wide association studies (GWAS), to date, performed mainly in European Americans, have implicated a number of genomic loci. Despite these successes, association signals for blood cell traits are often associated with uncertain effects on gene function or regulation, and therefore not readily translatable to clinical practice or treatment. Several recent advancements hold promise for translating genetic association findings for blood cell traits into mechanism-based therapeutic approaches for clinical disease. First, genome-wide mapping of blood cell type- and lineage-specific promoter and enhancer elements, transcription factor binding patterns and epigenetic profiling now provide a detailed picture of the cis- and trans- regulatory landscape during hematopoiesis. Second, experimental approaches utilizing genome engineering (RNA- guided CRISPR-Cas9) can characterize critical regulatory elements and functional variants of modest effect that are essential for stage-specific, lineage-restricted effects on gene expression. This proposal will utilize the wealth of newly available genetic data in multiple large AA cohorts, including high-coverage whole genome sequence (WGS) data available on ~3,500 JHS participants and exome array data on ~11,400 participants from the REasons for Geographical And Regional Differences in Stroke (REGARDS), the Jackson Heart (JHS) and Women's Health Initiative (WHI) studies to discover and functionally characterize novel genetic associations. These data will be combined with existing GWAS and exome array data on thousands of additional AAs with measured blood cell traits to form the largest and most comprehensive genetic study of blood cell traits ever conducted in AAs. Our study will use novel and established analytic and experimental approaches, consistent with the goals and directives of this initiative, to identify important genetic variants affecting these important blood-based biomarkers.

循环血细胞计数代表了多种疾病的重要中间表型， 心血管、肺、血液和免疫疾病。这些特征不同 研究非洲人的这些定量血液特征的遗传学， 美国人（AAs）可能会揭示新的生物途径，最终有助于我们 了解血细胞产生的生物学和血液与 CVD和其他慢性疾病对AA的影响不成比例。 迄今为止，全基因组关联研究（GWAS）主要在欧洲进行， 美国人，有牵连的一些基因位点。尽管取得了这些成功， 血细胞性状的关联信号通常与对血细胞性状的不确定影响有关。 基因功能或调控，因此不易转化为临床实践或 治疗最近的几项进展为翻译遗传关联带来了希望 血细胞性状的研究结果转化为基于机制的临床治疗方法 疾病首先，血细胞类型和谱系特异性启动子的全基因组定位 和增强子元件，转录因子结合模式和表观遗传分析 现在提供了一个详细的图片顺式和反式监管景观， 造血第二，利用基因组工程（RNA- 引导的CRISPR-Cas9）可以表征关键的调控元件和功能元件。 对阶段特异性、谱系限制性效应至关重要的适度效应变体 对基因表达的影响这项建议将利用新获得的丰富的基因数据 在多个大型AA队列中，包括高覆盖率全基因组测序（WGS） 约3，500名JHS参与者的数据和约11，400名参与者的外显子组阵列数据 根据中风的地理和地区差异的原因（REGARDS）， 杰克逊心脏（JHS）和妇女健康倡议（WHI）研究发现， 在功能上表征新的遗传关联。这些数据将与 现有的GWAS和外显子组阵列数据上的数千个额外的AA与测量 血细胞性状，形成最大和最全面的遗传研究的血细胞 在AA中进行的所有测试。我们的研究将使用新的和既定的分析和 根据本倡议的目标和指示， 确定影响这些重要血液生物标志物的重要遗传变异。