Prevalence and temporal dynamics of clonal mutations associated with the risk of hematological cancer in a cohort of clinically healthy Nigerians

临床健康尼日利亚人队列中与血液癌风险相关的克隆突变的患病率和时间动态

• 批准号: 10610478
• 负责人: Kolapo Oyebola
• 金额: $ 9.4万
• 依托单位: NIGERIAN INSTITUTE OF MEDICAL RESEARCH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-22 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10610478
• 关键词: Address; Adopted; Africa; African; African American population; African ancestry; Age; American; Architecture; Award; Behavioral; Bioinformatics; Biological Assay; Blood Cells; Blood specimen; Cardiovascular Diseases; Caucasians; Cell Lineage; Chronic; Clinical; Clonal Expansion; Computer Analysis; DNA Library; Data; Data Analyses; Data Science; Databases; Detection; Diagnosis; Disease; Drug Targeting; Frequencies; Gene Frequency; Genes; Genetic; Genotype; Goals; Hematologic Neoplasms; Hematological Disease; Hematology; Hematopoiesis; Hematopoietic; Hematopoietic Neoplasms; Hematopoietic stem cells; Human; Individual; Inflammation; Inflammatory; Intercept; Laboratories; Leadership; Malignant - descriptor; Malignant Neoplasms; Medical; Medical Research; Mentors; Minor; Minority; Mutate; Mutation; Myeloid Leukemia; Myeloproliferative disease; National Heart, Lung, and Blood Institute; Nigeria; Nigerian; Non-Insulin-Dependent Diabetes Mellitus; Outcome; Patients; Population; Population Genetics; Preparation; Prevalence; Research; Research Activity; Research Personnel; Risk; Risk Factors; Signal Transduction; Somatic Mutation; Technology; Testing; Therapeutic Intervention; Time; Time trend; Training; Training Activity; Trans-Omics for Precision Medicine; United States National Institutes of Health; Variant; Whole Blood; age related; cancer genetics; career; career development; chemokine; cohort; comorbidity; cytokine; data management; data visualization; drug development; follow-up; genetic analysis; genetic variant; genome database; genome sequencing; genome wide association study; inflammatory marker; interest; leukemia; magnetic beads; mortality; normal aging; peripheral blood; post-doctoral training; pressure; rare variant; risk prediction; skill acquisition; skills; study population; targeted sequencing; targeted treatment; variant detection; volunteer; whole genome

PROJECT SUMMARY/ABSTRACT The burden of non-communicable diseases, especially hematological malignancies and cardiovascular diseases (CVDs), is rising in Africa. Clonal Hematopoiesis of Indeterminate Potential (CHIP) is an age-related risk factor for all-cause mortality, blood cancer and CVDs, prompting huge interests in the development of drugs targeting CHIP mutations to intercept progression to malignancies. However, individuals of African descent are a minority in these CHIP studies hence the need to understand the spectrum and frequency of CHIP variants in African populations. My long-term research goal is to generate a pan-African database of somatic mutations associated with the risk of developing myeloid leukemia. Recent genome-wide association analyses have identified germline loci predisposing individuals to increased risk of CHIP acquisition. These include the rs144418061 intergenic variant near TET2 found only in African-ancestry populations. The central hypothesis is that there is a high burden of CHIP variants in normal-aging Africans compared to age-matched healthy Caucasians. To address this, I propose the following specific aims: Aim 1 determines the frequency of CHIP mutations in a cohort of clinically healthy Nigerians. Whole blood samples from healthy Nigerian volunteers ≥40 years will be collected and error-corrected targeted sequencing will be carried out to genotype 54 genes known to be frequently mutated in myeloid malignancies. Aim 2 describes temporal trends and clinical outcomes of CHIP acquisition over a three-year period. Each subject will be followed up for three years and the temporal dynamics of CHIP clonal dominance over the period will be determined. In addition, hematological changes correlating with the CHIP architecture will be described. It is suspected that varying behavioral and clinical states will impact the rate of CHIP progression in different individuals. Aim 3 will determine the inflammatory markers associated with CHIP burden in the study population. Here, Luminex-based Human Cytokine/Chemokine assay will be adopted to tease out inflammatory signals correlating with CHIP burden. This K43 project will generate information on CHIP mutations in normal-aging Nigerians. This aligns with the study I am currently leading on CHIP burden in Nigerians with varying comorbidities. My career development goal of this K43 application is to gain skills on error-corrected sequencing, variant calling as well as data analysis and generate sufficient data for a competitive hypothesis-driven R01 submission by the fifth year of this award. This will enable me to build research capacity for blood cancer genetics in Nigeria and establish my independence as an Africa-based medical geneticist. My training and research activities will benefit from a strong committee of mentors comprising established US and Africa-based researchers in hematology, population genetics, bioinformatics and computational analysis. I will maximize my time at the Nigerian Institute of Medical Research carrying out hematological analysis and sequencing while taking advantage of hands-on training activities, important data science and research leadership courses available at the National Institutes of Health.

项目摘要/摘要 非通信疾病的伯恩（Burnen），尤其是血液学恶性肿瘤和心血管疾病 （CVD），在非洲正在上升。不确定潜力（芯片）的克隆造血症是与年龄有关的危险因素 对于全因死亡率，血液癌和CVD 切屑突变以拦截恶性肿瘤。但是，非洲血统的个人是少数 在这些芯片研究中，因此需要了解非洲芯片变体的频谱和频率 人群。我的长期研究目标是生成一个泛非的体细胞突变数据库 与患有髓样白血病的风险有关。最近全基因组关联分析具有 鉴定出种系基因座易于增加芯片获取风险。这些包括 rs144418061仅在非洲官员种群中发现的TET2附近的基因间变体。中心假设是 与年龄匹配的健康相比 高加索人。为了解决这个问题，我提出以下特定目的：目标1确定芯片的频率 一系列临床健康的尼日利亚人的突变。来自健康尼日利亚志愿者的全血样本 将收集≥40岁的40年，并将错误校正的靶向测序进行到基因型54基因 已知经常在髓样恶质中突变。 AIM 2描述了临时趋势和临床 在三年内获得芯片获取的结果。每个主题将被跟踪三年， 将确定芯片克隆主导地位的临时动力学。另外，血液学 将描述与芯片架构相关的更改。怀疑行为和 临床状态将影响不同个体的芯片进展率。 AIM 3将确定 研究人群中与芯片伯嫩有关的炎症标记。在这里，基于Luminex的人 将采用细胞因子/趋化因子测定法，以取消与CHIP负担相关的炎症信号。这 K43项目将生成有关正常尼日利亚人芯片突变的信息。这与研究一致 目前，尼日利亚人的合并症不同。我的职业发展目标 此K43应用程序是为了获得错误校正的测序，变体调用以及数据分析和 该奖项的第五年为竞争性假设驱动的R01提交生成足够的数据。这 将使我能够在尼日利亚建立血液癌遗传学的研究能力并建立我的独立性 作为基于非洲的医学遗传学家。我的培训和研究活动将受益于强大的委员会 完成既定美国和非洲血液学，人口遗传学研究人员的导师， 生物信息学和计算分析。我将在尼日利亚医学研究所最大化我的时间 在利用动手培训活动的同时，进行血液学分析和测序， 重要的数据科学和研究领导力课程可在美国国立卫生研究院提供。

项目成果

Molecular docking, simulation and binding free energy analysis of small molecules as PfHT1 inhibitors.

• DOI: 10.1371/journal.pone.0268269
• 发表时间: 2022
• 期刊: PloS one
• 影响因子: 3.7

Computational identification of potential modulators of heme-regulated inhibitor (HRI) for pharmacological intervention against sickle cell disease.

血红素调节抑制剂（HRI）潜在调节剂的计算鉴定，用于针对镰状细胞病的药物干预。

• DOI: 10.21203/rs.3.rs-3755458/v1
• 发表时间: 2023
• 期刊: Research square
• 作者: Owoloye,AfolabiJ;Olubode,SamuelO;Ogunleye,Adewale;Idowu,EmmanuelT;Oyebola,KolapoM
• 通讯作者: Oyebola,KolapoM