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: 10292857
• 负责人: Kolapo Oyebola
• 金额: $ 9.31万
• 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/10292857
• 关键词: Address; Adopted; Africa; African; African American; Age; 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; Institutes; 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; base; 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; 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.

项目概要/摘要 非传染性疾病，特别是血液恶性肿瘤和心血管疾病的负担 （CVD）在非洲呈上升趋势，不确定性克隆造血（CHIP）是一个与年龄相关的危险因素。 降低全因死亡率、血癌和心血管疾病，引发了人们对开发靶向药物的巨大兴趣 CHIP 突变可阻止恶性肿瘤的进展然而，非洲人后裔只占少数。 在这些 CHIP 研究中，因此需要了解非洲 CHIP 变异的频谱和频率 我的长期研究目标是建立一个泛非洲体细胞突变数据库。 最近的全基因组关联分析表明，与发生髓性白血病的风险有关。 已确定的生殖系基因座使个体易患 CHIP 的风险增加，其中包括 仅在非洲血统人群中发现 TET2 附近的 rs144418061 基因间变异。 与年龄匹配的健康人相比，正常衰老的非洲人的 CHIP 变异负担很高 为了解决这个问题，我提出以下具体目标： 目标 1 确定 CHIP 的频率 来自健康尼日利亚志愿者的全血样本中的突变。 收集≥40年，对54个基因进行纠错靶向测序 已知在骨髓恶性肿瘤中经常发生突变。目标 2 描述了时间趋势和临床。 三年内 CHIP 收购的结果将被跟踪三年。 此外，还将确定该时期 CHIP 克隆优势的时间动态。 将描述与 CHIP 架构相关的变化，怀疑不同的行为和变化。 临床状态将影响不同个体的 CHIP 进展速度，目标 3 将决定。 此处，基于 Luminex 的人类研究与 CHIP 负担相关。 将采用细胞因子/趋化因子测定来梳理与 CHIP 负荷相关的炎症信号。 K43 项目将生成有关正常衰老尼日利亚人的 CHIP 突变的信息，这与研究 I 一致。 我目前在患有各种合并症的尼日利亚人中处于领先地位，我的职业发展目标是。 该 K43 应用程序旨在获得纠错测序、变异调用以及数据分析和分析方面的技能 在该奖项颁发的第五年之前，为竞争性假设驱动的 R01 提交生成足够的数据。 将使我能够在尼日利亚建立血癌遗传学研究能力并建立我的独立性 作为一名非洲医学遗传学家，我的培训和研究活动将受益于强大的委员会。 人口导师由美国和非洲的血液学、遗传学、 我将最大限度地利用在尼日利亚医学研究所的时间。 在利用实践培训活动的同时进行血液学分析和测序， 美国国立卫生研究院提供重要的数据科学和研究领导力课程。