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

项目总结/摘要 非传染性疾病，特别是恶性血液病和心血管疾病的负担 （心血管疾病），在非洲正在上升。不确定潜能的克隆性造血（CHIP）是一种与年龄相关的危险因素 全因死亡率，血癌和心血管疾病，促使人们对开发靶向药物产生巨大兴趣 CHIP突变阻断恶性肿瘤进展。然而，非洲人后裔是少数， 因此，在这些CHIP研究中，需要了解非洲人CHIP变体的谱和频率， 人口。我的长期研究目标是建立一个泛非洲的体细胞突变数据库 与患髓性白血病的风险有关。最近的全基因组关联分析 确定了使个体易感CHIP获得风险增加的生殖系基因座。其中包括 TET 2附近的rs 144418061基因间变异仅在非洲血统人群中发现。核心假设是 与年龄匹配的健康人相比，正常衰老的非洲人中CHIP变体的负担很高， 白种人为了解决这个问题，我提出了以下具体目标：目标1确定CHIP的频率 在一群临床上健康的哥伦比亚人中发现了突变。来自尼日利亚健康志愿者的全血样本 将收集≥40年，并对基因型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 在三年的时间里，CHIP收购的结果。每名受试者将被随访三年， 将确定CHIP克隆优势在这段时间内的时间动态。此外，血液学 将描述与CHIP体系结构相关的变化。人们怀疑，不同的行为和 临床状态将影响不同个体中CHIP进展的速率。目标3将决定 研究人群中与CHIP负荷相关的炎症标志物。在这里，基于Luminex的人类 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。这 K43项目将产生关于正常衰老的哥伦比亚人的CHIP突变的信息。这与研究I一致 我目前在患有不同合并症的尼日利亚人中领导CHIP负担。我的职业发展目标 这个K43应用程序是为了获得纠错测序，变异调用以及数据分析的技能， 在该奖项的第五年之前，为竞争性假设驱动的R 01提交生成足够的数据。这 这将使我能够在尼日利亚建立血癌遗传学的研究能力，并建立我的独立性 作为一个非洲的医学遗传学家。我的培训和研究活动将受益于一个强大的委员会， 导师包括美国和非洲的血液学，群体遗传学， 生物信息学和计算分析。我会尽量利用我在尼日利亚医学研究所的时间 进行血液学分析和测序，同时利用实践培训活动， 重要的数据科学和研究领导课程，可在美国国立卫生研究院。

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.