Understanding the contribution of genotype-by-lifestyle interactions to cardiometabolic risk in individuals of east African ancestry

了解基因型与生活方式的相互作用对东非血统个体心脏代谢风险的影响

• 批准号: 10537570
• 负责人: Kristina Marie Garske
• 金额: $ 6.72万
• 依托单位: PRINCETON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10537570
• 关键词: ATAC-seq; Acute; Address; African American population; African ancestry; Biological Markers; Biological Process; Blood Glucose; Cardiometabolic Disease; Chromatin; Chronic; Cities; Collaborations; Communities; Complex; Data; Detection; Development; Disease; Environment; Exhibits; Exposure to; Faculty; Fellowship; Gene Expression; Genes; Genetic; Genetic Transcription; Genetic Variation; Genetic study; Genome; Genomics; Genotype; Goals; Health; Homeostasis; Human Genetics; In Vitro; Individual; Individual Differences; Inflammatory; Inflammatory Response; Institutes; Kenya; Knowledge; Lead; Life; Life Style; Mentorship; Metabolic; Metabolic Diseases; Metabolic stress; Modernization; Molecular; Molecular Genetics; Non-Insulin-Dependent Diabetes Mellitus; Nutritional status; Obesity; Pathway interactions; Pattern; Peripheral Blood Mononuclear Cell; Persons; Physical environment; Plague; Population; Predisposition; Process; Prognosis; Quantitative Genetics; Recording of previous events; Reporting; Research; Research Personnel; Risk; Role; Rural; Sampling; Signal Transduction; Source; Stimulus; Stress; System; Testing; Training; Training Support; Transcript; United States National Institutes of Health; Variant; Work; cardiometabolic risk; cardiometabolism; disorder risk; environmental stressor; experience; feeding; gene network; genetic variant; global health; health difference; high body mass index; improved; migration; molecular phenotype; monocyte; obesogenic; phenotypic data; precision medicine; pressure; programs; resilience; response; rural-urban migration; skills; stem; trait; transcriptome sequencing; urban area; urban setting

ABSTRACT Globally, dramatic changes in our environments are leading to increases in non-communicable diseases that are determined by the complex interplay between our genetics and environment. Knowing why and how some individuals are more sensitive than others to environmental perturbations remains a major gap in our understanding of traits for which the genetic effects are environmentally dependent. To address this gap, we have partnered with a subsistence-level community in northwest Kenya, the Turkana, who very recently initiated a transition from a traditional lifestyle to an urban one and are in parallel showing increases in cardiometabolic disorders. I propose to study molecular responses to this drastic lifestyle change in the context of inflammatory mechanisms that confer increased risk for metabolic diseases. First, I will identify disruptions in coordinated biological processes following the shift toward a Western lifestyle, through the detection of metabolic gene network disturbances in PBMCs. Next I will identify genomic regulatory (ATAC-seq) and transcriptional (RNA- seq) responses to in vitro pro-inflammatory stimulation in monocytes, wherein differential responses across the lifestyle gradient in the Turkana will inform how chronic obesogenic signaling (in an urban environment) alters acute inflammatory processes that typically occur in response to nutritional status. I will then identify the genetic contribution to variation in monocyte pro-inflammatory responses and ask to what degree these genetic effects are modulated by an individual’s lifestyle (i.e. genotype-by-environment interaction). Finally, I will ask to what degree these loci explain inter-individual differences in health-related biomarkers. Because of the Turkana’s unique history and current migration patterns, they are uniquely poised to study the health impact of rapid environmental shift, as well as the degree to which genotype predisposes individuals toward vulnerability or resilience in the face of environmental challenges (i.e. a western lifestyle). Addressing these important questions in a largely understudied population of African ancestry has important implications toward global health and precision medicine in African-Americans. Taken together, these Aims align with the NIH objectives, as they involve understanding individual susceptibility to disease and risk across populations; and understanding the pathobiology of the Western environment on our cardiometabolic health. My fellowship training plan will focus on improving my quantitative skills, as I aim to build a research program focused on understanding the contribution of genotype-by-environment interactions to cardiometabolic risk. This development will be enabled by the mentorship from Dr. Julien Ayroles, who is an expert in systems and quantitative genetics and recently initiated the Turkana Health and Genomics project at the core of this application. My interactions with the Ayroles group and collaborations with the diverse faculty at the Lewis-Sigler Institute for Integrative Genomics at Princeton will support the training and academic network necessary to succeed in my goal of becoming an independent investigator.

抽象的 在全球范围内，环境的巨大变化正在导致非传染性疾病的增加 由我们的遗传和环境之间复杂的相互作用决定。知道为什么以及如何一些 个人对环境扰动比其他人更敏感仍然是我们的一个主要差距 了解遗传效应依赖于环境的性状。为了解决这一差距，我们 与肯尼亚西北部的图尔卡纳 (Turkana) 社区合作，该社区最近发起了 从传统生活方式向城市生活方式的转变，同时显示出心脏代谢的增加 失调。我建议研究在炎症背景下对这种生活方式的剧烈改变的分子反应 增加代谢疾病风险的机制。首先，我将确定协调中的干扰 通过检测代谢基因，向西方生活方式转变后的生物过程 PBMC 中的网络干扰。接下来我将确定基因组调控（ATAC-seq）和转录（RNA- seq）对单核细胞体外促炎刺激的反应，其中跨 图尔卡纳的生活方式梯度将揭示慢性肥胖信号（在城市环境中）如何改变 通常因营养状况而发生的急性炎症过程。然后我会鉴定基因 对单核细胞促炎症反应变化的贡献，并询问这些遗传效应的程度 受个人生活方式的调节（即基因型与环境的相互作用）。最后我会问什么 这些位点在一定程度上解释了健康相关生物标志物的个体间差异。因为图尔卡纳 由于独特的历史和当前的迁徙模式，他们具有独特的能力来研究快速迁移对健康的影响 环境变化，以及基因型使个体易受脆弱性或影响的程度 面对环境挑战的复原力（即西方生活方式）。解决这些重要问题 在很大程度上未被充分研究的非洲血统人群中，对全球健康和健康具有重要影响 非裔美国人的精准医疗。总的来说，这些目标与 NIH 的目标是一致的，因为它们 涉及了解不同人群对疾病和风险的个体易感性；并了解 西方环境对我们心脏代谢健康的病理生物学。我的奖学金培训计划将重点 提高我的定量技能，因为我的目标是建立一个专注于理解 基因型与环境相互作用对心脏代谢风险的贡献。此开发将启用 由系统和定量遗传学专家 Julien Ayroles 博士指导，最近 启动了作为该应用程序核心的图尔卡纳健康和基因组学项目。我与艾罗尔斯的互动 小组以及与刘易斯-西格勒综合基因组学研究所的不同教师的合作 普林斯顿大学将支持必要的培训和学术网络，以帮助我成功实现成为一名 独立调查员。