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，我们环境的巨大变化导致非通信疾病的增加 由我们的遗传学和环境之间的复杂相互作用决定。知道为什么以及如何 个人比其他人对环境扰动更敏感，这仍然是我们的主要差距 了解遗传效应在环境上依赖的性状。为了解决这个差距，我们 图尔卡纳（Turkana 从传统生活方式到城市的过渡，并平行显示心脏代谢的增加 疾病。我建议在炎症的背景下研究对这种剧烈生活方式改变的分子反应 会议的机制增加了代谢疾病的风险。首先，我将确定协调的中断 通过检测代谢基因，转向西方生活方式之后的生物过程 PBMC中的网络疾病。接下来，我将确定基因组调节（ATAC-SEQ）和转录（RNA- SEQ）对单核细胞中体外促炎刺激的反应，其中跨整个差异反应 图尔卡纳的生活方式梯度将告知慢性肥胖信号（在城市环境中）如何改变 急性炎症过程通常是响应营养状况而发生的。然后，我将确定通用 对单核细胞促炎反应变异的贡献，并询问这些遗传效应的程度 由个人的生活方式（即基因型 - 环境相互作用）调节。最后，我会问什么 学位这些基因座解释了与健康相关的生物标志物的个体间差异。因为图尔卡纳的 独特的历史和当前的迁移模式，它们被毒死了，以研究快速的健康影响 环境转变，以及基因型在多大程度上使人倾向于脆弱性或 面对环境挑战（即西方生活方式）的韧性。解决这些重要问题 在广泛了解的非洲血统人群中，对全球卫生和 非裔美国人的精密医学。综上所述，这些目标与NIH目标一致 涉及了解个人对疾病和风险的个人易感性；并了解 西方环境的病理生物学对我们的心脏代谢健康。我的奖学金培训计划将集中精力 在提高我的定量技能方面，我旨在建立一个专注于理解的研究计划 逐个环境相互作用对心脏代谢风险的贡献。将启用此开发 通过朱利安·亚略（Julien Ayroles 启动了本应用程序核心的Turkana Health and Genomics项目。我与陶龙的互动 小组和与刘易斯 - 西格勒综合基因组学研究所的潜水员教师合作 普林斯顿将支持我成功成为成功的培训和学术网络 独立研究者。