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

摘要 在全球范围内，我们环境的急剧变化正在导致非传染性疾病的增加， 这是由我们的遗传和环境之间复杂的相互作用决定的。知道为什么和如何一些 个体对环境扰动比其他人更敏感，这仍然是我们研究的一个主要空白。 理解遗传效应依赖于环境的性状。为了弥补这一差距，我们 与肯尼亚西北部的一个仅能维持生计的社区图尔卡纳人合作， 从传统生活方式向城市生活方式的转变，同时显示心脏代谢的增加 紊乱我建议在炎症背景下研究这种剧烈的生活方式变化的分子反应， 增加代谢疾病风险的机制。首先，我将确定协调的中断 随着向西方生活方式的转变，通过检测代谢基因， 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）对单核细胞中的体外促炎刺激的应答，其中在单核细胞中的差异应答 图尔卡纳的生活方式梯度将告知慢性致肥胖信号（在城市环境中）如何改变 急性炎症过程，通常发生在对营养状况的反应。然后我会鉴定出 在单核细胞促炎反应的变化的贡献，并询问在多大程度上这些遗传效应 受个体生活方式的调节（即基因型与环境的相互作用）。最后，我想问一下 这些基因座在一定程度上解释了健康相关生物标志物的个体间差异。因为图尔卡纳人 独特的历史和目前的移民模式，他们是独特的准备研究健康的影响，快速 环境变化，以及基因型使个体倾向于脆弱性的程度， 面对环境挑战的适应能力（即西方生活方式）。解决这些重要问题 在非洲血统的人口中，对全球健康有重要的影响， 非裔美国人的精准医疗总之，这些目标与NIH的目标一致，因为它们 包括了解个体对疾病的易感性和人群中的风险; 西方环境的病理生物学对我们心脏代谢健康的影响。我的奖学金培训计划将集中在 提高我的定量技能，因为我的目标是建立一个研究计划，重点是了解 基因型与环境相互作用对心脏代谢风险的影响。这一发展将使 Julien Ayroles博士是系统和定量遗传学专家，最近 启动了图尔卡纳健康和基因组学项目，这是该应用程序的核心。我和艾若尔夫妇的互动 小组和合作与不同的教师在刘易斯西格勒研究所整合基因组学在 普林斯顿大学将支持必要的培训和学术网络，以成功地实现我成为一名 独立调查员

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.