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，我们环境的戏剧性变化正在导致非传染性疾病的增加，这些疾病 由我们的基因和环境之间复杂的相互作用决定的。知道为什么以及如何 个人比其他人对环境扰动更敏感仍然是我们的一个主要差距 对遗传效应与环境有关的性状的理解。为了解决这一差距，我们 与肯尼亚西北部一个勉强维持生计的社区图尔卡纳人合作，图尔卡纳人最近发起了 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 精神错乱。我建议在炎症性疾病的背景下研究这种生活方式剧烈变化的分子反应 增加代谢性疾病风险的机制。首先，我将确定协调中的中断 通过检测代谢基因，了解向西方生活方式转变后的生物学过程 PBMC中的网络干扰。接下来我将鉴定基因组调控(atac-seq)和转录(rna-seq)。 SEQ)对体外单核细胞促炎刺激的反应，其中 图尔卡纳人的生活方式梯度将告诉我们慢性肥胖信号(在城市环境中)是如何改变的 通常因营养状况而发生的急性炎症过程。然后我会鉴定出基因 并询问这些遗传效应在多大程度上影响单核细胞促炎反应的变异 受个人生活方式的影响(即基因与环境的相互作用)。最后，我会问你要做什么 这些基因座在一定程度上解释了健康相关生物标记物的个体间差异。因为图尔卡纳人 独特的历史和当前的迁徙模式，他们独一无二地准备研究快速 环境变化，以及基因在多大程度上使个人容易受到伤害或 面对环境挑战(即西方的生活方式)时的应变能力。解决这些重要问题 在很大程度上未被研究的非洲血统人口中，对全球健康和 非裔美国人的精准医学。总而言之，这些目标与NIH的目标一致，因为它们 包括了解人群中个人对疾病的易感性和风险；以及了解 西方环境的病理生物学对我们心脏代谢健康的影响。我的团契培训计划将重点放在 关于提高我的量化技能，因为我的目标是建立一个研究计划，专注于理解 基因与环境的交互作用对心脏代谢风险的贡献。这一开发将启用 由朱利安·艾若尔斯博士指导，他是系统和数量遗传学方面的专家，最近 启动了图尔卡纳健康和基因组学项目，该项目是该应用程序的核心。我与艾瑞斯夫妇的互动 刘易斯-西格勒整合基因组学研究所的小组和与不同教职员工的合作 普林斯顿将支持培训和学术网络，以实现我成为一名 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.