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

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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.