Our Program Project is focused on the genetic dissection of metabolic syndrome (MetSyn) traits relevant to cardiometabolic disease. We believe that our proposal is unique in its use of multifaceted and integrative approaches to measure and analyze mouse and human populations. During the current grant cycle, each of the four projects has been highly productive and also highly interactive, as described in the Program Introduction. We now propose three Projects and four Cores. The projects represent direct continuations of the present Projects 1, 2, and 4. Project 1 will focus on gene-by-diet interactions in metabolic syndrome traits. Project 2 will utilize systems genetics approaches to understand the regulation of bile acid metabolism and its connection to metabolic syndrome. Project 3 will focus on systems genetics analyses of plasma lipoprotein metabolism in ethnically diverse human populations. Each of the projects will utilize two important resources developed during the present grant cycle. The first of these is the Hybrid Mouse Diversity Panel (HMDP), a renewable population of about 100 inbred strains of mice that can be used for high-resolution association mapping of complex traits and systems genetics. The second is the METSIM population developed by Maarku Laakso, University of Kuopio, Finland. This population consists of more than 10,000 men aged 50-65, that have been characterized in great detail for metabolic syndrome traits as well as for sequence variation and gene expression in adipose. In addition to these resources, we examine two biologic scales that appear to be particularly relevant to MetSyn: the gut microbiome and DNA methylation. Each of the projects will interact significantly with one another and with all of the Cores to address several interrelated critical questions relating to MetSyn: What is the nature of gene-by-diet interactions contributing to MetSyn? How do genetic variations influence bile acid and triglyceride metabolism? How do ethnic differences contribute to MetSyn?