Location: Obesity and Metabolism ResearchTitle: Sexual dimorphism of atherosclerosis and plasma lipids: Analysis of complex traits in a diversity outbred F1 mouse population
|KIM, MYUNGSUK - University Of California, Davis|
|RINDY, ALEXA - University Of California, Davis|
|QUE, EXCEL - University Of California, Davis|
|HUDA, NAZMUL - University Of California, Davis|
Submitted to: Meeting Abstract
Publication Type: Abstract Only
Publication Acceptance Date: 2/26/2019
Publication Date: 7/19/2019
Citation: Sexual dimorphism of atherosclerosis and plasma lipids: Analysis of complex traits in a diversity outbred F1 mouse population. Meeting Abstract. (39)1. https://doi.org/10.1161/atvb.39.suppl_1.154.
Technical Abstract: Introduction: Atherosclerosis is a complex multifactorial disease that develops through the interaction of various genetic and environmental factors. Genetic studies in mice have often focused on risk factors and casual variants within a single genetic context, the C57BL/6J mouse. These studies have identified numerous genes and pathways contributing to atherosclerotic lesion development and one approach to improve our understanding of atherosclerotic disease is to expand these studies to include a variety of genetic backgrounds. Methods and Results: We crossed male mice transgenic for both apolipoprotein E-Leiden (ApoE*3Leiden) and cholesterol ester transfer protein (CETP) which are susceptible to atherosclerosis with ~200 female Diversity Outbred (DO) mice, a population of mice derived from 8 inbred strains that carries over 40 million SNPs. Following a high fat/cholesterol (HFHC) diet for 12 weeks, the off spring (262 female and 269 male mice) of this cross (DO-F1) were examined for over 20 cardio-metabolic traits including lesion size, blood pressure, bone mass, ALT, total cholesterol (TC), triglyceride (TG), and glucose. We assessed the population for a number of relationships and observed sexual dimorphism in these traits. For example, female mice were significantly more susceptible to atherosclerosis higher lesion area (p < 0.0001, 339% higher) and hyperlipidemia plasma levels of TC (p < 0.0001, 71% higher) and TG (p < 0.001, 20% higher) than male mice. Adiposity and circulating levels of glucose were also sexually dimorphic with male mice having higher plasma glucose levels (p < 0.0001, 12% higher), and body fat percentage (p < 0.01, 14% higher) and bone mass (p < 0.001, 5% higher) than female mice. We also compared the effects of the HFHC diet on our plasma risk factors and observed a significant effect of diet on the following traits: increased plasma levels of ALT and TC, and bone mass but decreased plasma levels of glucose, and TG. Conclusion: To the best of our knowledge, this study suggests the first example of complex interactions of sexually dimorphic traits associated with atherosclerosis using DO-F1 mice. Future studies will include quantitative trait locus analysis (QTL) to identify novel genetic regulators.