Integrative analysis of hepatic transcriptional profiles reveals genetic regulation of atherosclerosis in hyperlipidemic Diversity Outbred-F1 mice

Authors: KIM, MYUNGSUK - University Of California, Davis; HUDA, NAZMUL - University Of California, Davis; Evans, Levi; QUE, EXCEL - Non ARS Employee; Gertz, Erik; MAEDA-SMITHIES, NOBUYO - University Of North Carolina; Bennett, Brian

Submitted to: Scientific Reports
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 5/25/2023
Publication Date: 6/10/2023
Citation: Kim, M., Huda, N., Evans, L.W., Que, E., Gertz, E.R., Maeda-Smithies, N., Bennett, B.J. 2023. Integrative analysis of hepatic transcriptional profiles reveals genetic regulation of atherosclerosis in hyperlipidemic Diversity Outbred-F1 mice. Scientific Reports. 13. Article 9475. https://doi.org/10.1038/s41598-023-35917-8.
DOI: https://doi.org/10.1038/s41598-023-35917-8

Interpretive Summary: Most of the experiments with mice so far have been performed in a small number of mouse strains and limited genetic variations, so they have not been genetically representative of the human. However, our study showed that by using a mouse model with a human-like genetic architecture, sex had a profound effect on atherosclerosis (buildup of fats on the artery walls) and gene expression in the liver. Differences in atherosclerosis between mice with different genetic backgrounds motivates us to find comparable phenotypic variations across the human population. Understanding the atherosclerosis and liver transcriptome (set of all gene expression) in response to sex will be important to highlight the potential of personalized nutrition and to understand interpersonal variability in cardiovascular disease risk.

Technical Abstract: Aims: The sexual dimorphism in the incidence and complications of atherosclerosis is well known in human and rodent models; however, the underlying mechanisms by which sex as a biological variable affects atherosclerosis remains unclear. In order to examine the role of sex and gene-by-sex interactions that affect disease-related traits, we studied F1 mice from a cross between Diversity Outbred (DO) mice and a hyperlipidemic strain. Methods and Results: We collected offspring from a cross between atherosclerosis-susceptible male C57BL/6J mice, transgenic for both human apolipoprotein E-Leiden and cholesterol ester transfer protein genes, and female DO mice, a population derived from 8 inbred strains. We fed the offspring a high-fat/cholesterol diet for 16 weeks. We then examined cardiometabolic traits and liver transcriptome using RNA-sequencing. Our results demonstrate the tremendous effects of sex on cardiometabolic traits and hepatic gene expression. In support of this, genetic loci associated with the traits and transcripts frequently showed sex specificity. We revealed sex-specific candidate genes that were mapped to the quantitative trait loci for aortic lesion area and whose expression was regulated locally regulated via global liver transcriptome. A number of sexually dimorphic transcripts such as Pten are identified as candidates for sex-specific QTL for atherosclerosis. Finally, global analysis of gene expression identified a sex-specific regulation of the liver transcription factor LXRa (Nr1h3) which affected expression of target genes and gene-trait correlations. Conclusions: Collectively, this study provides a rich resource for investigating the sex-differentiated pathogenesis of atherosclerosis, and DO mice can be utilized in conjunction with integrative genetics approaches to identify genes and genetic variants that contribute to atherosclerosis.