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

• Published in: Scientific reports 2023-06, Vol.13 (1), p.9475-17, Article 9475
• Main Authors: Kim, Myungsuk, Huda, M. Nazmul, Evans, Levi W., Que, Excel, Gertz, Erik R., Maeda-Smithies, Nobuyo, Bennett, Brian J.
• Format: Article
• Language: English
• Subjects: 631/208; 631/553; 692/4019; Animals; Aorta; Arteriosclerosis; Atherogenesis; Atherosclerosis; Atherosclerosis - genetics; Cardiovascular diseases; Cholesterol; Cholesteryl ester transfer protein; Collaborative Cross Mice - genetics; Correlation analysis; Environmental factors; Female; Females; Gene mapping; Gene regulation; Genetic crosses; Genetic factors; Genome-wide association studies; Genome-Wide Association Study; Genomes; High cholesterol diet; High fat diet; Humanities and Social Sciences; Humans; Hyperlipidemia; Lipids; Liver; Male; Mice; Mice, Inbred C57BL; multidisciplinary; PTEN protein; Quantitative trait loci; quantitative traits; Science; Science (multidisciplinary); transcription (genetics); Transcription factors; Transcriptomes
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-023-35917-8

Atherogenesis is an insipidus but precipitating process leading to serious consequences of many cardiovascular diseases (CVD). Numerous genetic loci contributing to atherosclerosis have been identified in human genome-wide association studies, but these studies have limitations in the ability to control environmental factors and to decipher cause/effect relationships. To assess the power of hyperlipidemic Diversity Outbred (DO) mice in facilitating quantitative trait loci (QTL) analysis of complex traits, we generated a high-resolution genetic panel of atherosclerosis susceptible (DO-F1) mouse cohort by crossing 200 DO females with C57BL/6J males carrying two human genes: encoding apolipoprotein E3-Leiden and cholesterol ester transfer protein. We examined atherosclerotic traits including plasma lipids and glucose in the 235 female and 226 male progeny before and after 16 weeks of a high-fat/cholesterol diet, and aortic plaque size at 24 weeks. We also assessed the liver transcriptome using RNA-sequencing. Our QTL mapping for atherosclerotic traits identified one previously reported female-specific QTL on Chr10 with a narrower interval of 22.73 to 30.80 Mb, and one novel male-specific QTL at 31.89 to 40.25 Mb on Chr19. Liver transcription levels of several genes within each QTL were highly correlated with the atherogenic traits. A majority of these candidates have already known atherogenic potential in humans and/or mice, but integrative QTL, eQTL, and correlation analyses further pointed Ptprk as a major candidate of the Chr10 QTL, while Pten and Cyp2c67 of the Chr19 QTL in our DO-F1 cohort. Finally, through additional analyses of RNA-seq data we identified genetic regulation of hepatic transcription factors, including Nr1h3, contributes to atherogenesis in this cohort. Thus, an integrative approach using DO-F1 mice effectively validates the influence of genetic factors on atherosclerosis in DO mice and suggests an opportunity to discover therapeutics in the setting of hyperlipidemia.