Dataset Information

Regional Variation in Genetic Control of Atherosclerosis in Hyperlipidemic Mice.

ABSTRACT: Atherosclerosis is a polygenic disorder that often affects multiple arteries. Carotid arteries are common sites for evaluating subclinical atherosclerosis, and aortic root is the standard site for quantifying atherosclerosis in mice. We compared genetic control of atherosclerosis between the two sites in the same cohort derived from two phenotypically divergent Apoe-null (Apoe ^-/-) mouse strains. Female F2 mice were generated from C57BL/6 (B6) and C3H/He (C3H) Apoe ^-/- mice and fed 12 weeks of Western diet. Atherosclerotic lesions in carotid bifurcation and aortic root and plasma levels of fasting lipids and glucose were measured. 153 genetic markers across the genome were typed. All F2 mice developed aortic atherosclerosis, while 1/5 formed no or little carotid lesions. Genome-wide scans revealed 3 significant loci on chromosome (Chr) 1, Chr15, 6 suggestive loci for aortic atherosclerosis, 2 significant loci on Chr6, Chr12, and 6 suggestive loci for carotid atherosclerosis. Only 2 loci for aortic lesions showed colocalization with loci for carotid lesions. Carotid lesion sizes were moderately correlated with aortic lesion sizes (r = 0.303; P = 4.6E-6), but they showed slight or no association with plasma HDL, non-HDL cholesterol, triglyceride, or glucose levels among F2 mice. Bioinformatics analyses prioritized Cryge as a likely causal gene for Ath30, Cdh6 and Dnah5 as causal genes for Ath22 Our data demonstrate vascular site-specific effects of genetic factors on atherosclerosis in the same animals and highlight the need to extend studies of atherosclerosis to sites beyond aortas of mice.

SUBMITTER: Jones MB

PROVIDER: S-EPMC7718748 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Regional Variation in Genetic Control of Atherosclerosis in Hyperlipidemic Mice.

Jones Michael B MB An Alexander A Shi Lisa J LJ Shi Weibin W

G3 (Bethesda, Md.) 20201203 12

Atherosclerosis is a polygenic disorder that often affects multiple arteries. Carotid arteries are common sites for evaluating subclinical atherosclerosis, and aortic root is the standard site for quantifying atherosclerosis in mice. We compared genetic control of atherosclerosis between the two sites in the same cohort derived from two phenotypically divergent Apoe-null (Apoe-/-) mouse strains. Female F2 mice were generated from C57BL/6 (B6) and C3H/He (C3H) Apoe ...[more]

PMID: 33109727

Similar Datasets

Project description: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.

Dataset Information

Regional Variation in Genetic Control of Atherosclerosis in Hyperlipidemic Mice.

Publications

Regional Variation in Genetic Control of Atherosclerosis in Hyperlipidemic Mice.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets