Atherosclerosis is a complex and heritable disease with a vast number of interacting genes, networks and molecular pathways. Mouse genetics has been utilized as a powerful tool to study human atherosclerosis and has identified hundreds of candidate genes; recent human genetic studies have also identified hundreds of suggestive genetic loci for atherosclerotic coronary artery disease (CAD). However, commonalities and differences of biological mechanisms in atherosclerosis between humans and mice are poorly examined. In this study, we aim to provide a systematic biological overview comparing mice and humans on pathway level. We first comprehensively reviewed and summarized known mouse genes associated with atherosclerosis based on studies of genetically modified mouse models. This effort revealed 743 mouse atherosclerosis genes from over 9,000 Pubmed publications, retrieved using the terms “atherosclerosis” or “atherogenesis” and “gene” or “qtl” and “mouse” or “mice” and “apoe” or “ldlr”, and followed by manual review and confirmation of the effects on atherosclerosis. Second, we conducted pathway analysis of the mouse atherosclerosis genes using data from Biocarta, Kyoto Encyclopedia of Genes and Genomes (KEGG) and Reactome. We found pathways including cytokine interactions or dependency to the immune system are highly over-represented among the mouse atherosclerosis genes. Many of these pathways (e.g., metabolism of lipids and lipoproteins) converged with those reported for human GWAS loci, but also highlighted several pathways (e.g., GPCR signaling) having a hitherto unknown effect on atherosclerosis in mice. Our results suggest that although there are certain differences in individual candidate genes, mouse models remain a promising approach to identify complex molecular pathways of atherosclerosis, and insights gained from mouse genetics of atherosclerosis could be validated and transferred to CAD in humans. Future network analysis of the mouse and human genes and pathways will provide further elucidation of the shared or distinct gene-gene regulation and interactions between species. This study might provide new starting points for drug development, therapeutic treatment and prevention of atherosclerosis and CAD in humans.
Mouse models of cancer: Sleeping Beauty transposons for insertional mutagenesis screens and reverse genetic studies