Abstract
Atherosclerosis is a multifactorial chronic disease that affects large arteries and may lead to fatal consequences. According to current understanding, inflammation and lipid accumulation are the two key mechanisms of atherosclerosis development. Animal models based on genetically modified mice have been developed to investigate these aspects. One such model is low-density lipoprotein (LDL) receptor knockout (KO) mice (ldlr−/−), which are characterized by a moderate increase of plasma LDL cholesterol levels. Another widely used genetically modified mouse strain is apolipoprotein-E KO mice (apoE−/−) that lacks the primary lipoprotein required for the uptake of lipoproteins through the hepatic receptors, leading to even greater plasma cholesterol increase than in ldlr−/− mice. These and other animal models allowed for conducting genetic studies, such as genome-wide association studies, microarrays, and genotyping methods, which helped identifying more than 100 mutations that contribute to atherosclerosis development. However, translation of the results obtained in animal models for human situations was slow and challenging. At the same time, genetic studies conducted in humans were limited by low sample sizes and high heterogeneity in predictive subclinical phenotypes. In this review, we summarize the current knowledge on the use of KO mice for identification of genes implicated in atherosclerosis and provide a list of genes involved in atherosclerosis-associated inflammatory pathways and their brief characteristics. Moreover, we discuss the approaches for candidate gene search in animals and humans and discuss the progress made in the field of epigenetic studies that appear to be promising for identification of novel biomarkers and therapeutic targets.
Highlights
Atherosclerosis is a chronic vascular disease that affects large and small arteries and is characterized by the development of lipid-rich plaques in the vascular wall
Genes that were found in mouse quantitative trait loci (QTL) studies can be further tested in human association studies to check whether they are associated with atherosclerosis [11]
QTL analysis on F2 intercrosses of SM/J- apoE−/− and BALB/cJ- apoE−/− mice revealed that tnfaip3 was the most potent causal gene. These results show the importance of the use of different strains in the studies aimed at identification of the genetic causes of the atherosclerosis [15]
Summary
Atherosclerosis is a chronic vascular disease that affects large and small arteries and is characterized by the development of lipid-rich plaques in the vascular wall. The search for genetic determinants of atherosclerosis has been ongoing for decades This line of research is focused on identifying the candidate genes implicated in known atherogenesis pathways and conducting association studies to evaluate their roles in the pathology development. This approach resulted in establishing the pro-atherogenic roles of numerous genes [8]. Genome-wide linkage studies were carried out to identify atherogenesis-regulating quantitative trait loci (QTL) This approach appears to be promising for identifying new atherosclerosis-related genes in an unbiased manner [9]. Genes that were found in mouse QTL studies can be further tested in human association studies to check whether they are associated with atherosclerosis [11]
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