Using Mice to Dissect Genetic Factors in Atherosclerosis

Abstract

Abstract-The genes that contribute to common, complex forms of atherosclerosis remain largely unknown. Genetic studies in humans have, for the most part, focused on identifying genes that predispose to the traditional risk factors, such as lipid levels and blood pressure, but apart from rare, single-gene disorders, there have been few successes to date. The use of mice to dissect the complex genetic etiology of atherosclerosis offers a viable alternative to human studies, because experimental parameters, such as environment, breeding scheme, and detailed phenotyping, can be controlled. Herein we review how mouse genetics can lead to the identification of genes, some of which would otherwise not have been considered as candidates for atherosclerosis, and provide an overview of the prospects for successful gene discovery in the future.

Genetic Association with Coronary Artery Disease

“…3 Other studies reported that CHD in first-degree relatives raised the risk by 2-3 times more. 4,5 The extent to which the familial clustering of CAD can be explained by heritable quantitative variation in the classical risk factors such as cholesterol and BP is contentious, and the small but significant residual familial relative risk after regression on these conventional risk factors suggests the presence of unmeasured genetic risk factors, raising the possibility of a high level of genetic control by a small number of genes that control fundamental physiological systems 6,7,9,11 Heritability A study in Danish twins revealed a higher incidence of CHD and deaths among monozygotic (44%) rather than dizygotic (14%) twins . 6 Another study in twins highlighted the strong genetic basis of CHD and its main complication, myocardial infarction, in addition to other modifiable risk factors.…”

“…Nevertheless, many serological markers that were often studied, such as ABO blood groups and types of leukocyte antigens checked for their connection to disease, in fact reflected the level of genetic alterations of DNA and represented it in a way. 11 The transition from protein representatives tï DNA polymorphisms marked the beginning of the genome study. In 1980, the construction of a genetic linkage map (Southern blot analysis) was attempted using restriction fragment length polymorphisms of DNA (RFLPs).…”

“…The correlation between a genotypic polymorphism and the measurement of the quantitative trait provides an assessment of the effect magnitude. 11 When specifying the association of a polymorphism with a disease or a disease trait, the position of this variable within the genome is studied as well as the proximal genomic environment, which is described as the place (locus).…”

Spontaneous Atherosclerosis in Pigeons: A Good Model of Human Disease

“…New atherogenic theories must be explored to explain the occurrence of atherosclerotic heart disease in individuals displaying no dyslipidemia. Most of the more than twenty unique quantitative trait loci (QTL) identified in mice do not influence plasma lipid levels or blood pressure (Allayee et al, 2003;Colinayo et al, 2003). This finding has been especially interesting because these QTL were identified in hypothesis-driven experiments exploring cholesterol metabolism in LDLR and/or apoE knockout mice.…”

“…Only 2% of the homozygous apoE2 null mice developed aortic lesions at all, and the contribution of this mutation to the overall human disease burden has been questioned (Visvikis- Siest & Marteau, 2006). Subsequent studies have shown contradictory results, as the nature of the lesion appears to be dependent on the parental strain used in the experiment rather than the particular knockout gene (Allayee et al, 2003;Getz, 2000;Sigmund, 2000;Smith et al, 2006). The largest effect in these hyper-cholesterolemic models resulted from the macrophage colony stimulation factor (MCSF) impact on lesion progression (Knowles & Maeda, 2000).…”