Genetic Susceptibility to Atherosclerosis

Abstract

Atherosclerotic cardiovascular disease (ASCVD) frequently clusters in families. Although environmental factors such as diet, exercise, and smoking play a role in ASCVD, genetic factors are a major determinant of ASCVD risk. For example, in a study of Swedish twins, males with a dizygotic twin who died of premature coronary heart disease had a 4.3-fold increased risk of also dying from coronary heart disease, and if the twin was monozygotic, this risk increased to 14.9-fold.1 The genetic risk of ASCVD is conferred in part through known metabolic risk factors such as hypertension, dyslipidemia, and diabetes mellitus. However, these risk factors alone do not account for the entire genetic contribution to risk of ASCVD, and there remains substantial interest in the identification of additional genetic cardiovascular risk factors. Like humans, mouse strains differ considerably in their genetic predisposition to atherosclerosis.2 Most mouse strains are resistant to atherosclerosis even when fed an atherogenic diet; the C3H strain is a prototypical-resistant mouse strain. In contrast, C57BL/6J mice have been extensively studied as the mouse strain that is most susceptible to atherosclerosis when fed an atherogenic high-fat, high-cholesterol, cholic acid–containing diet.3 Initially, the focus on C57BL/6J mice centered on differences in plasma lipid levels, especially reduced HDL cholesterol levels, in response to the atherogenic diet4 and attempts to map gene loci linked to the phenotype of low HDL cholesterol.5 However, previous studies did not distinguish whether these differences in lipid profiles were restricted to particular dietary challenges or reflect an underlying genetic factor that contributes to atherosclerosis susceptibility. Furthermore, recent studies have suggested that C57BL/6J mice differ from less-susceptible strains in their response to inflammatory stimuli.6 7 Given the interest in atherosclerosis as an inflammatory disease,8 this has led to the hypotheses that C57BL/6J mice may be genetically …