Genetics of Common Forms of Heart Disease

Most of our current understanding of the genetic underpinnings of heart disease, including atherosclerosis, heart failure, and arrhythmias, is based on Mendelian forms of these disorders or on transgenic/knockout mouse models. But the vast majority of heart disease is complex as a result of the interactions of many genetic and environmental factors. Clearly, an understanding of the genes and interactions contributing to these common forms of disease has the potential to improve diagnosis and treatment greatly. In this issue of Circulation Research , Rodriguez et al1 use mouse models to convincingly identify a novel gene contributing to a complex form of atherosclerosis. The gene, Raet1e , seems to act by influencing the immune system, independently of traditional risk factors such as plasma cholesterol levels. In addition, the work is important as an exemplar of the dissection of a complex trait in mice.Article, see p 1054The story has its beginning ≈2 decades ago with the development by Plump, Breslow, and colleagues2 of a spontaneous mouse model for atherosclerosis, the apolipoprotein E ( apoE ) knockout mouse, followed by the finding several years later that the effects of the apoE mutation differed remarkably between different inbred strains of mice. For example, although C57BL/6J (B) mice carrying the mutation exhibited large lesions, strain FVB (F) mice were almost free of lesions.3 To identify loci contributing to genetic differences in atherosclerosis susceptibility, a cross was constructed between strains B and F on …