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For many years, I have taught medical students about dyslipidemia and atherosclerosis. Invariably, an alert student will ask how cholesterol causes atherosclerosis. The honest answer is that we do not know.
Genetic studies in humans and transgenic mice have established a strong link between dyslipidemia (typically high VLDL/LDL cholesterol or low HDL) and atherosclerosis. However, as a phenotype, atherosclerosis is a perfect example of a complex trait. In short, the relationship between genotype and phenotype is influenced by additional genes, termed modifier genes.1,2
Two studies have identified genes that, when knocked out in transgenic mice, attenuate the atherosclerosis that would normally occur in the severely hyperlipidemic apoE-null mouse. First, Cyrus et al3 showed a diminution of atherosclerosis in the apoE-null mouse when the 12/15 lipoxygenase gene was also disrupted. More recently, a similar suppression of atherosclerosis in the apoE-null mouse was achieved by knocking out the fatty acid–binding protein gene, ap2.4 In an elegant study, Makowski et al4 showed that replenishment of macrophages of apoE−/− ap2+/+ with macrophages from ap2-knockout mice through bone marrow transplantation produced the same result, indicating a novel role for macrophage ap2 expression in atherogenesis. These two studies show that loss of function in either of two distinct loci can partially nullify the atherogenic risk posed by severe hypercholesterolemia.
How many other genes can modify atherosclerosis? Can a broad genetic approach be used to identify additional atherosclerosis modifier genes? In this issue of Circulation Research, Mehrabian et al5 in the Lusis laboratory …