Context-dependent and invariant associations between APOE genotype and levels of lipoproteins and risk of ischemic heart disease: a review

Apolipoprotein E (APOE) plays a pivotal role in the catabolism of triglyceride-rich lipoproteins by serving as a ligand for lipoprotein receptors. The common three-allele (epsilon 2/epsilon 3/epsilon 4) variation in the APOE gene is the most studied susceptibility polymorphism to date, identified in more than 50 different populations worldwide. Differences in the associations between APOE genotype and lipids, lipoproteins, and risk of ischemic heart disease between and within studies have raised the possibility that this gene is expressed in a context-dependent rather than invariant manner. The objective of this review was to focus on studies that in particular yield information about such context-dependent associations of the APOE polymorphism. The well-documented pattern of increasing cholesterol levels from epsilon 2 to epsilon 3 to epsilon 4 seems invariant across different populations; however, the magnitude of this association appears to be modifiable by gender, exogenous estrogens, diet and perhaps by body size. The less pronounced associations between the APOE polymorphism and high-density lipoprotein (HDL) cholesterol and triglycerides appear to differ by gender, to be enhanced by hyperglycemia and alcohol consumption, and abolished by exogenous estrogens in women, thus suggesting strong context dependency. The APOE polymorphism explains more of the variation in levels of cholesterol and apolipoprotein B (APOB) in women than in men, whereas a larger fraction of the variation in triglycerides is explained by the APOE polymorphism in men than in women. Finally, relative to epsilon 33 individuals, epsilon 32 women may be protected while epsilon 43 and epsilon 44 men may be particularly susceptible to ischemic heart disease. In conclusion, differences in magnitude or presence of APOE gene associations across studies or across subgroups within studies appear to be due to the influence of gender, exogenous estrogens, diet, hyperglycemia, alcohol consumption and perhaps body size. Consequently, these contexts should be considered when APOE polymorphism is studied.