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Editorials |
1 From the Department of Medicine, Columbia University, New York.
See corresponding articles on page 736 and 746.
Interest has increased in understanding the interaction between genes and nutrients in the development of atherosclerosis (1). Many studies have addressed the role of such interactions in the response of plasma lipid concentrations to variations in intakes of primarily fat and cholesterol. In the field of lipid and lipoprotein research, several candidate genes have attracted attention but the polymorphism at the apolipoprotein E gene (APOE) locus perhaps has the most extensive effects on lipoprotein metabolism in humans (2). This reflects the important functions of APOE in the lipolytic catabolism and receptor-mediated uptake of triacylglycerol-rich lipoproteins. The role of APOE has been extended to intracellular lipoprotein trafficking (3, 4). Over the years, a rich database has accumulated showing that variation at the APOE locus is associated with differences in risk of premature atherosclerosis and in the development of Alzheimer disease. In general, carriers of the APOE*E4 (E4) allele have higher and carriers of the APOE*E2 (E2) allele have lower LDL-cholesterol concentrations, and variation at the APOE locus accounts for 
7% of the population variance in total and LDL-cholesterol concentrations (5). However, this pattern seems to some extent to be dependent on age. In elderly subjects and in children, there is less difference in LDL-cholesterol concentrations in carriers than in noncarriers of the E4 allele (6, 7). Interestingly, in both of these age groups, the presence of the E2 allele was associated with an antiatherogenic lipoprotein pattern. This pattern variation with age suggests that the effect of genetic variation in APOE on plasma lipids can be modified.
Currently, different and partially contradictory results were obtained in studies of the associations of APOE variation with plasma lipid responses to dietary variations. Although some studies found more pronounced dietary responsiveness in carriers of the E4 allele, others reported no difference in response across APOE allele types to changes in dietary fat, cholesterol, or both (1, 2). An interesting and rather consistent finding, however, was the presence of an apparent sex effect. Thus, even in studies in which there was a response of plasma lipid concentrations, the APOE effect was generally seen in men but not in women (2, 8). In this issue of the Journal, 2 articles address gene-nutrient interactions at the APOE locus (9, 10).
Corella et al (9) investigated the plasma lipid response to alcohol across APOE genotypes in the Framingham Offspring Study population. It is interesting to note that this study also found a difference in the responses of men and women. In men, the expected pattern for LDL cholesterol, ie, higher concentrations in carriers of the E4 allele than in carriers of the E2 allele, was seen only among drinkers. Among nondrinkers, no significant difference in LDL-cholesterol concentrations across APOE genotypes was found, although there were substantially fewer nondrinkers than drinkers. In women, LDL cholesterol was significantly higher in carriers of the E4 allele than in carriers of the E2 allele among both drinkers and nondrinkers. The exact mechanisms involved remain to be clarified. Because associations between APOE allele types and plasma cholesterol responses were observed primarily in subjects susceptible to hypercholesterolemia, the results suggest that the metabolic stress of alcohol consumption might uncover underlying differences in cholesterol, triacylglycerol, or lipoprotein metabolism.
Although the E4 allele is associated with increased cholesterol concentrations, the E2 allele has been associated with lower cholesterol concentrations along with a slower clearance of triacylglycerol-rich lipoprotein remnants. Previous studies found a more pronounced triacylglycerol response in carriers of the E2 allele when the dietary carbohydrate and fiber contents of the diet varied (2). The study by Erkkilä et al (10) provides further support for the association of carbohydrate and triacylglycerol metabolism with the E2 allele. These authors evaluated plasma lipid responses to dietary fat and carbohydrate in men and women with coronary artery disease. Overall, carriers of the E2 allele had lower LDL-cholesterol concentrations and a tendency to higher triacylglycerol concentrations relative to carriers of the E3 and E4 alleles. In addition, there was a positive association between dietary sucrose (6–7% of the total energy intake) and plasma triacylglycerol concentrations only in carriers of the E2 allele. As in most other studies, however, it is important to note that the number of E2 allele carriers was small (5% of all subjects) and in the present study they were mostly male. Thus, it is appropriate to exercise caution when interpreting the data.
Although it is difficult to speculate about the mechanisms behind these effects, one can envision several possibilities. First, E2 allele carriers may have a compromised clearance system for triacylglycerol-rich lipoproteins. Thus, even a modestly increased VLDL production in response to sucrose could result in an increased plasma triacylglycerol concentration. Alternatively, in addition to affecting uptake of triacylglycerol-containing remnant particles, the APOE polymorphism may play a role in the intrahepatic synthesis and catabolism of triacylglycerol-rich lipoproteins (3, 4). Further work is needed to define whether variation at the APOE locus affects these pathways.
Although a growing number of studies address gene-nutrient interactions, in most studies this has been a secondary aim, usually analyzed a posteriori. It is important to keep in mind that multiple comparisons as well as low allele frequency could lead to spurious associations; therefore, these observations need verification. Because the APOE locus is an example of a polymorphism with important effects on plasma lipid patterns, the 2 studies in this issue of the Journal (9, 10) add fuel to the fire. However, our ability to confirm the presence of gene-nutrient interactions and to understand their metabolic basis will require larger and more detailed studies.
REFERENCES
2 allele is associated with an anti-atherogenic lipoprotein profile in children: The Columbia University Biomarkers Study. Pediatrics 2000;106:568–75.This article has been cited by other articles:
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  J. L Halliday, V. R Collins, M. A. Aitken, M. P M Richards, and C. A Olsson Genetics and public health--evolution, or revolution? J Epidemiol Community Health, November 1, 2004; 58(11): 894 - 899. [Abstract] [Full Text] [PDF]
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 J. A. Luchsinger, M.-X. Tang, S. Shea, and R. Mayeux Caloric Intake and the Risk of Alzheimer Disease Arch Neurol, August 1, 2002; 59(8): 1258 - 1263. [Abstract] [Full Text] [PDF]
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