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EDITORIAL |
1 From the Department of Nutrition (JSF); the Rowe Program in Genetics (CHW); the Department of Pediatrics (CHW); the Division of Clinical Nutrition, Endocrinology, and Vascular Biology (CHW); and the Section of Neurobiology, Physiology, and Behavior (CHW), University of California, Davis, Davis, CA
2 Reprints not available. Address correspondence to CH Warden, Rowe Program in Genetics, University of California, Davis, Davis, CA 95616. E-mail: chwarden{at}ucdavis.edu.
See corresponding article on page 1429.
Nutritional guidelines have long been a mainstay of the prevention and treatment of dyslipidemias, including low HDL-cholesterol concentrations, a risk factor for coronary artery disease. Low HDL-cholesterol concentrations are typical in diabetes, obesity, and the metabolic syndrome. Guidelines for the prevention and treatment of low HDL-cholesterol concentrations emphasize reducing the intake of saturated fat and cholesterol and increasing physical activity, which can also prevent obesity. Yet, there is great variation in the response of plasma lipids to dietary modification, and at least part of that variation is due to each person’s genotype.
Nutritional genomics (or nutrigenomics) is the newly developing science of how a person’s diet interacts with his or her genotype to influence the balance between health and disease (1, 2). This science is made possible by the application of high-throughput genomic tools to nutrition studies. Two experimental designs, dietary intervention and observational studies of habitual diet, are typically used in subjects of known genotype.
The effect of genetic variation on blood lipid response to dietary change has been systematically reviewed (3, 4). The blood lipid response to diet is influenced by polymorphisms within genes for the apolipoproteins as well as within those for enzymes, such as hepatic lipase, that are involved in lipid metabolism. Hepatic lipase is a lipolytic enzyme involved in the hydrolysis of triacylglycerols and phospholipids from plasma lipoproteins, and it may also play a role as a ligand in the cellular uptake of lipoproteins. Higher hepatic lipase concentrations are associated with smaller, denser HDL particles and a more atherogenic profile. An early intervention study with a low-saturated-fat, low-cholesterol diet found that, although significant improvements in fasting lipids occurred, there was no difference in response between genotypes at the hepatic lipase gene (LIPC) polymorphism measured (5). However, this study of 83 subjects may not have had adequate power to detect a modest effect of genotype (4).
Three larger observational studies on the effect of a common polymorphism in the LIPC promoter gene –514C
T on the response of HDL cholesterol to dietary fat intake have been published (6-8). In examining the effects of the –514CT LIPC polymorphism x dietary fat interaction on HDL in 2130 men and women participating in the Framingham Study, Ordovas et al (6) found that the rarer TT genotype was associated with significantly higher HDL-cholesterol concentrations only in subjects consuming <30% of energy from fat. This same interaction was found for saturated and monounsaturated fats but not for polyunsaturated fat (6). A second association study, in an Asian population of 2170 subjects, found that Asian Indian subjects with a total fat intake of <30% of energy and with TT genotype at the –514CT polymorphism had the highest HDL-cholesterol concentrations (7). This interaction, however, did not apply to the Chinese or Malay subjects in that study, and the significant interactions found for saturated or monounsaturated fats found by Ordovas et al (6) were not found in the study by Tai et al (7). However, these 2 studies are consistent with other studies showing that the TT genotype at –514CT is associated with higher HDL concentrations (9, 10), although, in 1 of those studies, this effect was attenuated by visceral obesity (10).
The third association study of the interaction between dietary fat and the –514CT polymorphism, by Zhang et al (8), is published in this issue of the Journal. From a study population of 18159 men, Zhang et al selected 780 men with confirmed type 2 diabetes. After adjustment for age, smoking, alcohol intake, exercise, and BMI, higher HDL-cholesterol concentrations were found in men with the CT or TT genotype, which is consistent with previous studies (6, 7, 9, 10). However, Zhang et al found significantly higher HDL-cholesterol concentrations in men with the CT/TT genotype who consumed large amounts of dietary fat (
32% of energy), saturated fat, and monounsaturated fat (8), a result that is apparently opposite to the findings of the other 2 association studies. Thus, the interaction effect of dietary fat with the –514CT polymorphism was not replicated.
Redden and Allison (11) discussed causes of nonreplication of genetic association studies in obesity and diabetes research that should apply to studies of dyslipidemias as well. An important cause of nonreplication is a lack of statistical power. For any polygenic model, such as models with complex phenotypes (eg, obesity, dyslipidemia, or type 2 diabetes), the effect size for any marker will be small to moderate (12). Thus, larger sample sizes are needed to ensure adequate power to observe an effect. In the study of Zhang et al, the problem of small sample size (despite the fact that >18000 men were screened to identify 
800 men with type 2 diabetes) is compounded by the fact that the TT genotype is rare (7), especially in a white population. Thus, only 30 subjects in that study had homozygous TT genotype at –514CT LIPC, and subjects with either the CT or TT genotype were pooled for analysis. Examination of the data of Ordovas et al (6) and Tai et al (7) found that the slope of predicted values for HDL cholesterol versus total fat intake as a percentage of energy is steeply negative in persons with the TT genotype, whereas it is positive for persons with the CT genotype. Assuming that the data of Zhang et al followed the same pattern, combining the smaller number (n = 30) of persons with the TT genotype with the larger number (n = 247) of persons with the CT genotype would mask the effects of percentage of dietary fat and the TT genotype on HDL-cholesterol concentrations. An additional complexity is that BMI and obesity phenotypes may also interact with dietary fat and LIPC genotype to modulate HDL-cholesterol concentrations (7, 8). Thus, the nonreplication in the study by Zhang et al of the findings of Ordovas et al and Tai et al is likely due to the small number of persons with the TT genotype who were available in the study of Zhang et al.
The ultimate goal of nutritional genomics is to provide sufficient knowledge to allow diagnosis and nutritional treatment recommendations based on an individual’s genotype. Defining the interaction effects of nutrients and genes on complex phenotypes will be the challenge of this field of nutrition research for some time to come.
ACKNOWLEDGMENTS
Neither author had any personal or financial conflicts of interest with respect to the manuscript by Zhang et al or to their study.
REFERENCES
T polymorphism in the hepatic lipase gene promoter on plasma lipid profiles in a multiethnic Asian population: the 1998 Singapore National Health Survey. J Nutr 2003;133:3399–408. polymorphism of the hepatic lipase gene and lifestyle factors in relation to HDL concentrations among US diabetic men. Am J Clin Nutr 2005;81:1429–1435.T polymorphism on plasma HDL-cholesterol levels in French-Canadian men. Mol Genet Metab 2003;78:31–6.[Medline]
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