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News — Researchers from the Jean Mayer USDA Human Nutrition Research Center (USDA HNRCA) at Tufts University and colleagues have found another link among genes, heart disease and diet. The study, published in Circulation, examined apolipoprotein A5 (APOA5), a gene that codes for a protein, which in turn plays a role in the metabolism of fats in the blood. The results show that people who carry a particular variant of APOA5 may have elevated risk factors that are associated with heart disease, but only if they also consumed high amounts of omega-6 fatty acids in their diets.

Corresponding author Chao-Qiang Lai, PhD, a USDA-Agricultural Research Service (ARS) scientist at the USDA HNRCA, and colleagues analyzed lipid levels and dietary assessment questionnaires of more than 2,000 participants in the Framingham Heart Study and quantified their intake of different types of fats.

Omega-6 fatty acids, as well as omega-3 fatty acids, are polyunsaturated fatty acids (PUFAs) and, according to a report from the National Institutes of Health Office of Dietary Supplements, most Americans consume about 10 times more omega-6s than omega-3s. Omega-3s are found in nuts, leafy green vegetables, fatty fish, and vegetable oils like canola and flaxseed, while omega-6s are found in grains, meats, vegetable oils like corn and soy, and also processed foods made with these oils. Both omega-3s and omega-6s, known as essential fatty acids, must be consumed in the diet because they are not made by the body.

"We know that some people are genetically predisposed to risk factors for heart disease, such as elevated low-density lipoprotein levels in the blood," says Lai, "and that APOA5 has an important role in lipoprotein metabolism. We wanted to determine if certain dietary factors change the role of APOA5 in metabolizing these lipoproteins and their components, such as triglycerides."

Lai and colleagues found that approximately 13 percent of both men and women in the study were carriers of the gene variant. Those individuals that consumed more than six percent of daily calories from omega-6 fatty acids displayed a blood lipid profile more prone to atherosclerosis (hardening of the arteries) and heart disease, including higher triglyceride levels.

Jose Ordovas, PhD, senior author of the study and director of the Nutrition and Genomics Laboratory at the USDA HNRCA, notes that "previous research points to polyunsaturated fatty acids like omega-3s and omega-6s as 'good' fats, thought to reduce risk of heart disease by lowering cholesterol levels if used in place of saturated fats that are mostly found in animal sources."

Ordovas continues, "Research hasn't shown us yet if there is an optimal ratio for omega- 3s to omega-6s, or if consuming a certain amount of omega-6s might negate the benefits of omega-3s. We do know that omega-6s are necessary for the body and can be a source of healthful fat in the diet, but for the 13 percent who are carriers of the particular APOA5 gene variant, consuming fewer omega-6s in relation to omega-3s may be important, as it might help reduce the risk of developing precursors to heart disease."

The carriers of the variant who ate more than six percent of total calories from omega-6s had a 21 percent increase in triglyceride levels, as well as an approximately 34 percent elevation of certain atherogenic lipoprotein particles in the blood.

Carriers who consumed less than six percent of total calories from omega-6s did not show a significant increase in the lipid levels that are risk factors for heart disease. In contrast to omega-6s, higher consumption of omega-3s decreased triglyceride and atherogenic lipoprotein particle levels in the blood, regardless of a person's APOA5 gene variant.

Although the researchers analyzed information on several types of dietary fat, including saturated fat and monounsaturated fat, the interactions between diet and APOA5 were seen only with PUFAs, "adding evidence to the prominent role of PUFAs as modulators of genetic effects in lipid metabolism," write the authors. They go on to explain that "a more complete understanding of these factors and a thoughtful use of this information should help in the identification of vulnerable populations who will benefit from more personalized dietary recommendations."

A second study published by Ordovas, Lai, and colleagues in the Journal of Lipid Research also studied variants of the APOA5 gene in participants in the Framingham Heart Study to determine if the gene is related to atherosclerosis. The authors, including corresponding author Christopher O'Donnell of the National Heart, Lung, and Blood Institute's Framingham Heart Study, and first author Roberto Elosua, a former Fulbright-Generalitat de Cataluña fellow who works with Ordovas, found that while most variants of the APOA5 gene were not associated with carotid intimal medial thickness (IMT), a surrogate measure of atherosclerosis burden, particular gene variants were "significantly associated with carotid IMT in obese participants."

Carriers of the particular gene variants who were obese expressed the effects of the gene variant differently than carriers who were not obese, showing a greater build-up of plaque in the heart. This was true for participants who were obese regardless of fat and cholesterol levels in the blood, age, gender, smoking or diabetes status, weight-for-height and blood pressure, all factors which are thought to influence risk of heart disease. Lai notes that "although obesity is a known contributing factor to heart disease, the association was strengthened in carriers of the rare APOA5 variant who were obese."

"It may be more important for some people to make preventive dietary and lifestyle changes than others, depending on their genetic makeup," says Ordovas. "The 'bad' genotype, in this study, doesn't seem to be that bad unless it's triggered by obesity," he concludes. "The observations, while strong, should be considered with caution and confirmed in other studies. Also, the findings were restricted to a Caucasian cohort and may not be generalizable to other ethnic cohorts."

The Agricultural Research Service (ARS) is the U.S. Department of Agriculture's chief scientific research agency.

Lai CQ, Corella D, Demissie S, Cupples A, Adiconis X, Yueping Z, Parnell LD, Tucker KL, Ordovas JM. Circulation (May 2) 2006;113: 2062 " 2070. "Dietary Intake of n-6 Fatty Acids Modulates Effect of Apolipoprotein A5 Gene on Plasma Fasting Triglycerides, Remnant Lipoprotein Concentrations, and Lipoprotein Particle Size: The Framingham Heart Study."

Elosua R, Ordovas JM, Cupples LA, Lai CQ, Demissie S, Fox CS, Polak JF, Wolf PA, D'Agostino RB, O'Donnell CJ. Journal of Lipid Research (May ) 2006;47: 990-996 "Variants at the APOA5 locus, association with carotid atherosclerosis, and modification by obesity: the Framingham Study."

The Gerald J. and Dorothy R. Friedman School of Nutrition Science and Policy at Tufts University is the only independent school of nutrition in the United States. The school's eight centers, which focus on questions relating to famine, hunger, poverty, and communications, are renowned for the application of scientific research to national and international policy. For two decades, the Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University has studied the relationship between good nutrition and good health in aging populations. Tufts research scientists work with federal agencies to establish the USDA Dietary Guidelines, the Dietary Reference Intakes, and other significant public policies.