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Apolipoprotein C-III, n-3 Polyunsaturated Fatty Acids, and "Insulin-Resistant" T–455C APOC3 Gene Polymorphism in Heart Disease Patients: Example of Gene-Diet Interaction

¹ Unit of Internal Medicine, Department of Clinical and Experimental Medicine, ² Institute of Clinical Chemistry, and ³ Section of Biology and Genetics, Department of Mother and Child and Biology-Genetics, University of Verona, Verona, Italy.

^aAddress correspondence to this author at: Dipartmento Medicina Clinica e Sperimentale, Cattedra di Medicina Interna, Università di Verona, Policlinico Borgo Roma, 37134 Verona, Italy. Fax 39-45-580111; e-mail oliviero.olivieri{at}univr.it.

Background: Apolipoprotein C-III (apo C-III) is a marker of cardiovascular disease risk associated with triglyceride (TG)-rich lipoproteins. The T–455C polymorphism in the insulin-responsive element of the APOC3 gene influences TG and apo C-III concentrations. Long-chain n-3 polyunsaturated fatty acids (PUFAs) contained in fish have well-known apo C-III-lowering properties.

Methods: We investigated the possibility of an interactive effect between the APOC3 gene variant and erythrocyte n-3 PUFAs, suitable markers of dietary intake of fatty acids, on apo C-III concentrations in a population of 848 heart disease patients who had coronary angiography.

Results: In the population as a whole, apo C-III concentrations were significantly inversely correlated with total erythrocyte PUFAs, but the correlation was not significant when only –455CC homozygous individuals were taken into account. In the total population and in subgroups with the –455TT and –455CT genotypes, the relative proportions of individuals presenting with increased apo C-III (i.e., above the 75th percentile value calculated on the entire population after exclusion of individuals taking lipids-lowering medications) decreased progressively as the n-3 PUFA and docosahexaenoic acid concentrations increased. The opposite situation was observed in the homozygous –455CC subgroup, in whom increasing erythrocyte n-3 PUFA and docosahexaenoic acid concentrations were associated with higher proportions of individuals with high apo C-III. A formal interactive effect between genotype and n-3 PUFAs was confirmed even after adjustment for possible confounding variables [age, sex, body mass index, smoking, coronary artery disease (CAD)/CAD-free status, or use of lipid-lowering medications] by logistic models.

Conclusion: Patients homozygous for the –455C APOC3 variant are poorly responsive to the apo C-III-lowering effects of n-3 PUFAs.