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

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.