Results suggest that genetic factors and the percentages of n-3 PUFA in RBCs influence CVD risk factors in the Inuit population. Specifically, results demonstrate that 8 SNPs in 5 candidate genes: CETP ((rs5882) (rs183130) and (rs4783961)), AGT (rs699), APOA5 ((rs651821) and (rs662799)), APOA4 Asn147Ser (rs5104), and APOC3 (rs5128), are associated with plasma lipid concentrations in interaction with the percentages of n-3 PUFA in RBCs in the Inuit population.
Higher percentage of n-3 PUFA in the Inuit population were associated with lower TG levels, higher TC including HDL-C and LDL-C concentrations without affecting the TC/HDL ratio and plasma apoB100 levels. In the same way, a meta-analysis that combined 21 trials with consumption of fish oil, reported a decrease in plasma TG concentrations and an increase in HDL-C and LDL-C concentrations without changes in TC concentrations . Thus, the beneficial effects of higher percentages of n-3 PUFA in RBCs on CVD risk factors in the Inuit population are similar to those previously reported; however, gene-nutrient interactions contribute the inter-individual variability observed in the plasma lipid levels in this population.
Heterozygotes for CETP C4502T (rs183130) or G-971A (rs4783961) had lower plasma TG concentrations with higher percentages of n-3 PUFA compared to the homozygotes for the minor allele. In addition, these heterozygotes for CETP C4502T or G-971A had lower plasma TC levels or TC/HDL ratio with higher percentages of n-3 PUFA compared to homozygotes for the rare allele, respectively. CETP plays a central role in HDL-C metabolism by shuttling cholesteryl esters from HDL particles to apoB- containing particles, partly in exchange for TG . It is well-known that several genetic variants in the CETP gene are associated with altered plasma HDL-C concentrations, lipoprotein particle sizes, CETP plasma concentrations and activity, and perhaps the risk of coronary artery disease . Earlier, Corella et al.,  demonstrated no gene-environment interactions, including total fat, saturated fat and monounsaturated fat- for the CETP C4502T SNP on HDL-C concentrations. We have also demonstrated no interaction with total fat or saturated fat intake with this SNP on plasma lipid levels ; however, in the present study, the inclusion of n-3 PUFA in the diets of wild-type or heterozygotes for CETP would favor an improved cardiovascular risk profile compare to carriers of the minor allele.
Further, carriers of the T allele for CETP Ile405Val (rs5882) decreased plasma TC and increased plasma HDL-C concentrations with higher percentages of n-3 PUFA. This functional SNP, corresponding to the substitution of a valine for an isoleucine caused by a C → T mutation, has been associated with lower CVD risk via lowering of CETP protein concentration and activity; consequently, increasing HDL-C levels and lipoprotein particle sizes . Previously, Darabi et al.,  demonstrated that subjects carrying the C allele of CETP Ile405Val had greater reduction in plasma HDL-C and apoAI concentrations than subjects carrying a T allele when a high-PUFA: saturated diet was replaced with a low- PUFA: saturated diet . Together, these studies suggest that PUFA intake in individuals with CETP Ile405Val polymorphism contributes to the variability of plasma lipids concentrations.
Similarly, higher percentage of n-3 PUFA in carriers of the T allele of AGT M235T (rs699) were associated with lower plasma TC and LDL-C concentrations than carriers of the wild-type allele. The M235T polymorphism in the AGT gene has been associated to an increased CVD risk in the presence of hypercholesterolemia . In a previous study with this Inuit population, we demonstrated that carriers of the minor allele of M235T AGT with high total and saturated fat intake exhibited higher plasma TC and LDL-C concentrations . Taken together, these results suggest that carriers of the AGT M235T should consume a diet high in n-3 PUFA and low in saturated fat, to reduce their risk of CVD.
In contrast, G allele carriers of APOA5 -3 A/G (rs651821) or C allele carriers of APOA5 T-1131C (rs662799) had a more deteriorated lipid profile including higher plasma LDL-C and apoB100 concentrations, a higher TC/HDL ratio together with lower plasma HDL-C concentrations with higher percentage of n-3 PUFA in RBCs. APOA5 regulates TG metabolism; therefore, different SNPs in APOA5 may be associated with TG concentrations and CVD risk factors . Variations in this gene have been previously associated with plasma lipid levels via modulation of dietary intake. First, an interaction of the APOA5 T-1131C polymorphism with energy intake and total fat was observed for plasma TG and TC concentrations in a population of Puerto Rican older adults . Secondly, a study in the Mediterranean population reported a positive association between fat intake and obesity in homozygotes for the T allele of APOA5 T-1131C, whereas in subjects carrying the APOA5 T-1131C polymorphism, higher fat intakes were not associated with higher BMI and TG-rich lipoproteins . Finally, Lai et al.,  suggest that high PUFA-rich diets, specifically n-6 PUFAs, are related to a more atherogenic lipid profile in individuals of the Framingham Heart Study with the APOA5 T-1131C polymorphism. Overall, results suggest that SNPs in APOA5 are determinants of variation in lipid response to n-3 PUFA intake; however, the outcome of these gene-nutrient interactions needs to be investigated further.
Further, carriers of the G allele of APOA4 Asn147Ser (rs5104) had higher apoB100 levels with higher percentages of n-3 PUFA in RBCs. It has been suggested that APOA4 plays an important role in the metabolism of TG-rich lipoproteins . APOA4 variants may alter protein and thus have been linked to baseline TG concentrations  and TG in response to fenofibrate treatment . A study demonstrated that carriers of the minor allele of APOA4 Asn147Ser had lower plasma apoA1 concentrations in a postprandial state after a high saturated meal . Together, results demonstrate that carriers of the minor allele of APOA4 Asn147Ser may be more sensitive to changes in dietary fat.
Similarly, carriers of the APOC3 G minor allele of SstI (rs5128) had increased TC/HDL ratio and plasma apoB100 concentrations with higher percentages of n-3 PUFA. APOC3 increases plasma TG concentrations by inhibiting the lipoprotein lipase activity and by altering the Apo-E mediated uptake of TGs. The G- allele has been associated with elevated plasma TC, TG, and apoC-III concentrations . Lopez-Miranda et al.,  demonstrated an increase in plasma LDL-C concentrations in the CC subjects after consumption of a diet high in monounsaturated fatty acids whereas a decrease was observed in the CG subjects. Taken as a whole, results demonstrate that carriers of the APOC3 G allele of SstI may benefit more from a high monounsaturated diet compared to an n-3 PUFA diet.
Since the effect size of each SNP was small even if the interaction was statistically significant, we demonstrated an additive effect of these SNPs in interaction with percentage of n-3 PUFA for all CVD risk factors. Thus, this demonstrates that it is possible to develop models with advantageous and disadvantageous alleles together with dietary intake data and predict the risk of a deteriorated lipid profile in a specific population. However, the major limitation for the study is the limited number of SNPs chosen based on previous research findings. If such models would be developed, large studies using numerous genetic variations should be included to be able to assess the greatest variability.