Abstract
BACKGROUND: Intake of the marine omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) reduces fasting triglyceride (TG) levels and may thereby lower cardiovascular disease risk. However, there are large inter-individual differences in the TG-lowering effect of omega-3 supplementation. Genotype differences partly explain this variation, but gene-environment interactions leading to gene expression differences may also be important. In this study, we aimed to investigate baseline differences and differences in the change in peripheral blood mononuclear cell (PBMC) gene expression and lipoprotein subclass TG levels between TG responders and non-responders to omega-3 fatty acid supplementation. METHODS: In a previous randomized controlled trial, healthy normotriglyceridemic subjects (n = 35, 71% women) received 1.6 g EPA + DHA/day for 7 weeks. In this exploratory sub-study, we defined TG responders as subjects having a TG reduction beyond the 20% day-to-day variation and non-responders as having a TG change between - 20% and + 20% after omega-3 supplementation. PBMC gene expression was measured using microarray, and lipoprotein subclasses were measured using nuclear magnetic resonance spectroscopy. RESULTS: Eight subjects were defined as responders with a median TG reduction of 37%, and 16 subjects were defined as non-responders with a median TG change of 0%. At baseline, responders had higher TG levels in two of four high-density lipoprotein (HDL) subclasses and 909 gene transcripts (p ≤ 0.05) were differentially expressed compared to non-responders. During the intervention, the plasma TG reduction among responders was reflected in TG reductions in four of six different very low-density lipoprotein subclasses and three of four different HDL subclasses. Compared to non-responders, the expression of 454 transcripts was differentially altered in responders (p ≤ 0.05). Pathway analyses revealed that responders had altered signaling pathways related to development and immune function. In addition, two of the top 10 enriched pathways in responders compared to non-responders were related to lysophosphatidic acid signaling. CONCLUSION: TG responders and non-responders to omega-3 supplementation have different lipoprotein subclass and PBMC gene expression profiles at baseline and different lipoprotein subclass and PBMC gene expression responses to omega-3 supplementation. These gene expression differences may partially explain the variability in TG response observed after omega-3 supplementation. GRAPHICAL ABSTRACT: Based on free images from Servier Medical Art (Creative Commons Attribution License) and image from www.colourbox.com.