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Genetics, Omega-3s & Serum Lipids

iStock-1418152314The effect of omega-3 fatty acid supplementation on serum lipids and other cardiovascular risk markers, with results stratified by PPARG genotype, were recently determined in a randomized and double-blinded placebo-controlled clinical trial published in Nutrients. One hundred and two adults between the ages of 40 to 75 with an LDL-C between 70 and 190 mg/dL received either placebo or 2g omega-3 per day (1.2 g eicosapentaenoic acid and 0.6g g docosahexaenoic acid), for 90 days.

PPARG genotyping of study participants was also done; PPARG (Peroxisome Proliferator-Activated Receptor Gamma) encodes for the transcription factor PPARγ, known to have a range of biological effects influencing lipid and glucose metabolism, modulating the expression of enzymes involved in cholesterol transport, fatty acid oxidation, etc. PPARγ stimulates the formation and differentiation of fat cells, and also increases insulin sensitivity, with several genetic variants in PPARG linked to serum lipid levels, as well as cardiovascular disease and diabetes risk. This study evaluated genotypes for 4 polymorphisms within the PPARG gene (rs10865710, rs7649970, rs1801282, and rs3856806), with participants that had at least one of the minor alleles in these four SNPs (single nucleotide polymorphism) classified as having a PPARG polymorphism, with a separate analysis done in both the placebo and omega-3 groups.

At the study’s conclusion, a significant difference was observed between groups among participants with a minor allele of a PPARG SNP. Omega-3 supplementation was found to reduce LDL-C by 15.4% compared to only a 2.6% reduction in the group receiving placebo (among participants that had at least one minor allele), a significant difference. In contrast, among participants without a PPARG polymorphism, omega-3s reduced LDL-C by only 3.7%, not significantly different from the 2.9% reduction observed in the placebo group. Similarly, triglycerides dropped 13.4% more (21.3% overall) in the group receiving omega-3 fatty acids that possessed a PPARG polymorphism when compared to placebo, a significant difference, compared to a non-significant 7.4% greater reduction in the group without a PPARG polymorphism. No significant differences in total cholesterol, HDL-C, and hsCRP were observed between groups.

The meaningful drops in LDL-C and triglycerides suggest that omega-3s may be particularly important for those individuals with one of the minor alleles in PPARG, approximately 42% of this study’s population. The authors of the study conclude that genetic profiling, at least of the PPARG gene, may be a critical guide to determine who will benefit the most clinically from omega-3 supplementation, and that mixed results of previous studies may be attributed to genetic differences.

This is not the first study to find different outcomes in response to omega-3 supplementation when a genomic analysis was included. In the randomized OMEGA-REMODEL placebo-controlled trial, high-dose omega-3s (4g per day) were found to attenuate the adverse remodeling of the left ventricle which occurs following a myocardial infarction, as well as reduce myocardial fibrosis and systemic inflammation. However, an analysis of this trial published in PLOS ONE indicates that a fairly common SNP of the FADS2 gene (rs1535) was shown to modify the outcomes; individuals with the GG genotype had the greatest benefit with supplementation, in terms of improved left ventricle remodeling and reduced non-infarct myocardial fibrosis. The FADS2 gene encodes for delta-6 desaturase, the enzyme that converts linoleic acid and alpha-linolenic acid into arachidonic acid and EPA, respectively. The G allele is associated with reduced activity of this enzyme and a subsequent decrease in EPA synthesis, a plausible mechanism to explain why EPA supplementation is particularly beneficial among individuals with the GG genotype.

Other SNPs within the FADS2 gene have also been associated with varied responses to omega-3 supplementation. For example, the rs174602 SNP was shown to influence the effect of DHA supplementation during pregnancy on the development of a metabolic syndrome (Met-S) score of their children by age 11. In a double-blind and randomized study, children of mothers with the TT genotype of this SNP who were given DHA from mid-pregnancy until delivery had a lower Met-S score at age 11, while children whose mothers had the CC genotype had higher Met-S scores compared to placebo. This SNP also modified the effect of DHA (given during pregnancy) on the cognitive development of children by age 5, and influenced the effect of DHA on the metabolome of infants at 3 months of age.

All of these findings make a strong case for precision or genomic medicine, i.e., utilizing the results of genetic analyses to help determine the efficacy of medical and nutritional interventions. Targeted SNP analysis has been found to predict the efficacy of omega-3 supplementation for LDL-C and triglyceride reduction, the ability to minimize damage and inflammation following a heart attack, and the cognitive and metabolic development of children based on their mother’s genotype and supplementation during pregnancy. These SNPs are not rare, affecting a substantial portion of the population, and assessment of the genome can help guide which of our patients are likely to benefit the most.

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