Abstract
Omega-3 (n-3) polyunsaturated fatty acids (PUFA) and their metabolites have long been recognized to protect against inflammation-related diseases including heart disease. Recent reports present conflicting evidence on the effects of n-3 PUFAs on major cardiovascular events including death. While some studies document that n-3 PUFA supplementation reduces the risk for heart disease, others report no beneficial effects on heart disease composite primary outcomes. Much of this heterogeneity may be related to the genetic variation in different individuals/populations that alters their capacity to synthesize biologically active n-3 and omega 6 (n-6) PUFAs and metabolites from their 18 carbon dietary precursors, linoleic acid (LA, 18:2 n-6) and alpha-linolenic (ALA, 18:3, n-3). Here, we discuss the role of a FADS gene-by-dietary PUFA interaction model that takes into consideration dietary exposure, including the intake of LA and ALA, n-3 PUFAs, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in determining the efficacy of n-3 PUFA supplementation. We also review recent clinical trials with n-3 PUFA supplementation and coronary heart disease in the context of what is known about fatty acid desaturase (FADS) gene-by-dietary PUFA interactions. Given the dramatic differences in the frequencies of FADS variants that impact the efficiency of n-3 and n-6 PUFA biosynthesis, and their downstream signaling products among global and admixture populations, we conclude that large clinical trials utilizing “one size fits all” n-3 PUFA supplementation approaches are unlikely to show effectiveness. However, evidence discussed in this review suggests that n-3 PUFA supplementation may represent an important opportunity where precision interventions can be focused on those populations that will benefit the most from n-3 PUFA supplementation.
Highlights
Introduction published maps and institutional affilLipid signaling metabolites including eicosanoids, resolvins, protectins, lipoxins and endocannabinoids all play critical roles in physiology and pathophysiology
Kothapalli et al showed that the metabolic flux through the FADS1 step, as measured by the product to precursor ratio of arachidonic acid (ARA) to dihomogammalinolenic acid (DGLA), increases by 84% when examining the differences between the DD to II genotype of the fatty acid desaturase (FADS) insertion–deletion (Indel), rs66698963 [60]
Authors reported no differences between n-3 3 LC-polyunsaturated fatty acids (PUFA) supplementation and placebo for their primary end point of major cardiovascular events; the rate of myocardial infarction was significantly reduced by 28%
Summary
Chronic health problems in the US including obesity [30], cardiovascular disease [31], hypertension [32] and type-2 diabetes (T2D) [33] can be partially attributed to diet. The substitution of dietary saturated fat with largely n-6 PUFAs markedly enhanced circulating levels of n-6 PUFAs, n-6 to n-3 PUFA ratios, and lowered circulating n-3 LCPUFA concentrations [1] Contemporary diets such as the MWD typically have n-6 to n-3 PUFA ratios > 10:1 and as high as 20:1 [43]. A marked increase in LA along with competition between n-6 and n-3 substrates within the pathway has been shown in animal and human models to shift the pathway toward the biosynthesis of high levels of n-6 LC-PUFA and decreased levels of n-3 LC-PUFAs [48,49,50] This shift in the balance of n-6 to n-3 LC-PUFAs in turn impacts the metabolic products and their ratios (such as n-6 to n-3 oxylipins and endocannabinoids), potentially impacting systemic inflammation and the risk for multiple chronic diseases
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