Prospective clinical trial examining the impact of genetic variation in FADS1 on the metabolism of linoleic acid- and ɣ-linolenic acid-containing botanical oils

Abstract

Background: Unexplained heterogeneity in clinical trials has resulted in questions regarding the effectiveness of ɣ-linolenic acid (GLA)-containing botanical oil supplements. This heterogeneity may be explained by genetic variation within the fatty acid desaturase (FADS) gene cluster that is associated with circulating and tissue concentrations of arachidonic acid (ARA) and dihomo-ɣ-linolenic acid (DGLA), both of which may be synthesized from GLA and result in proinflammatory and anti-inflammatory metabolites, respectively.

Objectives: The objective of this study was to prospectively compare the capacity of a non-Hispanic white cohort, stratified by FADS genotype at the key single-nucleotide polymorphism (SNP) rs174537, to metabolize 18-carbon omega-6 (n-6) PUFAs in borage oil (BO) and soybean oil (SO) to GLA, DGLA, and ARA.

Methods: Healthy adults (n = 64) participated in a randomized, double-blind, crossover intervention. Individuals received encapsulated BO (Borago officinalis L.; 37% LA and 23% GLA) or SO [Glycine max (L.) Merr.; 50% LA and 0% GLA] for 4 wk, followed by an 8-wk washout period, before consuming the opposite oil for 4 wk. Serum lipids and markers of inflammation (C-reactive protein) were assessed for both oil types at baseline and during weeks 2 and 4 of the intervention.

Results: SO supplementation failed to alter circulating concentrations of any n-6 long-chain PUFAs. In contrast, a modest daily dose of BO elevated serum concentrations of GLA and DGLA in an rs174537 genotype-dependent manner. In particular, DGLA increased by 57% (95% CI: 0.38, 0.79) in GG genotype individuals, but by 141% (95% CI: 1.03, 2.85) in TT individuals. For ARA, baseline concentrations varied substantially by genotype and increased modestly with BO supplementation, suggesting a key role for FADS variation in the balance of DGLA and ARA.

Conclusions: The results of this study clearly suggest that personalized and population-based approaches considering FADS genetic variation may be necessary to optimize the design of future clinical studies with GLA-containing oils. This trial was registered at clinicaltrials.gov as NCT02337231.

Keywords: PUFAs; arachidonic acid; borage oil; gamma-linolenic acid; gene–diet interaction; n-3 fatty acids; n-6 fatty acids; precision nutrition; randomized cross-over design; soybean oil.

Copyright © The Author(s) 2020.

Figures

FIGURE 1

Omega 6 PUFA pathway. The PUFA metabolic pathway consists of alternating desaturation (FADS) and carbon chain elongation (ELOVL) steps. The FAs administered in botanical oil supplements (LA and GLA) enter the pathway as shown. The bioactive lipids derived from DGLA and ARA are indicated. The omega 6 (n-6) side of the pathway is shown, but the same enzymes utilize omega-3 (n-3) substrates (not shown) in a competitive manner. Bioactive lipid mediators derived from n = 6 PUFAs are indicated in dashed boxes. ARA, arachidonic acid; DGLA, dihomo-ɣ-linolenic acid; FADS, FA desaturase; ELOVL, elongation of very long-chain FAs; GLA, ɣ-linolenic acid; HETE, hydroxyeicosatetraenoic acid; HODE, hydroxyoctadecadienoic acid; LA, linoleic acid.

FIGURE 2

Recruitment and study design. (A) The recruitment and retention summary is shown for this nutritional intervention study. (B) The study design is that of a double-blind, randomized, crossover type. Participants were stratified by the FADS SNP rs174537 genotype (GG, GT, TT). After the consenting and screening process, eligible subjects (of each genotype) were randomized to begin 4-wk consumption of either daily soybean or borage oil capsules, followed by an 8-wk washout period and then another 4-wk period of consumption of the opposite oil. Participant genotype and oil consumption order were blind to both the participants and study team. The 2 baseline visits (V2 and V5) preceding the 2 supplementation periods are indicated. FADS, FA desaturase gene; GLA, ɣ-linolenic acid; SNP, single-nucleotide polymorphism; V, visit.

FIGURE 3

Time course of serum n-6 PUFA concentrations (as % of total) after supplementation with botanical oils. This figure shows the changes in circulating n-6 PUFAs with either SO (blue) or BO (red) supplementation over the course of the 4-wk study period by the rs174537 genotype. Points represent the estimated mean values from the mixed models and bars represent 95% CIs. For both GLA and DGLA, BO supplementation resulted in dramatic increases from baseline values, both P < 1 × 10−11. For GLA, values at week 4 were similar across genotypes, P = 0.80, while for DGLA they varied significantly,P = 8.05 × 10−7. GLA and DGLA values at week 2 and 4 were also significantly different from the corresponding values for SO at week 2 and 4, all P < 1 × 10−6. For ARA, changes were modest and initial baseline differences by genotype were carried forward such that the initial ordering (GG > GT > TT) was preserved. ARA, arachidonic acid; BO, borage oil; DGLA, dihomo-ɣ-linolenic acid; n-6, omega-6; GLA, ɣ-linolenic acid; SO, soybean oil.