Background Nutrition in the intensive care unit (ICU) is vital for patient care; however, immunomodulatory diets rich in polyunsaturated fatty acids (PUFAs) like γ-linolenic acid (GLA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) remain controversial among patients with acute respiratory distress syndrome (ARDS). We postulate that genetic variants impacting PUFA metabolism contribute to mixed responses to PUFA-rich diets. Objective In this study, we aimed to test the effects of single nucleotide polymorphism (SNP) rs174537 on differential responses to PUFA-rich diets. Design We performed a secondary analysis of the OMEGA trial (NCT00609180) where 129 subjects received placebo and 143 received omega-oil. DNA was extracted from buffy coats and used to genotype rs174537; plasma was used to quantitate PUFAs. We tested for SNP-diet interactions on PUFA levels, inflammatory biomarkers, and patient outcomes. Results We observed that all individuals receiving omega-oil, displayed significantly higher levels of GLA, EPA, and DHA (all P < 0.0001), but they did not vary by genotype at rs174537. Statistically significant SNP-diet interactions were observed on circulating DHA levels in African Americans. Specifically, African American T-allele carriers on placebo illustrated elevated DHA levels. Additionally, all individuals receiving omega-oil had higher levels of EPA-derived urinary F3-Isoprostane (Caucasians: P = 0.0011; African Americans: P = 0.0002). Despite these findings, we did not detect any significant SNP-diet interactions on pulmonary functional metrics, clinical outcomes, and mortality. Conclusions This study highlights the importance of genetic and racial contributions to PUFA metabolism and inflammation. In particular, rs174537 had a significant impact on circulating DHA and urinary isoprostane levels. Given our relatively small sample size, further investigations in larger multi-ethnic cohorts are needed to evaluate the impact of rs174537 on fatty acid metabolism and downstream inflammation.
Nutritional support in the intensive care unit (ICU) is a vital element of patient care. Polyunsaturated fatty acids (PUFAs) like γ‐linolenic acid (GLA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have been recommended in immunomodulatory diets because of their anti‐inflammatory effects. However, clinical trials have failed to show unanimous benefit with PUFA‐rich diets. Metabolic conversion of these PUFAs are dependent on fatty acid desaturase (FADS) and elongase (ELOVL) enzymes, which are unequal across humans. In fact, several genetic variants within FADS and ELOVL genes have been shown to impact PUFA metabolism. Select variants are also differentially expressed in African Americans. We hypothesize that these genetic variants may help explain the differential responses to PUFA‐rich diets. In this study, we aimed to investigate gene‐diet interactions in patients with acute lung injury (ALI).Banked DNA and plasma samples from the OMEGA randomized clinical trial (NCT00609180) were used to conduct a secondary analysis on genetic variants within FADS and ELOVL regions; 43 SNPs were genotyped. Plasma PUFA levels were quantified using gas chromatography. Of the 272 enrolled, 143 received omega‐rich vs. 129 placebo diets. All statistical analyses were stratified by race and adjusted for age and gender.Several SNPs were associated with PUFA levels. Notably, SNP rs174537 had a significant impact on arachidonic acid (ARA). Caucasian T allele carriers on the omega‐rich diet had lower ARA levels (p=0.022, Fig. 1). Interestingly, this SNP had a major impact on PUFAs within African Americans on both placebo and omega‐rich diets. ARA levels were significantly higher and DHA levels were low (p=0.0007) in African Americans. Genotype at rs174537 was associated with patient outcomes; Caucasians with the T allele had significantly more VENT‐free and ICU‐free days (~>12%) than GGs, but this was not observed within African Americans. Instead, a significant interaction between gender and diet was seen, with African American women on placebo diet having 40% fewer VENT‐free (p=0.009) and ICU‐free days (p=0.022) than African American men. Mortality was highest in GGs receiving omega‐rich diets in both races, however this was not statistically significant. These data suggest strong ethnic, gender and genetic factors influencing the response to omega‐rich diets. Further investigation on other gene‐gene interactions (e.g. between FADS and ELOVL variants), and epigenetic modifications are needed to understand the underlying mechanisms regulating PUFA metabolism and biosynthesis in critically injured and ill patients.Support or Funding InformationNIH K25 HL133611This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
The Modern Western Diet has been associated with the rise in metabolic and inflammatory diseases, including obesity, diabetes, and cardiovascular disease. This has been attributed, in part, to the increase in dietary omega-6 polyunsaturated fatty acid (PUFA) consumption, specifically linoleic acid (LA), arachidonic acid (ARA), and their subsequent metabolism to pro-inflammatory metabolites which may be driving human disease. Conversion of dietary LA to ARA is regulated by genetic variants near and within the fatty acid desaturase (FADS) haplotype block, most notably single nucleotide polymorphism rs174537 is strongly associated with FADS1 activity and expression. This variant and others within high linkage disequilibrium may potentially explain the diversity in both diet and inflammatory mediators that drive chronic inflammatory disease in human populations. Mechanistic exploration into this phenomenon using human hepatocytes is limited by current two-dimensional culture models that poorly replicate in vivo functionality. Therefore, we aimed to develop and characterize a three-dimensional hepatic construct for the study of human PUFA metabolism. Primary human hepatocytes cultured in 3D hydrogels were characterized for their capacity to represent basic lipid processing functions, including lipid esterification, de novo lipogenesis, and cholesterol efflux. They were then exposed to control and LA-enriched media and reproducibly displayed allele-specific metabolic activity of FADS1, based on genotype at rs174537. Hepatocytes derived from individuals homozygous with the minor allele at rs174537 (i.e., TT) displayed the slowest metabolic conversion of LA to ARA and significantly reduced FADS1 and FADS2 expression. These results support the feasibility of using 3D human hepatic cultures for the study of human PUFA and lipid metabolism and relevant gene-diet interactions, thereby enabling future nutrition targets in humans.
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