Kaitlin Roke

Polymorphisms in FADS1 and FADS2 alter desaturase activity in young Caucasian and Asian adults

Recent evidence indicates that genetic variation in fatty acid desaturases 1 and 2 (FADS1 and FADS2) is associated with changes in plasma fatty acid profiles; however, the association with altered desaturase activity has not been examined in different ethnic populations. The present study examined whether genetic variation in the FADS gene cluster regulates desaturase activity in two populations of young Canadian adults (Caucasian and Asian) and whether altered desaturase activity was reflected in both n-3 and n-6 fatty acid profiles. FADS1 and FADS2 were genotyped in a random subset of participants (Caucasian, n=78; Asian, n=69) from the Toronto Nutrigenomics and Health study using MALDI-TOF mass spectrometry, and plasma fatty acids were measured by gas chromatography. Desaturase activities were estimated using the following fatty acid ratios: γ-linoleic acid to linoleic acid (GLA:LA), arachidonic acid to linoleic acid (AA:LA), arachidonic acid to dihomo-γ-linoleic acid (AA:DGLA), and eicosapentaneoic acid to α-linolenic acid (EPA:ALA). Nineteen single nucleotide polymorphisms (SNPs) were examined, and several SNPs (9 in Caucasians and 8 in Asians) were associated with various desaturase activities. The most significant association detected was between the FADS1 rs174547 SNP and AA:LA in both Caucasians (p=4.0 × 10(-8)) and Asians (p=5.0 × 10(-5)). Although the minor allele for this SNP differed between Caucasians (T) and Asians (C), carriers of the C allele had a lower desaturase activity than carriers of the T allele in both groups. To determine whether rs174547 was a dominant SNP in the FADS gene cluster, we constructed an additional model which included this SNP as a covariate. Only one SNP (rs498793 in FADS2) remained associated with the EPA:ALA ratio (p=1.1 × 10(-5)) in Asians. This study shows that genetic variation in the FADS gene cluster (in particular rs174547) can alter desaturase activity in subjects of Caucasians and Asian descent.

Enzymatic activity and genetic variation in SCD1 modulate the relationship between fatty acids and inflammation.

Fatty acids (FA) represent a diverse class of molecules known to regulate inflammatory pathways. Therefore enzymes that regulate FA metabolism are attractive candidates to better understand the relationship between FA and inflammation. Stearoyl-CoA desaturase 1 (SCD1) is rate limiting for the conversion of saturated FA (SFA) to monounsaturated FA (MUFA). Evidence suggests that SCD1 activity may be positively associated with inflammation. Moreover, genetic variation in SCD1 may alter enzyme activity; however, it is unknown whether this affects inflammatory status. The goal of this study was to examine the relationships between plasma FA, SCD1 activity, and SCD1 polymorphisms with C-reactive protein (CRP) levels in young adults. SFA, MUFA, and CRP were measured in fasted plasma samples from European (n=279, 198 female and 81 male) and Asian (n=249, 179 female and 70 male) subjects, 20-29 years old. Circulating levels of palmitic (16:0), palmitoleic (16:1), stearic (18:0), and oleic acids (18:1) were measured by gas chromatography and SCD1 activity was estimated by the ratio of product to precursor (16:1/16:0; 18:1/18:0). Positive associations were identified between CRP levels and 16:0 (p<2.0×10(-4)), 16:1 (p<0.05), and the SCD1 index (18:1/18:0; p<6.0×10(-3)) in European and Asian females, while 18:0 was inversely associated with CRP (p<2.0×10(-4)) in both groups. Ten single nucleotide polymorphisms (SNPs) in SCD1 were genotyped in all subjects. One SNP (rs2060792) was associated (p<0.05) with 16:0 and 18:0 levels in females of European descent. This same SNP was also associated with CRP levels in both groups of females (p<0.05). Overall, SCD1 activity and genetic variation have an important role in modulating the relationship between FA and inflammation in young adults.

Variation in the FADS1/2 gene cluster alters plasma n−6 PUFA and is weakly associated with hsCRP levels in healthy young adults

INTRODUCTION Past research has reported that single nucleotide polymorphisms (SNPs) in fatty acid desaturase 1 and 2 (FADS1/2) can influence plasma fatty acid (FA) profiles. Changes in FA profiles are known to influence inflammatory processes; therefore both FA and SNPs in FADS1/2 may affect inflammation. The goals of this study were to (i) examine the relationships between individual n-6 FA and estimates of FA desaturation with circulating high sensitivity C-reactive protein (hsCRP) levels, and (ii) determine whether SNPs in FADS1/2 are associated with changes in hsCRP. METHODS FA and hsCRP were measured in fasted plasma samples from 878 healthy young adults (20-29yrs). Circulating levels of plasma linoleic (LA), γ-linolenic (GLA), dihomo-γ-linolenic (DGLA) and arachidonic (AA) acids were measured by gas chromatography and used to calculate desaturase indices for FADS1/2. Nineteen SNPs in FADS1/2 were genotyped in all subjects and six (rs174579, rs174593, rs174626, rs526126, rs968567 and rs17831757) were further analyzed. RESULTS Significant inverse associations were found between LA and hsCRP (p=8.55×10(-9)) and the FADS1 desaturase index and hsCRP (p=4.41×10(-6)). A significant positive association was found between DGLA and hsCRP (p=9.10×10(-11)). Several SNPs were associated with circulating levels of individual FA and desaturase indices, with minor allele carriers having lower AA levels and reduced desaturase indices. A single SNP in FADS2 (rs526126) was weakly associated with hsCRP (p=0.05). CONCLUSIONS This study highlights the relationships between FA and hsCRP, and confirms that FA are strongly influenced by SNPs in FADS1/2. Furthermore, we found weak evidence that SNPs in FADS1/2 may influence hsCRP levels in young adults.

The Role of FADS1/2 Polymorphisms on Cardiometabolic Markers and Fatty Acid Profiles in Young Adults Consuming Fish Oil Supplements

Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are omega-3 (n-3) fatty acids (FAs) known to influence cardiometabolic markers of health. Evidence suggests that single nucleotide polymorphisms (SNPs) in the fatty acid desaturase 1 and 2 (FADS1/2) gene cluster may influence an individual’s response to n-3 FAs. This study examined the impact of a moderate daily dose of EPA and DHA fish oil supplements on cardiometabolic markers, FA levels in serum and red blood cells (RBC), and whether these endpoints were influenced by SNPs in FADS1/2. Young adults consumed fish oil supplements (1.8 g total EPA/DHA per day) for 12 weeks followed by an 8-week washout period. Serum and RBC FA profiles were analyzed every two weeks by gas chromatography. Two SNPs were genotyped: rs174537 in FADS1 and rs174576 in FADS2. Participants had significantly reduced levels of blood triglycerides (−13%) and glucose (–11%) by week 12; however, these benefits were lost during the washout period. EPA and DHA levels increased significantly in serum (+250% and +51%, respectively) and RBCs (+132% and +18%, respectively) within the first two weeks of supplementation and remained elevated throughout the 12-week period. EPA and DHA levels in RBCs only (not serum) remained significantly elevated (+37% and +24%, respectively) after the washout period. Minor allele carriers for both SNPs experienced greater increases in RBC EPA levels during supplementation; suggesting that genetic variation at this locus can influence an individual’s response to fish oil supplements.

Ethnicity, sex, FADS genetic variation, and hormonal contraceptive use influence delta-5- and delta-6-desaturase indices and plasma docosahexaenoic acid concentration in young Canadian adults: a cross-sectional study

BackgroundThere is great interest in the relationship between polyunsaturated fatty acids and health. Yet, the combinatory effect of factors such as sex, ethnicity, genetic polymorphisms and hormonal contraceptives (HC) on the concentrations of these fatty acids is unknown. Therefore, we sought to determine the effects of FADS polymorphisms, and HC use in females, on aggregate desaturase indices (ADI), and plasma docosahexaenoic acid (DHA) concentrations in Caucasian and East Asian males and females.MethodsFasting plasma samples were collected from subjects (Caucasian males: 113 and females: 298; East Asian males: 98 and females: 277) from the Toronto Nutrigenomics and Health Study. Fatty acid concentrations were measured by gas chromatography. ADI were estimated by dividing concentrations of arachidonic acid by linoleic acid (n-6 ADI) and eicosapentaenoic acid (EPA) by α-linolenic acid (n-3 ADI). [DHA/EPA] desaturase index was used to determine effects of FADS2 polymorphisms and HC use on EPA conversion to DHA.ResultsIn Caucasians, associations between n-6 ADI and multiple SNP (FADS1 rs174547, FADS2 rs174576, and rs174611 in males; FADS1 rs174547, FADS2 rs174570, rs174576, rs174679, rs174611, rs174593, rs174626, rs2072114, rs2845573, and rs2851682 in females) withstood multiple testing. In East Asian females, 5 SNP-n-6 ADI associations (FADS2 rs174602, rs174626, rs2072114, rs2845573, and rs2851682) withstood multiple testing. One FADS2 SNP was associated with altered [DHA/EPA] desaturase index in Caucasian females only (rs174576, p < 0.0001). HC use had a significant effect on DHA concentrations in Caucasian females only (P < 0.0001).ConclusionsWe demonstrate ethnic- and sex-specific effects of FADS polymorphisms on desaturase indices, and ethnic-specific effect of HC use on plasma DHA concentrations.

Evaluating Changes in Omega-3 Fatty Acid Intake after Receiving Personal FADS1 Genetic Information: A Randomized Nutrigenetic Intervention

Nutrigenetics research is anticipated to lay the foundation for personalized dietary recommendations; however, it remains unclear if providing individuals with their personal genetic information changes dietary behaviors. Our objective was to evaluate if providing information for a common variant in the fatty acid desaturase 1 (FADS1) gene changed omega-3 fatty acid (FA) intake and blood levels in young female adults (18–25 years). Participants were randomized into Genetic (intervention) and Non-Genetic (control) groups, with measurements taken at Baseline and Final (12 weeks). Dietary intake of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) was assessed using an omega-3 food frequency questionnaire. Red blood cell (RBC) FA content was quantified by gas chromatography. Implications of participation in a nutrigenetics study and awareness of omega-3 FAs were assessed with online questionnaires. Upon completion of the study, EPA and DHA intake increased significantly (p = 1.0 × 10−4) in all participants. This change was reflected by small increases in RBC %EPA. Participants in the Genetic group showed increased awareness of omega-3 terminology by the end of the study, reported that the dietary recommendations were more useful, and rated cost as a barrier to omega-3 consumption less often than those in the Non-Genetic group. Providing participants FADS1 genetic information did not appear to influence omega-3 intake during the 12 weeks, but did change perceptions and behaviors related to omega-3 FAs in this timeframe.

Association between circulating ascorbic acid, α-tocopherol, 25-hydroxyvitamin D, and plasma cytokine concentrations in young adults: a cross-sectional study

BackgroundInflammation and oxidative stress are associated with the development of numerous chronic diseases. Circulating ascorbic acid, α-tocopherol, and 25-hydroxyvitamin D (25(OH)D) may help reduce concentrations of pro-inflammatory cytokines through their antioxidant and anti-inflammatory properties. These micronutrients may act synergistically, and they may have different anti-inflammatory effects, but previous studies have assessed the link between each of these micronutrients and inflammation in isolation without controlling for the other micronutrients. Our objective was to examine the association between circulating concentrations of ascorbic acid, α-tocopherol, and 25(OH) D and a panel of pro-inflammatory cytokines in an ethnically diverse population of young adults.MethodsParticipants (n = 1,007) from the Toronto Nutrigenomics and Health study provided fasting blood samples for biomarker measurements and were subsequently categorized into tertiles for each micronutrient based on their circulating concentrations. We conducted Pearson’s correlation analyses across all micronutrients and cytokines. The associations between individual micronutrients and cytokines were examined using analysis of covariance with age, sex, waist circumference, ethnicity, physical activity, season of blood collection, total cholesterol, hormonal contraceptive use among women, and the other two micronutrients as covariates.ResultsWe observed weak micronutrient-cytokine correlations, moderate correlations between certain cytokines, and strong correlations between specific cytokines, particularly interleukin 1- receptor antagonist (IL-1RA), interferon-γ (IFN-γ), and platelet-derived growth factor BB (PDGF-bb). After full covariate adjustment, circulating α-tocopherol was inversely associated with IFN-γ and regulated upon activation normal T-cell expressed and secreted (RANTES). We observed an unexpected positive association between ascorbic acid and IFN-γ. 25(OH)D was not associated with altered concentrations of any inflammatory biomarkers.ConclusionsThese findings suggest that α-tocopherol, but not ascorbic acid or 25(OH)D, is inversely associated with inflammation in healthy young adults.

Fish oil regulates blood fatty acid composition and oxylipin levels in healthy humans: A comparison of young and older men.

SCOPE Increased consumption of fish oils rich in eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) is associated with improved cardiometabolic health and inflammatory status; however, age-related responses remain poorly described. METHODS AND RESULTS In a placebo-controlled study, healthy young and older men consumed five fish oil capsules daily, providing 2.0 g/d EPA and 1.0g/d DHA, for three months. Both young and older men experienced a ∼30% reduction in blood triglycerides with fish oil supplementation. A significant group × time interaction was observed for DHA, with young men experiencing a ∼twofold increase in DHA in serum and RBCs, while older men showed negligible increases. Other fatty acids were differentially regulated between young and older men, most notably osbond acid and several saturates. Small changes were observed in serum oxylipins, with both groups of men responding similarly: 5-HETE was reduced, while PGF2α and 17-HDoHE were increased. Changes in oxylipins occurred independent of changes in whole blood expression of key genes regulating oxylipin production. CONCLUSION Our study suggests that both young and older men experience the triglyceride-lowering benefits associated with fish oil supplements, but show differential responses in blood fatty acids. Additionally, fish oil promotes an improved oxylipin profile in both groups of men.

FADS2 genotype influences whole-body resting fat oxidation in young adult men.

Considerable evidence supports an association between fatty acid desaturase 2 (FADS2) polymorphisms and the efficiency of converting alpha-linolenic acid (ALA) into eicosapentaenoic acid (EPA) via the desaturation-elongation pathway. However, ALA conversion into EPA represents only 1 of the metabolic fates for this essential fatty acid, as ALA is also highly oxidized. This study demonstrates for the first time that genetic variation in FADS2 (rs174576) is not only associated with the activity of the desaturation-elongation pathway, but also whole-body fat oxidation.

Lack of effects of fish oil supplementation for 12 weeks on resting metabolic rate and substrate oxidation in healthy young men: A randomized controlled trial.

Fish oil (FO) has been shown to have beneficial effects in the body via incorporation into the membranes of many tissues. It has been proposed that omega-3 fatty acids in FO may increase whole body resting metabolic rate (RMR) and fatty acid (FA) oxidation in human subjects, but the results to date are equivocal. The purpose of this study was to investigate the effects of a 12 week FO supplementation period on RMR and substrate oxidation, in comparison to an olive oil (OO) control group, in young healthy males (n = 26; 22.8 ± 2.6 yr). Subjects were matched for age, RMR, physical activity, VO2max and body mass, and were randomly separated into a group supplemented with either OO (3 g/d) or FO containing 2 g/d eicosapentaenoic acid (EPA) and 1 g/d docosahexaenoic acid (DHA). Participants visited the lab for RMR and substrate oxidation measurements after an overnight fast (10–12 hr) at weeks 0, 6 and 12. Fasted blood samples were taken at baseline and after 12 weeks of supplementation. There were significant increases in the EPA (413%) and DHA (59%) levels in red blood cells after FO supplementation, with no change of these fatty acids in the OO group. RMR and substrate oxidation did not change after supplementation with OO or FO after 6 and 12 weeks. Since there was no effect of supplementation on metabolic measures, we pooled the two treatment groups to determine whether there was a seasonal effect on RMR and substrate oxidation. During the winter season, there was an increase in FA oxidation (36%) with a concomitant decrease (34%) in carbohydrate (CHO) oxidation (p < 0.01), with no change in RMR. These measures were unaffected during the summer season. In conclusion, FO supplementation had no effect on RMR and substrate oxidation in healthy young males. Resting FA oxidation was increased and CHO oxidation reduced over a 12 week period in the winter, with no change in RMR. Trial Registration: ClinicalTrials.gov NCT02092649