👤 David G Mutch

Omega-3 long-chain polyunsaturated fatty acids (n3-LCPUFAs) have strong triglyceride-lowering and anti-inflammatory properties, and high levels of these fatty acids have been associated with reduced risk of cardiovascular disease. The synthesis of n3-LCPUFA, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), and n6-LCPUFA, arachidonic acid, share a common pathway mediated by fatty acid desaturase genes, FADS1 and FADS2. LCPUFA synthesis is regulated by both modifiable and non-modifiable factors. Of particular interest is the role of genetic variants in the FADS gene cluster, which are associated with altered FADS1 and FADS2 expression, as well as LCPUFA levels. However, the specific functional variants and the precise molecular mechanisms by which these variants regulate FADS gene expression remain to be elucidated. Variation in the FADS gene cluster is thought to have arisen through natural selection and changing dietary patterns. Available evidence suggests these variants, either individually or as a haplotype, may alter FADS gene expression by modifying DNA methylation in regulatory regions, as well as microRNA and transcription factor binding sites. This review explores the current state of knowledge regarding the functional roles of these variants on LCPUFA synthesis and how these new insights will help support precision nutrition strategies aimed at improving an individual's n3-LCPUFA status and health. Identifying specific functional variants in or near the FADS gene cluster and elucidating the mechanisms by which these variants impact LCPUFA synthesis requires further investigation. However, hypothesis generating in vitro studies have revealed roles for epigenetics, non-coding RNAs, and modification of transcription factor binding sites. This knowledge will generate new insights that will help improve our understanding of the genetic basis underlying LCPUFA synthesis and how this may differ across populations. Show less

The omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have numerous benefits, including strong anti-inflammatory and triglyceride-lowering properties. EPA and DHA are primarily obtained by consuming fatty fish; however, they are also endogenously synthesized primarily in the liver from α-linolenic acid (ALA) through a pathway mediated by the delta-6 desaturase (D6D) enzyme. Previous reports in rodents and humans suggest that dietary proteins such as soy and dairy may impact this pathway differently. The primary aim was to investigate the effects of diets containing either soy or milk protein on the expression, abundance, and enzymatic activity of the desaturases and elongases regulating hepatic omega-3 fatty acid biosynthesis. Male C57BL/6N mice (n = 16 per group) were fed a moderate-fat diet for 8 weeks containing either 1% or 3% energy from ALA. Protein content (15% energy) corresponded to either skim milk powder (SMP) or soy protein isolate (SPI). Hepatic fatty acid content was quantified by gas chromatography-flame ionization detection. Gene expression and protein expression were assessed by RT-qPCR and western blotting, respectively. D6D activity was measured in isolated hepatic microsomes. Fat oxidation was examined using a high-resolution respirometer. Hepatic omega-3 fatty acids (ALA, SDA, EPA, DPAn-3) were lower in SPI-fed mice compared to SMP-fed mice. Fads1, Fads2, Elovl2, and Elovl5 expression was higher in SPI-fed mice compared to those fed SMP, while Srebp-1c expression was lower and Cpt1a expression higher in SPI-fed mice. Consistent with the changes seen at the gene expression levels, FADS2 protein abundance was higher in SPI-fed mice, whereas ELOVL5 protein expression was lower in the SPI groups. Little to no differences in microsomal D6D activity and mitochondrial respiration were detected. Our findings suggest that SPI-related reductions in hepatic omega-3 fatty acid content occur independent of changes in desaturase gene expression, protein expression, enzymatic activity, or mitochondrial respiration. Further studies investigating the influence of dietary proteins on ALA metabolism are therefore warranted. Show less

The production of the omega-3 long-chain polyunsaturated fatty acids (n-3 LCPUFA) eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) from alpha-linolenic acid (ALA) relies on the delta-6 desaturase (D6D) enzyme encoded by the Fads2 gene. While EPA and DHA reduce hepatic triacylglycerol (TAG) storage and regulate lipogenesis, the independent impact of ALA is less understood. To address this gap in knowledge, hepatic fatty acid metabolism was investigated in male wild-type (WT) and Fads2 knockout (KO) mice fed diets (16% kcal from fat) containing either lard (no n-3 LCPUFA), flaxseed oil (ALA-rich), or menhaden oil (EPA/DHA rich) for 21 weeks. Fat content and composition, as well as markers of lipogenesis, glyceroneogenesis, and TAG synthesis, were analyzed using histology, gas chromatography, and reverse transcription quantitative PCR (RT-qPCR). Mice fed the menhaden diet had significantly lower hepatic TAG compared to both lard- and flax-fed mice, concomitant with changes in n-3 and n-6 LCPUFA in both TAG and phospholipid (PL) fractions (all P < 0.05). Flax-fed WT mice had lower liver TAG content compared to their KO counterparts. Menhaden-fed mice had significantly lower expression of key lipogenic (Scd1, Srebp-1c, Fasn, Fads1, and Fads2), glyceroneogenic (Pck1), and TAG synthesis (Agpat3) genes compared to lard, with flax-fed mice showing some intermediate effects. Gene expression effects were independent of D6D activity, since no differences were detected between WT and KO mice fed the same diet. This study demonstrates that EPA/DHA and not ALA itself is critical for the prevention of hepatic steatosis. Show less

Docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) are two omega-3 fatty acids that can be synthesized out of their precursor alpha-linolenic acid (ALA). FADS and ELOVL genes encode the desaturase and elongase enzymes required for EPA and DHA synthesis from ALA; however, single nucleotide polymorphisms (SNPs) in FADS and ELOVL genes could modify the levels of EPA and DHA synthesized from ALA although there is no consensus in this area. This review aims to investigate EPA and DHA circulating levels in human blood and their association with FADS or ELOVL. PubMed, Cochrane, and Scopus databases were used to identify research articles. They were subsequently reviewed by two independent investigators. Initially, 353 papers were identified. After removing duplicates and articles not meeting inclusion criteria, 98 full text papers were screened. Finally, this review included 40 studies investigating FADS and/or ELOVL polymorphisms. A total of 47 different SNPs in FADS genes were reported. FADS1 rs174537, rs174547, rs174556 and rs174561 were the most studied SNPs, with minor allele carriers having lower levels of EPA and DHA. SNPs in the FADS genes were in high linkage disequilibrium. SNPs in FADS were correlated with levels of EPA and DHA. No conclusion could be drawn with the ELOVL polymorphisms since the number of studies was too low. Specific SNPs in FADS gene, such as rs174537, have strong associations with circulating levels of EPA and DHA. Continued investigation regarding the impact of genetic variants related to EPA and DHA synthesis is warranted. Show less

Lipid uptake by white adipose tissue (WAT) is critically important for storage of excess energy and to protect peripheral tissues from ectopic lipid deposition. When WAT becomes dysfunctional (i.e., with obesity), it is characterized by impaired lipid uptake and increased lipolysis which, together, promote whole-body dyslipidemia. Omega-3 polyunsaturated fatty acids (N-3 PUFA) are widely studied for their triacylglycerol (TAG)-lowering properties and cardiometabolic health benefits. One potential mechanism underlying these benefits is the modification of WAT lipid uptake; however, there are gaps in our understanding regarding the specific mechanisms by which N-3 PUFA function. Evidence to date suggests that N-3 PUFA promote TAG clearance by increasing lipoprotein lipase (LPL) activity and the abundance of fatty acid transporters. Specifically, N-3 PUFA have been shown to increase LPL activity through increased gene transcription and modifications of endogenously produced LPL regulators such as apolipoprotein C-II/III and angiopoietin-like proteins. This review presents and discusses the available in vitro and in vivo research to provide a comprehensive overview of N-3 PUFA regulation of WAT lipid uptake in healthy and obese contexts. Additionally, we highlight areas where more research is necessary to better understand the contribution of increased WAT lipid uptake in relation to the TAG-lowering properties associated with N-3 PUFA. Show less

Ovarian cancer is the leading cause of gynecologic cancer-related deaths. The propensity for metastasis within the peritoneal cavity is a driving factor for the poor outcomes associated with this disease, but there is currently no effective therapy targeting metastasis. In this study, we investigate the contribution of stromal cells to ovarian cancer metastasis and identify normal stromal cell expression of the collagen receptor, discoidin domain receptor 2 (DDR2), that acts to facilitate ovarian cancer metastasis. In vivo, global genetic inactivation of Ddr2 impairs the ability of Ddr2-expressing syngeneic ovarian cancer cells to spread throughout the peritoneal cavity. Specifically, DDR2 expression in mesothelial cells lining the peritoneal cavity facilitates tumor cell attachment and clearance. Subsequently, omentum fibroblast expression of DDR2 promotes tumor cell invasion. Mechanistically, we find DDR2-expressing fibroblasts are more energetically active, such that DDR2 regulates glycolysis through AKT/SNAI1 leading to suppressed fructose-1,6-bisphosphatase and increased hexokinase activity, a key glycolytic enzyme. Upon inhibition of DDR2, we find decreased protein synthesis and secretion. Consequently, when DDR2 is inhibited, there is reduction in secreted extracellular matrix proteins important for metastasis. Specifically, we find that fibroblast DDR2 inhibition leads to decreased secretion of the collagen crosslinker, LOXL2. Adding back LOXL2 to DDR2 deficient fibroblasts rescues the ability of tumor cells to invade. Overall, our results suggest that stromal cell expression of DDR2 is an important mediator of ovarian cancer metastasis. DDR2 is highly expressed by stromal cells in ovarian cancer that can mediate metastasis and is a potential therapeutic target in ovarian cancer. Show less

Zinc is an essential trace mineral that serves as a cofactor for the delta-5 and delta-6 desaturases (D5D, D6D) that are critical for long-chain polyunsaturated fatty acid (LC-PUFA) synthesis. While plasma zinc levels are generally reported to be associated with D5D and D6D indices in humans, it remains unclear if dietary zinc intake can be similarly associated with desaturase indices. Therefore, the present investigation examined if zinc intake determined by food frequency questionnaire (FFQ) is associated with desaturase indices in young Canadian adults. Additionally, we explored whether desaturase indices were modified by an interaction between dietary zinc intake and a common variant in the FADS1 gene. Dietary zinc intake (FFQ), plasma fatty acids (gas chromatography) and the FADS1 rs174547 polymorphism were analyzed in young men and women (n = 803) from the cross-sectional Toronto Nutrigenomics and Health Study. Product-to-precursor fatty acid ratios were used to determine desaturase enzyme indices (D5D = 20:4n-6/20:3n-6; D6D = 18:3n-6/18:2n-6). Individuals were grouped according to dietary zinc intake, as well as by their rs174547 genotype (TT vs. TC+CC). Data were analyzed by 1-way and 2-way ANCOVA. Plasma fatty acids and D5D/D6D indices did not differ between individuals grouped according to dietary zinc intake. Further, the recently proposed biomarker of zinc intake, 20:3n-6/18:2n-6, was not associated with dietary zinc intake. Although the FADS1 rs174547 SNP was significantly associated with D5D and D6D indices in both men and women (p < 0.0001), we did not find evidence of a dietary zinc intake - FADS1 SNP interaction on D5D or D6D indices. Dietary zinc intake, as determined using FFQs, does not predict differences in desaturase indices, irrespective of FADS1 genotype. Show less

Single nucleotide polymorphisms (SNPs) in FADS1/FADS2 genes are associated with changes in serum and tissue polyunsaturated fatty acid (PUFA) content. PUFA regulate inflammatory signaling pathways in adipose tissue; however, the effect of SNPs in FADS1/FADS2 on adipose tissue inflammation is equivocal. The present study examined if SNPs in FADS1/FADS2 modify human subcutaneous adipose tissue (SAT) fatty acid profiles and the expression of genes associated with inflammation/immune function, lipid metabolism, and cellular differentiation. SAT fatty acids and the expression of 117 genes were measured in 174 men and women from the DiOGenes Study using gas chromatography and qRT-PCR, respectively. Associations between fatty acids, gene expression, and SNPs in FADS1/FADS2 were investigated by linear regression and multivariate analysis. Four SNPs (rs174537, rs174546, rs174556, rs174601) in FADS1/FADS2 were significantly associated with SAT fatty acids. All SNPs were in high linkage disequilibrium with the commonly reported rs174537 SNP in FADS1. Minor allele carriers for rs174537 (GT+TT) had reduced 20:4n-6 (p = 1.74E-5), lower delta-5 desaturase enzyme activity (p = 2.09E-9), and lower FADS1 gene expression (p = 0.03) compared to major GG carriers. Multivariate analysis revealed that 20:4n-6 and 20:3n-6 explained ~19% of the variance between rs174537 genotypes, while gene expression explained <7%. Receiver operating characteristic (ROC) curves indicated that rs174537 genotype can be distinguished with SAT fatty acids (AUC = 0.842), but not gene expression (AUC = 0.627). No differences in SAT inflammatory gene expression were observed between rs174537 genotypes. SAT 20:3n-6 levels were positively correlated with the expression of several inflammatory genes, and inversely correlated with FADS1 expression. This study showed that FADS1 genotype is distinguished by SAT fatty acid profiles, but not inflammatory gene expression. Show less

Evidence shows that proteins secreted from skeletal muscle influence a broad range of metabolic signaling pathways. We previously reported that essential polyunsaturated fatty acids (PUFA) improved whole-body glucose homeostasis in obese Zucker rats; however, the mechanisms underlying these benefits remain enigmatic. While PUFA and obesity influence skeletal muscle function, their effects on the secretome are unknown. The aim of this work was to determine if improvements in whole-body glucose homeostasis in obese Zucker rats fed diets supplemented with either linoleic acid (LA) or alpha-linolenic acid (ALA) for 12 wk are related to changes in the skeletal muscle secretome. Secreted proteins were identified with a predictive bioinformatic analysis of microarray gene expression from red tibialis anterior skeletal muscle. Approximately 130 genes were differentially expressed (false discovery rate = 0.05) in obese rats compared with lean controls. The expression of 15 genes encoding secreted proteins was differentially regulated in obese controls, obese LA-supplemented, and obese ALA-supplemented rats compared with lean controls. Five secreted proteins ( Col3a1, Col15a1, Pdgfd, Lyz2, and Angptl4) were differentially regulated by LA and ALA. Most notably, ALA supplementation reduced Angptl4 gene expression compared with obese control and obese-LA supplemented rats and reduced circulating ANGPTL4 serum concentrations. ALA also influenced Angptl4 gene expression and ANGPTL4 secretion from differentiated rat L6 myotubes. Altogether, the present data indicate that obesity has a greater global impact on skeletal muscle gene expression than either essential PUFA; however, LA and ALA may exert their metabolic benefits in part by regulating the skeletal muscle secretome. Show less

Metabolic syndrome (MetS) comprises a cluster of risk factors including central obesity, hypertension, dyslipidemia, and impaired glucose homeostasis. Lifestyle interventions that promote improvements in diet quality and physical activity represent a first line of therapy for MetS. However, varying responses to lifestyle interventions are well documented and may be partially explained by underlying genetic differences. The aim of this study was to investigate if variants in genes previously associated with MetS influence the magnitude of change in MetS risk during a 1-year lifestyle intervention. The present study used data collected from the Canadian Health Advanced by Nutrition and Graded Exercise study cohort (n = 159 men and women) to investigate the effect of 17 candidate single nucleotide polymorphisms (SNPs) on response to a 1-year lifestyle intervention. Associations between SNPs and the continuous MetS (cMetS) score, as well as individual MetS components, were examined. Reductions in cMetS score at both 3 months and 1 year were significantly associated with 2 variants: rs662799 (A/G) in apolipoprotein A5 (APOA5) and rs1501299 (G/T) in adiponectin (ADIPOQ). Individuals carrying a minor T allele in rs1501299 experienced a greater reduction in cMetS score at both 3 months and 1 year, whereas major allele AA homozygotes in rs662799 experienced greater reductions in cMetS score during the intervention. No associations were identified between the aforementioned SNPs and individual components of MetS. Both un-weighted and weighted genetic risk scores (GRS) using these 2 SNPs revealed that individuals carrying none of the risk alleles experienced significantly greater reductions in cMetS score after 1 year. The findings from the current study suggest that individuals with certain genotypes may benefit more from a lifestyle intervention for MetS and that specific variants, either independently or as part of a GRS, could be used as a nutrigenomic tool to tailor the intervention to reduce the risk of MetS. Show less

Blood lipids are associated with cardiovascular disease (CVD) risk. Moreover, circulating lipid and fatty acid levels vary between men and women, and evidence demonstrates these traits may be influenced by single nucleotide polymorphisms (SNP). Sex-genotype interactions related to blood lipids and fatty acids have been poorly investigated and may help elucidate sex differences in CVD risk. The goal of this study was to investigate if the influence of SNPs previously associated with blood lipids and fatty acids varies in a sex-specific manner. Lipids and fatty acids were measured in serum and red blood cells (RBC), respectively, in 94 adults (18-30 years) from the GONE FISHIN' cohort and 118 age-matched individuals from the GOLDN cohort. HDL-c levels were higher and the total cholesterol/HDL-c (TC/HDL-c) ratio was lower in women versus men (p < 0.01). RBC palmitoleic acid and the stearoyl-CoA desaturase index were both higher in women (p < 0.01). Fatty acid desaturase (FADS) pathway activity (estimated using the ratio of eicosapentaenoic acid/alpha-linolenic acid) was higher in men (p < 0.01). The AA genotype for rs1800775 in CETP had a lower TC/HDL-c ratio in men, but not women (p Show less

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 ( Show less

There 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. Fasting 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. In 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). We demonstrate ethnic- and sex-specific effects of FADS polymorphisms on desaturase indices, and ethnic-specific effect of HC use on plasma DHA concentrations. Show less

Polyunsaturated fatty acids (PUFAs) regulate fatty acid desaturase (FADS1, FADS2) expression in the liver; however, it is unknown whether PUFAs regulate FADS in adipocytes. This is important to study considering reports that link altered desaturase activity with adipose tissue PUFA profiles, body weight, and whole-body glucose homeostasis. Therefore, the present study aimed to determine the direct effects of PUFAs on FADS expression in differentiated 3T3-L1 adipocytes. Differentiated 3T3-L1 adipocytes were treated with either α-linolenic (ALA), linoleic (LA), eicosapentaenoic (EPA), or arachidonic acid (AA). Gene expression, protein abundance, and cellular PUFA content were analyzed by real-time RT-PCR, Western blotting, and gas chromatography, respectively. Fads1 and Fads2 gene expression was reduced by EPA and AA, but not ALA or LA. Reductions in gene expression were reflected in FADS2 protein levels, but not FADS1. Treating cells with ALA and LA led to significant increases in the cellular content of downstream PUFAs. Neither ALA nor EPA changed docosahexaenoic acid content. Differentiated 3T3-L1 adipocytes have a functional FADS pathway that can be regulated by PUFA. Therefore, this common adipocyte model is suitable to study dietary regulation of the FADS pathway. Show less

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. Show less

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. 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. 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). 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. Show less

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. Show less

Perturbations in lipid metabolism characterize many of the chronic diseases currently plaguing our society, such as obesity, diabetes, and cardiovascular disease. Thus interventions that target plasma lipid levels remain a primary goal to manage these diseases. The determinants of plasma lipid levels are multi-factorial, consisting of both genetic and lifestyle components. Recent evidence indicates that fatty acid desaturases have an important role in defining plasma and tissue lipid profiles. This review will highlight the current state-of-knowledge regarding three desaturases (Scd-1, Fads1 and Fads2) and their potential roles in disease onset and development. Although research in rodent models has provided invaluable insight into the regulation and functions of these desaturases, the extent to which murine research can be translated to humans remains unclear. Evidence emerging from human-based research demonstrates that genetic variation in human desaturase genes affects enzyme activity and, consequently, disease risk factors. Moreover, this genetic variation may have a trans-generational effect via breastfeeding. Therefore inter-individual variation in desaturase function is attributed to both genetic and lifestyle components. As such, population-based research regarding the role of desaturases on disease risk is challenged by this complex gene-lifestyle paradigm. Unravelling the contribution of each component is paramount for understanding the inter-individual variation that exists in plasma lipid profiles, and will provide crucial information to develop personalized strategies to improve health management. Show less