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Association of genetic-variants in the FADS1-FADS2-gene-cluster with fatty-acid-composition in blood of adult-populations is well established. We analyze this genetic-association in two children-cohort-studies. In addition, the association between variants in the FADS-gene-cluster and blood-fatty-acid-composition with eczema was studied. Data of two population-based-birth-cohorts in The Netherlands and Germany (KOALA, LISA) were pooled (n = 879) and analyzed by (logistic) regression regarding the mutual influence of single-nucleotide-polymorphisms (SNPs) in the FADS-gene-cluster (rs174545, rs174546, rs174556, rs174561, rs3834458), on polyunsaturated fatty acids (PUFA) in blood and parent-reported eczema until the age of 2 years. All SNPs were highly significantly associated with all PUFAs except for alpha-linolenic-acid and eicosapentaenoic-acid, also after correction for multiple-testing. All tested SNPs showed associations with eczema in the LISA-study, but not in the KOALA-study. None of the PUFAs was significantly associated with eczema neither in the pooled nor in the analyses stratified by study-cohort. PUFA-composition in young children's blood is under strong control of the FADS-gene-cluster. Inconsistent results were found for a link between these genetic-variants with eczema. PUFA in blood was not associated with eczema. Thus the hypothesis of an inflammatory-link between PUFA and eczema by the metabolic-pathway of LC-PUFAs as precursors for inflammatory prostaglandins and leukotrienes could not be confirmed by these data. Show less

The delta-5 and delta-6 desaturases have long been known to be important enzymes in the endogenous formation of long-chain polyunsaturated fatty acids (LC-PUFAs). Cloning of the coding sequences and chromosomal localization of the desaturase encoding genes fatty acid desaturase 1 and 2 (FADS1 and FADS2) opened the way for analyses of genetic factors as regulators of desaturase activity and LC-PUFA homeostasis. The present review summarizes the recent association studies on FADS genotypes and LC-PUFA levels and suggests ideas how FADS genotypes can be integrated in future research. An initial candidate gene study reported highly significant associations between FADS gene cluster polymorphisms and fatty acid levels in serum phospholipids with an extraordinary high genetically explained variance for arachidonic acid levels of 28.5%. Carriers of the minor alleles had enhanced levels of desaturase substrates and decreased levels of desaturase products, suggesting a decline in desaturase expression or activity because of the polymorphisms. These results were replicated in several association studies additionally showing an effect in different human tissues as well as in a recent genome-wide association study on LC-PUFA levels. The validated strong association between FADS genotypes and fatty acid levels in diverse human tissues shows that FADS gene cluster polymorphisms are, in addition to nutritional regulation of fatty acid synthesis, a very important regulator of LC-PUFA synthesis. Show less

Delta-5 (D5D) and delta-6 (D6D) desaturases are key enzymes in PUFA metabolism. Several factors (e.g. hyperglycaemia, hypertension, blood lipids, statins and fatty acids in diet and biological tissues) may influence desaturase activity. The goals were to evaluate the associations between variation in genes encoding these desaturases (FADS1 and FADS2) and blood concentrations of n-6 PUFA and estimated D5D and D6D activities (evaluated as product/precursor ratio), and to investigate whether other factors influencing the activity of desaturases modify these associations. A random sample of 2066 participants from the European Prospective Investigation into Cancer and Nutrition-Potsdam study (n 27 548) was utilised in the analyses. Crude and adjusted associations between rs174546 genotypes (reflecting genetic variation in the FADS1 FADS2 gene cluster), n-6 PUFA in erythrocytes and estimated desaturase activities were evaluated using multiple linear regression. Potential effect modification was determined by performing stratified analyses and evaluating interaction terms. We found rs174546 genotypes to be related to linoleic (r² 0·060), γ-linolenic (r² 0·041), eicosadienoic (r² 0·034), arachidonic (r² 0·026), docosatetraenoic acids (r² 0·028), estimated D6D activity (r² 0·052) and particularly strongly to dihomo-γ-linolenic acid (DGLA, r² 0·182) and D5D activity (r² 0·231). We did not observe effect modifications with regard to the estimated D5D activity, DGLA and arachidonic acid (AA) for most of the factors evaluated; however, the genetic effect on D5D activity and DGLA may be modified by the dietary n-6:n-3-ratio (P-values for interaction: 0·008 and 0·002), and the genetic effect on DGLA and AA may be modified by lipid-lowering medication (P-values for interaction: 0·0004 and 0·006). In conclusion, genetic variation in the FADS1 FADS2 gene cluster affects n-6 PUFA profiles in erythrocytes reflecting altered D5D activity. Show less

Higher resting heart rate is associated with increased cardiovascular disease and mortality risk. Though heritable factors play a substantial role in population variation, little is known about specific genetic determinants. This knowledge can impact clinical care by identifying novel factors that influence pathologic heart rate states, modulate heart rate through cardiac structure and function or by improving our understanding of the physiology of heart rate regulation. To identify common genetic variants associated with heart rate, we performed a meta-analysis of 15 genome-wide association studies (GWAS), including 38,991 subjects of European ancestry, estimating the association between age-, sex- and body mass-adjusted RR interval (inverse heart rate) and approximately 2.5 million markers. Results with P < 5 × 10(-8) were considered genome-wide significant. We constructed regression models with multiple markers to assess whether results at less stringent thresholds were likely to be truly associated with RR interval. We identified six novel associations with resting heart rate at six loci: 6q22 near GJA1; 14q12 near MYH7; 12p12 near SOX5, c12orf67, BCAT1, LRMP and CASC1; 6q22 near SLC35F1, PLN and c6orf204; 7q22 near SLC12A9 and UfSp1; and 11q12 near FADS1. Associations at 6q22 400 kb away from GJA1, at 14q12 MYH6 and at 1q32 near CD34 identified in previously published GWAS were confirmed. In aggregate, these variants explain approximately 0.7% of RR interval variance. A multivariant regression model including 20 variants with P < 10(-5) increased the explained variance to 1.6%, suggesting that some loci falling short of genome-wide significance are likely truly associated. Future research is warranted to elucidate underlying mechanisms that may impact clinical care. Show less

Serum metabolite concentrations provide a direct readout of biological processes in the human body, and they are associated with disorders such as cardiovascular and metabolic diseases. We present a genome-wide association study (GWAS) of 163 metabolic traits measured in human blood from 1,809 participants from the KORA population, with replication in 422 participants of the TwinsUK cohort. For eight out of nine replicated loci (FADS1, ELOVL2, ACADS, ACADM, ACADL, SPTLC3, ETFDH and SLC16A9), the genetic variant is located in or near genes encoding enzymes or solute carriers whose functions match the associating metabolic traits. In our study, the use of metabolite concentration ratios as proxies for enzymatic reaction rates reduced the variance and yielded robust statistical associations with P values ranging from 3 x 10(-24) to 6.5 x 10(-179). These loci explained 5.6%-36.3% of the observed variance in metabolite concentrations. For several loci, associations with clinically relevant parameters have been reported previously. Show less

Accumulation of fat in the liver increases the risk to develop fibrosis and cirrhosis and is associated with development of the metabolic syndrome. Here, to identify genes or gene pathways that may underlie the genetic susceptibility to fat accumulation in liver, we studied A/J and C57Bl/6 mice that are resistant and sensitive to diet-induced hepatosteatosis and obesity, respectively. We performed comparative transcriptomic and lipidomic analysis of the livers of both strains of mice fed a high fat diet for 2, 10, and 30 days. We found that resistance to steatosis in A/J mice was associated with the following: (i) a coordinated up-regulation of 10 genes controlling peroxisome biogenesis and β-oxidation; (ii) an increased expression of the elongase Elovl5 and desaturases Fads1 and Fads2. In agreement with these observations, peroxisomal β-oxidation was increased in livers of A/J mice, and lipidomic analysis showed increased concentrations of long chain fatty acid-containing triglycerides, arachidonic acid-containing lysophosphatidylcholine, and 2-arachidonylglycerol, a cannabinoid receptor agonist. We found that the anti-inflammatory CB2 receptor was the main hepatic cannabinoid receptor, which was highly expressed in Kupffer cells. We further found that A/J mice had a lower pro-inflammatory state as determined by lower plasma levels and IL-1β and granulocyte-CSF and reduced hepatic expression of their mRNAs, which were found only in Kupffer cells. This suggests that increased 2-arachidonylglycerol production may limit Kupffer cell activity. Collectively, our data suggest that genetic variations in the expression of peroxisomal β-oxidation genes and of genes controlling the production of an anti-inflammatory lipid may underlie the differential susceptibility to diet-induced hepatic steatosis and pro-inflammatory state. Show less

The functions of distinct isoforms of solute carrier family 27 transporters (SLC27A1-6), acetyl-CoA carboxylase (ACACA, ACACB), stearoyl-CoA desaturase (SCD1-4), fatty acid desaturase (FADS1-3), LPIN (LPIN1-3), insulin-induced gene (INSIG1, 2), and peroxisome proliferator-activated receptor gamma coactivator1 (PPARGC1A, B) were studied in the mouse mammary gland from pregnancy to lactation. The relative mRNA abundance and percent change in real-time PCR were determined. mRNA expression of SLC27A3 and SLC27A4 was 37- and 1.4-fold more upregulated at 12 days of lactation, respectively (P < 0.01). Transcripts of SCD isoforms were the most abundant, accounting for 59% of all genes measured, and PPARGC1 isoforms were the least (0.06% of all genes measured). The mRNA abundance from ACC, FADS and LPIN accounted for 29, 9 and 2.6%, respectively. INSIG1 mRNA expression was 32-fold more upregulated (P < 0.05), while PPARGC1B was 0.18-fold downregulated at 18 days of lactation (P < 0.01). We concluded that mRNA abundance and expression of these isoforms are affected by the stage of lactation. Show less

The conversion of linoleic acid (LA) and alpha-linolenic acid (ALA) to long chain polyunsaturated fatty acids (LCPUFA) is known to involve desaturation and elongation steps. Although there is evidence that genes for these steps can be regulated by extremes of dietary PUFA, the degree to which there is meaningful regulation of LCPUFA levels in tissues by diet as a result of changes in expression of desaturase and elongase genes is unclear. In this study, we tested the effect of increasing ALA levels in diets of rats from 0.2% to 2.9% energy (en) against a constant LA level (1%en) on plasma and liver phospholipid LCPUFA content together with the expression of hepatic genes involved in PUFA metabolism, the desaturases FADS1 and FADS2, the elongases ELOV2 and ELOV5, and the transcription factors sterol regulatory element-binding protein-1c (SREBP-1c) and peroxisome proliferator-activated receptor alpha (PPARalpha). The levels of plasma and liver eicosapentaenoic acid (EPA) and docosapentaenoic acid (DPA) increased in proportion to dietary ALA whereas docosahexaenoic acid (DHA) increased only up to 1%en ALA. A low PUFA (0.4%en) reference diet stimulated the expression of delta 6 desaturase (FADS2) and elongase 2 (ELOVL2) when compared to higher PUFA diets. There was, however, no difference in the expression of any of the genes in rats, which were fed diets containing between 0.2%en and 2.9%en ALA and mRNA expression was unrelated to tissue/plasma LCPUFA content. These data suggest that the endogenous synthesis of n-3 LCPUFA from the precursor ALA is regulated independently of changes in the expression of the synthetic enzymes or regulatory transcription factor, and provides evidence that n-3 LCPUFA synthesis is regulated more by substrate competition for existing enzymes than by an increase in their mRNA expression. 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

Long-chain polyunsaturated fatty acids (PUFA) orchestrate immunity and inflammation through their capacity to be converted to potent inflammatory mediators. We assessed associations of FADS gene cluster polymorphisms and fasting serum PUFA concentrations in a fully ascertained, geographically isolated founder population of European descent. Concentrations of 22 PUFAs were determined by gas chromatography, of which ten fatty acids and five ratios defining FADS1 and FADS2 activity were tested for genetic association against 16 single nucleotide polymorphisms (SNP) in 224 individuals. A cluster of SNPs in tight linkage disequilibrium in the FADS1 gene (rs174537, rs174545, rs174546, rs174553, rs174556, rs174561, rs174568, and rs99780) were strongly associated with arachidonic acid (AA) (P = 5.8 x 10(-7) - 1.7 x 10(-8)) among other PUFAs, but the strongest associations were with the ratio measuring FADS1 activity in the omega-6 series (P = 2.11 x 10(-13) - 1.8 x 10(-20)). The minor allele across all SNPs was consistently associated with decreased omega-6 PUFAs, with the exception of dihomo-gamma-linoleic acid (DHGLA), where the minor allele was consistently associated with increased levels. Our findings in a geographically isolated population with a homogenous dietary environment suggest that variants in the Delta-5 desaturase enzymatic step likely regulate the efficiency of conversion of medium-chain PUFAs to potentially inflammatory PUFAs, such as AA. Show less

The tissue composition of polyunsaturated fatty acids is important to health and depends on both dietary intake and metabolism controlled by genetic polymorphisms that should be taken into consideration in the determination of nutritional requirements. Therefore at the same dietary intake of linoleic acid (LA) and alpha-linolenic acid (ALA), their respective health effects may differ due to genetic differences in metabolism. Delta-5 and delta-6 desaturases, FADS1 and FADS2, respectively, influence the serum, plasma and membrane phospholipid levels of LA, ALA and long-chain polyunsaturated fatty acids during pregnancy, lactation, and may influence an infant's IQ, atopy and coronary heart disease (CHD) risk. At low intakes of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), polymorphisms at the 5-lipoxygenase (5-LO) level increase the risk for CHD whereas polymorphisms at cyclooxgenase-2 increase the risk for prostate cancer. At high intakes of LA the risk for breast cancer increases. EPA and DHA influence gene expression. In future, intervention studies on the biological effects of LA, ALA and LC-PUFAs, and the effects of genetic variants in FADS1 and FADS2, 5-LO and cyclooxygenase-2 should be taken into consideration both in the determination of nutritional requirements and chronic disease risk. Furthermore, genome-wide association studies need to include environmental exposures and include diet in the interaction between genetic variation and disease association. Show less

Tissue availability of polyunsaturated fatty acids (PUFAs) depends on dietary intake and metabolic turnover and has a major impact on human health. Strong associations between variants in the human genes fatty acid desaturase 1 (FADS1, encoding Delta-5 desaturase) and fatty acid desaturase 2 (FADS2, encoding Delta-6 desaturase) and blood levels of PUFAs and long-chain PUFAs (LC-PUFAs) have been reported. The most significant associations and the highest proportion of genetically explained variability (28%) were found for arachidonic acid (20:4n-6), the main precursor of eicosanoids. Subjects carrying the minor alleles of several single nucleotide polymorphisms had a lower prevalence of allergic rhinitis and atopic eczema. Therefore, blood levels of PUFAs and LC-PUFAs are influenced not only by diet, but to a large extent also by genetic variants common in a European population. These findings have been replicated in independent populations. Depending on genetic variants, requirements of dietary PUFA or LC-PUFA intakes to achieve comparable biological effects may differ. We recommend including analyses of FADS1 and FADS2 polymorphism in future cohort and intervention studies addressing biological effects of PUFAs and LC-PUFAs. Show less

Long-chain omega-3 fatty acids (n-3 FAs) influence meat tenderness, juiciness, and flavor, and are beneficial to human health. The percentage of long-chain n-3 FAs in total FAs is termed the omega-3 index (O3I). It is thus of great interest to favor rising this index in bovine skeletal muscle, to obtain healthier, tastier, and more nutritive meat. This study was aimed to detect transcriptomic variations related to O3I in muscles in 15-month-old males of 4 Spanish cattle breeds raised under the same conditions. Through the analysis of extreme O3I phenotypes, 3 genes of interest (AANAT, UCP2 and AHA1) were identified. AANAT and UCP2 were strongly up-regulated, while AHA1 was repressed in animals with a high O3I. Moreover, gene expression differed between GDF8-null animal muscles (tested for nt821del11 and Q204X mutations) and the wild-type muscles for genes GDH1, IGF2R, FADS1, ASPH, and AIM1, all showing down-regulation in Asturiana de los Valles calves with muscle hypertrophy (GDF8-null). This shows that in GDF8-null animals other pathways are used for FA synthesis. Show less

The delta-5 and delta-6 desaturases, encoded by the FADS1 and FADS2 genes, are rate-limiting enzymes in polyunsaturated fatty acid (PUFA) biosynthesis. Single nucleotide polymorphisms in the FADS gene cluster region have been associated with both PUFA concentrations in plasma or erythrocyte membrane phospholipids and cholesterol concentrations in recent genome-wide association studies. We examined whether genetic variations in the FADS gene cluster region interact with dietary intakes of n-3 (omega-3) and n-6 (omega-6) PUFAs to affect plasma total, HDL-, and non-HDL-cholesterol concentrations. Dietary intakes of n-3 and n-6 PUFAs, plasma concentrations of total and HDL cholesterol, and rs174546, rs482548, and rs174570 in the FADS gene cluster region were measured in 3575 subjects in the second survey of the Doetinchem Cohort Study. Significant associations between rs174546 genotypes and total and non-HDL-cholesterol concentrations were observed in the group with a high intake of n-3 PUFAs (> or =0.51% of total energy; P = 0.006 and 0.047, respectively) but not in the low-intake group (P for interaction = 0.32 and 0.51, respectively). The C allele was associated with high total and non-HDL-cholesterol concentrations. Furthermore, the C allele was significantly associated with high HDL-cholesterol concentrations in the group with a high intake of n-6 PUFAs (> or =5.26% of total energy, P = 0.004) but not in the group with a low intake (P for interaction = 0.02). Genetic variation in the FADS1 gene potentially interacts with dietary PUFA intakes to affect plasma cholesterol concentrations, which should be investigated further in other studies. Show less

Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes. Show less

Iron is the major alloy component for a large variety of cardiovascular devices such as stents. In recent studies it has been shown that biodegradable iron or iron based stents exhibit good mechanical features with no pronounced neointimal proliferation. Whole genome gene profiling using DNA chip technology revealed that genes involved in cholesterol and fatty acid metabolism (low-density lipoprotein receptor, LDL-R; 3-hydroxy-3-methylglutaryl-Coenzyme A synthase 1 (HMGCS1) and fatty acid desaturase 1 (FADS1) are up-regulated after exposure of vascular smooth muscle cells with soluble ferrous iron. To analyze the effects of iron on these genes in detail we co-incubated human vascular smooth muscle cells for 12 and 24 h with different concentrations of ferrous (soluble iron(II)-gluconate) and ferric iron (soluble iron(III)-chloride), Ferrlecit, a commercially available drug (ferric iron-gluconate complex) and solid iron coils. The expression of LDL-R, HMGCS1 and FADS1 was analyzed using TaqMan Real-time PCR. After 24 h, all forms of iron led to a significant up-regulation of the examined genes. At high concentrations the expression rates declined, probably as a result of reduced metabolic activity. The most prominent effects were observed after co-incubation with Ferrlecit, probably caused by an increased bioavailability of the iron gluconate complex. We postulate that both, bi- and trivalent forms of iron induce the expression of LDL-R, HMGCS1 and FADS1 by generation of highly reactive oxygen species. Further animal experiments using tissues from iron-stented vessels may lead to a more profound insight into iron induced expression of cholesterol- and fatty acid metabolism related genes. Show less

Fatty acid desaturase 1 and 2 (FADS1 and FADS2) code for the key desaturase enzymes involved in the biosynthesis of long chain polyunsaturated fatty acids in mammals. FADS3 shares close sequence homology to FADS1 and FADS2 but the function of its gene product remains unknown. Alternative transcripts (AT) generated by alternative splicing (AS) are increasingly recognized as an important mechanism enabling a single gene to code for multiple gene products. We report the first AT of a FADS gene, FADS3, generated by AS. Aided by ORF Finder, we identified putative coding regions of eight AT for FADS3 with 1.34 kb (classical splicing), 1.14 (AT1), 0.77 (AT2), 1.25 (AT3), 0.51 (AT4), 0.74 (AT6), and 1.11 (AT7). In addition we identified a 0.51 kb length transcript (AT5) that has a termination codon within intron 8-9. The expression of each AT was analyzed in baboon neonate tissues and in differentiated and undifferentiated human SK-N-SH neuroblastoma cells. FADS3 AT are expressed in 12 neonate baboon tissues and showed reciprocal increases and decreases in expression changes in response to human neuronal cell differentiation. FADS3 AT, conserved in primates and under metabolic control in human cells, are a putative mediator of LCPUFA biosynthesis and/or regulation. Show less

Although emerging evidence suggests that schizophrenia (SZ) is associated with peripheral and central polyunsaturated fatty acid (PUFA) deficits, there is currently nothing known about the expression of genes that mediate PUFA biosynthesis in SZ patients. Here we determined Delta5 desaturase (FADS1), Delta6 desaturase (FADS2), elongase (HELO1 [ELOVL5]), peroxisomal (PEX19), and Delta9 desaturase (stearoyl-CoA desaturase, SCD) mRNA expression, and relevant fatty acid product:precursor ratios as estimates of enzyme activities, in the postmortem prefrontal cortex (PFC) of patients with SZ (n=20) and non-psychiatric controls (n=20). After correction for multiple comparisons, FADS2 mRNA expression was significantly greater in SZ patients relative to controls (+36%, p=0.002), and there was a positive trend found for FADS1 (+26%, p=0.15). No differences were found for HELO1 (+10%, p=0.44), PEX19 (+12%, p=0.44), or SCD (-6%, p=0.85). Both male (+34%, p=0.02) and female (+42%, p=0.02) SZ patients exhibited greater FADS2 mRNA expression relative to same-gender controls. Drug-free SZ patients (+37%, p=0.02), and SZ patients treated with typical (+40%, p=0.002) or atypical (+31%, p=0.04) antipsychotics, exhibited greater FADS2 mRNA expression relative to controls. Consistent with increased Delta6 desaturase activity, SZ patients exhibited a greater 20:3/18:2 ratio (+20%, p=0.03) and a positive trend was found for 20:4/18:2 (+13%, p=0.07). These data demonstrate abnormal, potentially compensatory, elevations in Delta6 desaturase (FADS2) expression in the PFC of SZ patients that are independent of gender and antipsychotic medications. Greater Delta6 desaturase expression and activity could have implications for central prostaglandin synthesis and proinflammatory signaling. Show less

Polyunsaturated fatty acids (PUFA) have a role in many physiological processes, including energy production, modulation of inflammation, and maintenance of cell membrane integrity. High plasma PUFA concentrations have been shown to have beneficial effects on cardiovascular disease and mortality. To identify genetic contributors of plasma PUFA concentrations, we conducted a genome-wide association study of plasma levels of six omega-3 and omega-6 fatty acids in 1,075 participants in the InCHIANTI study on aging. The strongest evidence for association was observed in a region of chromosome 11 that encodes three fatty acid desaturases (FADS1, FADS2, FADS3). The SNP with the most significant association was rs174537 near FADS1 in the analysis of arachidonic acid (AA; p = 5.95 x 10(-46)). Minor allele homozygotes had lower AA compared to the major allele homozygotes and rs174537 accounted for 18.6% of the additive variance in AA concentrations. This SNP was also associated with levels of eicosadienoic acid (EDA; p = 6.78 x 10(-9)) and eicosapentanoic acid (EPA; p = 1.07 x 10(-14)). Participants carrying the allele associated with higher AA, EDA, and EPA also had higher low-density lipoprotein (LDL-C) and total cholesterol levels. Outside the FADS gene cluster, the strongest region of association mapped to chromosome 6 in the region encoding an elongase of very long fatty acids 2 (ELOVL2). In this region, association was observed with EPA (rs953413; p = 1.1 x 10(-6)). The effects of rs174537 were confirmed in an independent sample of 1,076 subjects participating in the GOLDN study. The ELOVL2 SNP was associated with docosapentanoic and DHA but not with EPA in GOLDN. These findings show that polymorphisms of genes encoding enzymes in the metabolism of PUFA contribute to plasma concentrations of fatty acids. Show less

Genome-wide association studies (GWAS) of longitudinal birth cohorts enable joint investigation of environmental and genetic influences on complex traits. We report GWAS results for nine quantitative metabolic traits (triglycerides, high-density lipoprotein, low-density lipoprotein, glucose, insulin, C-reactive protein, body mass index, and systolic and diastolic blood pressure) in the Northern Finland Birth Cohort 1966 (NFBC1966), drawn from the most genetically isolated Finnish regions. We replicate most previously reported associations for these traits and identify nine new associations, several of which highlight genes with metabolic functions: high-density lipoprotein with NR1H3 (LXRA), low-density lipoprotein with AR and FADS1-FADS2, glucose with MTNR1B, and insulin with PANK1. Two of these new associations emerged after adjustment of results for body mass index. Gene-environment interaction analyses suggested additional associations, which will require validation in larger samples. The currently identified loci, together with quantified environmental exposures, explain little of the trait variation in NFBC1966. The association observed between low-density lipoprotein and an infrequent variant in AR suggests the potential of such a cohort for identifying associations with both common, low-impact and rarer, high-impact quantitative trait loci. Show less

Blood low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol and triglyceride levels are risk factors for cardiovascular disease. To dissect the polygenic basis of these traits, we conducted genome-wide association screens in 19,840 individuals and replication in up to 20,623 individuals. We identified 30 distinct loci associated with lipoprotein concentrations (each with P < 5 x 10(-8)), including 11 loci that reached genome-wide significance for the first time. The 11 newly defined loci include common variants associated with LDL cholesterol near ABCG8, MAFB, HNF1A and TIMD4; with HDL cholesterol near ANGPTL4, FADS1-FADS2-FADS3, HNF4A, LCAT, PLTP and TTC39B; and with triglycerides near AMAC1L2, FADS1-FADS2-FADS3 and PLTP. The proportion of individuals exceeding clinical cut points for high LDL cholesterol, low HDL cholesterol and high triglycerides varied according to an allelic dosage score (P < 10(-15) for each trend). These results suggest that the cumulative effect of multiple common variants contributes to polygenic dyslipidemia. Show less

The FADS1/FADS2 gene cluster encodes Delta-5 and Delta-6 desaturase, rate-limiting enzymes in metabolism of linoleic (LA) to arachidonic (ARA) and alpha-linolenic to eicosapentaenoic and docosahexaenoic acid (DHA). Single nucleotide polymorphisms (SNPs) in FADS1/FADS2 contribute to variability in blood lipid fatty acids. Altered n-6 and n-3 fatty acids have been related to perinatal depression (PPD). We genotyped rs174553, rs99780, rs174575, and rs174583 in FADS1/FADS2, analyzed blood lipid fatty acids and assessed PPD risk as an Edinburgh Postnatal Depression Scale (EPDS) score > or =10 for 69 pregnant women. 21, 12 and 15% women had an EPDS score > or =10 at 36 weeks' gestation, 2 and 6 months postpartum, respectively. Quantitative trait analysis showed an association between rs174575 and PPD risk at 36 weeks' gestation and 6 months postpartum. With haplotype ACCC (major alleles) for rs174553, rs99780, rs174575, rs174583, respectively, as reference, GTCT was positively associated with PPD risk at 36 weeks' gestation, p = 0.028, and higher LA and lower ARA in plasma (p = 0.0001, p < 0.0001) and RBC ethanolamine phospholipids (p = 0.007, p = 0.005). We show that SNPs in FADS1/FADS2 are associated with higher blood lipid LA and lower ARA and PPD risk. Show less

The present study gives further evidence for the recently found association between variants of the fatty acid desaturase 1 fatty acid desaturase 2 (FADS1 FADS2) gene cluster and PUFA in blood phospholipids and explores this association for cellular fatty acids in erythrocyte membranes. In a subgroup of adults participating in the Bavarian Nutrition Survey II, a cross-sectional population-based study conducted in Bavaria, Germany, allelic variation in three selected loci of the FADS1 FADS2 gene cluster was analysed and used for haplotype construction. Associations with plasma phospholipid PUFA (n 163) and PUFA in erythrocyte membranes (n 535) were investigated by regression analysis. All haplotypes of the original five-loci haplotypes of our previous study could be replicated. In addition, associations with serum phospholipid PUFA were confirmed in the present data set. Although less pronounced, associations between FADS1 FADS2 haplotypes and PUFA in erythrocyte membranes, particularly arachidonic and dihomo-gamma-linolenic acid, could be established. We provide the first replication of the association of the FADS1 FADS2 gene cluster with PUFA in blood phospholipids. For the first time, such associations were also shown for PUFA in cell membranes. Show less

Sphingolipids have essential roles as structural components of cell membranes and in cell signalling, and disruption of their metabolism causes several diseases, with diverse neurological, psychiatric, and metabolic consequences. Increasingly, variants within a few of the genes that encode enzymes involved in sphingolipid metabolism are being associated with complex disease phenotypes. Direct experimental evidence supports a role of specific sphingolipid species in several common complex chronic disease processes including atherosclerotic plaque formation, myocardial infarction (MI), cardiomyopathy, pancreatic beta-cell failure, insulin resistance, and type 2 diabetes mellitus. Therefore, sphingolipids represent novel and important intermediate phenotypes for genetic analysis, yet little is known about the major genetic variants that influence their circulating levels in the general population. We performed a genome-wide association study (GWAS) between 318,237 single-nucleotide polymorphisms (SNPs) and levels of circulating sphingomyelin (SM), dihydrosphingomyelin (Dih-SM), ceramide (Cer), and glucosylceramide (GluCer) single lipid species (33 traits); and 43 matched metabolite ratios measured in 4,400 subjects from five diverse European populations. Associated variants (32) in five genomic regions were identified with genome-wide significant corrected p-values ranging down to 9.08x10(-66). The strongest associations were observed in or near 7 genes functionally involved in ceramide biosynthesis and trafficking: SPTLC3, LASS4, SGPP1, ATP10D, and FADS1-3. Variants in 3 loci (ATP10D, FADS3, and SPTLC3) associate with MI in a series of three German MI studies. An additional 70 variants across 23 candidate genes involved in sphingolipid-metabolizing pathways also demonstrate association (p = 10(-4) or less). Circulating concentrations of several key components in sphingolipid metabolism are thus under strong genetic control, and variants in these loci can be tested for a role in the development of common cardiovascular, metabolic, neurological, and psychiatric diseases. Show less

Long-chain polyunsaturated fatty acids (LC-PUFAs) play an important role in several physiological processes and their concentration in phospholipids has been associated with several complex diseases, such as atopic disease. The level and composition of LC-PUFAs in the human body is highly dependent on their intake in the diet or on the intake of fatty acid precursors, which are endogenously elongated and desaturated to physiologically active LC-PUFAs. The most important enzymes in this reaction cascade are the Delta(5) and Delta(6) desaturase. Several studies in the last few years have revealed that single nucleotide polymorphisms (SNPs) in the 2 desaturase encoding genes (FADS1 and FADS2) are highly associated with the concentration of omega-6 and omega-3 fatty acids, showing that beside nutrition, genetic factors also play an important role in the regulation of LC-PUFAs. This review focuses on current knowledge of the impact of genetic polymorphisms on LC-PUFA metabolism and on their potential role in the development of atopic diseases. Show less

Peroxisome proliferator-activated receptor (PPAR)gamma is a key regulator in adipose tissue. The rare variant Pro12Ala of PPARgamma2 is associated with a decreased risk of insulin resistance. Being dietary PPARgamma ligands, conjugated linoleic acids (CLAs) received considerable attention because of their effects on body composition, cancer, atherosclerosis, diabetes, obesity and inflammation, although some effects were only demonstrated in animal trials and the results in human studies were not always consistent. In the present study effects of CLA supplementation on genome wide gene expression in adipose tissue biopsies from 11 Ala12Ala and 23 Pro12Pro men were investigated. Subjects underwent four intervention periods (4 wk) in a randomized double blind cross-over design receiving 4.25 g/d of either cis-9, trans-11 CLA, trans-10,cis-12 CLA, 1:1 mixture of both isomers or a reference linoleic acid oil preparation. After each intervention biopsies were taken, whole genome expression microarrays were applied, and genes of interest were verified by realtime PCR. The following genes of lipid metabolism were regulated by CLA: LDLR, FASN, SCD, FADS1 and UCP2 were induced, while ABCA1, CD36 and CA3 were repressed. Transcription factors PPARgamma, NFAT5, CREB5 and EBF1, the adipokine NAMPT, members of the insulin signaling cascade SORBS1 and IGF1 and IL6ST were repressed, while the adipokine THBS1 and GLUT4 involved in insulin signaling were induced. Compared to trans-10,cis-12 CLA and the CLA mixture the cis-9, trans-11 CLA isomer exerted weaker effects. Only CD36 (-1.2 fold) and THBS1 (1.5 fold) were regulated. The CLA effect on expression of PPARgamma and leptin genes depends on the PPARgamma2 genotype. The data suggest that the isomer specific influence of CLA on glucose and lipid metabolism is genotype dependent and at least in part mediated by PPARgamma. http://www.controlled-trials.com: ISRCTN91188075. Show less

Fatty acid desaturases introduce double bonds into growing fatty acid chains. The key desaturases in humans are Delta5-desaturase (D5D), Delta6-desaturase (D6D) and stearoyl-CoA desaturase (SCD). Animal and human data implicate hepatic desaturase activities in insulin resistance, obesity and dyslipidaemia. However, the role of desaturase activity in adipose tissue is uncertain. We therefore evaluated relationships between adipose mRNA expression, estimated desaturase activities (fatty acid ratios) in adipose tissue and insulin resistance. Subcutaneous adipose tissue mRNA expression of D5D (also known as FADS1), D6D (also known as FADS2) and SCD was determined in 75 individuals representative of the study population of 294 healthy 63-year-old men. Desaturation indexes (product/substrate fatty acid ratios) were generated from adipose tissue fatty acid composition in all individuals. Insulin resistance was defined as the upper quartile of the updated homeostasis model assessment (HOMA-2) index. The relevant desaturation indexes (16:1/16:0, 18:1/18:0, 20:4/20:3 and 18:3/18:2) reflected expression of SCD, but not of D5D or D6D in adipose tissue. Insulin-resistant individuals had a higher adipose tissue 18:1/18:0, but not 16:1/16:0 ratio than insulin-sensitive individuals. Individuals with a high adipose tissue 18:1/18:0 ratio were 4.4-fold (95% CI 1.8-11.8) more likely to be insulin resistant [threefold (95% CI 1.1-8.6) after adjustment for waist circumference and plasma triacylglycerol]. In a multiple regression model predicting HOMA-2, the independent effect of the 18:1/18:0 ratio was borderline (p=0.086). Adipose tissue desaturation indexes of SCD reflect the expression of the gene encoding the enzyme in this tissue. Elevated SCD activity within adipose tissue is closely coupled to the development of insulin resistance. Show less

Tissue availability of polyunsaturated fatty acids (PUFAs) is of major relevance for health, and it depends on both dietary intake and metabolic turnover. We found close associations between variants in the human genes of Delta5- and Delta6-desaturase, FADS1 and FADS2, and serum phospholipid contents of PUFAs and long-chain PUFAs (LCPUFAs). Polymorphisms and reconstructed haplotypes of FADS1 and the upstream region of FADS2 showed strong associations with levels of the n-6 LC-PUFA arachidonic acid (20:4n-6). Carriers of the less common polymorphisms and their respective haplotypes also had a lower prevalence of allergic rhinitis and atopic eczema. Our data demonstrate for the first time that the fatty acid composition of serum phospholipids is genetically controlled by the FADS1 FADS2 gene cluster. The investigated single nucleotide polymorphisms in this cluster explain 28% of the variance of serum phospholipid arachidonic acid and up to 12% of its precursor acids. Based on this genetic variation, individuals may require different amounts of dietary PUFAs or LC-PUFAs to achieve comparable biological effects. We strongly recommend including analyses of FADS1 and FADS2 polymorphism in future cohort and intervention studies addressing the biological effects of PUFAs and LC-PUFAs, which should enhance the sensitivity and precision of such studies. Show less

To investigate the gene expression profiles of adipose tissue of obese rats after central administration of neuropeptide Y-Y5 receptor antisense oligodeoxynucleotides (ODNs), Y5 receptor antisense, mismatched ODNs or vehicle was intracerebroventricularly injected and cDNA microarrays were undertaken. Central administration of NPY-Y5 receptor antisense ODNs decreased food intake, body weight and serum insulin compared with both vehicle and mismatched ODNs. The average area of adipocytes both at retroperitoneal and epididymal adipose tissue were fall in antisense group while only the weight of the retroperitoneal fat pats was reduced in antisense group. cDNA microarrays containing 18,000 genes/Ests were used to investigate gene expression of adipose tissue. Autoradiographic analysis showed that 404, 81, and 34 genes were differently expressed over twofold, threefold, and fivefold, respectively. The analysis of gene expression profiles indicated that 332 genes were up-regulated and 187 genes were down-regulated in response to Y5 receptor antisense ODNs treatment. Different clusters of genes associated with apoptosis, signal transduction, energy metabolism, lipid metabolism, etc., such as FXR1, PHLDA1, MAEA, PIK3R1, ICAM2, PITPN, CALM2, CAMK2D, PKIA, DRD2, SLC25A14, CKB, AADAC, LIPA, ACOX3, FADS1, were concerned. Analysis of differentially expressed genes will help to understand the effects of Y5 receptor antisense ODNs therapy. Show less

Dietary phytosterols significantly reduce plasma cholesterol concentrations and atherosclerosis in apolipoprotein E-knockout (apo E-KO) mice. We investigated the long-term effects of phytosterol treatment on gene expression in the liver of these mice. Male apo E-KO mice were fed an atherogenic diet supplemented with (n=6) or without (n=6) 2% (wt/wt) phytosterol mixtures for 14 weeks. Liver specimens were collected and stored in RNAlater immediately. mRNA was extracted and subjected to microarray analyses and real-time quantitative reverse transcription-polymerase chain reaction (RT-PCR) assay for confirmation. Oligonuleotide microarray analysis of pooled samples (n=3) revealed that the expression of 132 genes/transcripts was significantly altered in treated animals, considering the false discovery rate (FDR) of 0.23. Real-time RT-PCR techniques confirmed these alterations in the expression of several of these genes, including Hmgcr (2.16-fold; P=.0002), Hmgcs1 (1.79-fold; P=.001), Hsd17b7 (2.11-fold; P=.028), Sqle (2.03-fold; P=.01), Cyp51 (1.8-fold; P=.001), Fads1 (1.55-fold; P=.031), Fads2 (2.17-fold; P=.047), Lpin1 (3.67-fold; P=.001), Ppargc1b (PGC-1beta; a coactivator of sterol-regulatory element-binding proteins; 1.66-fold; P=.007) and Cyp7B1 (1.81-fold; P=.025). In summary, our data suggest that long-term dietary phytosterols can alter the expression of a number of hepatic genes that regulate sterol metabolism in apo E-KO mice. It is possible that these changes are due to inhibition of cholesterol absorption, but are not a direct effect of plant sterols. Further multivariate correlation or association analysis is needed to establish the relations between changes in the expression of these genes and prevention of atherosclerosis by phytosterols. Show less