FTO, obesity and the adolescent brain.

Genetic variations in fat mass- and obesity (FTO)-associated gene, a well-replicated gene locus of obesity, appear to be associated also with reduced regional brain volumes in elderly. Here, we examined whether FTO is associated with total brain volume in adolescence, thus exploring possible developmental effects of FTO. We studied a population-based sample of 598 adolescents recruited from the French Canadian founder population in whom we measured brain volume by magnetic resonance imaging. Total fat mass was assessed with bioimpedance and body mass index was determined with anthropometry. Genotype-phenotype associations were tested with Merlin under an additive model. We found that the G allele of FTO (rs9930333) was associated with higher total body fat [TBF (P = 0.002) and lower brain volume (P = 0.005)]. The same allele was also associated with higher lean body mass (P = 0.03) and no difference in height (P = 0.99). Principal component analysis identified a shared inverse variance between the brain volume and TBF, which was associated with FTO at P = 5.5 × 10(-6). These results were replicated in two independent samples of 413 and 718 adolescents, and in a meta-analysis of all three samples (n = 1729 adolescents), FTO was associated with this shared inverse variance at P = 1.3 × 10(-9). Co-expression networks analysis supported the possibility that the underlying FTO effects may occur during embryogenesis. In conclusion, FTO is associated with shared inverse variance between body adiposity and brain volume, suggesting that this gene may exert inverse effects on adipose and brain tissues. Given the completion of the overall brain growth in early childhood, these effects may have their origins during early development.

Umbilical cord PUFA are determined by maternal and child fatty acid desaturase (FADS) genetic variants in the Avon Longitudinal Study of Parents and Children (ALSPAC).

Fetal supply with long-chain PUFA (LC-PUFA) during pregnancy is important for brain growth and visual and cognitive development and is provided by materno-fetal placental transfer. We recently showed that maternal fatty acid desaturase (FADS) genotypes modulate the amounts of LC-PUFA in maternal blood. Whether FADS genotypes influence the amounts of umbilical cord fatty acids has not been investigated until now. The aim of the present study was to investigate the influence of maternal and child FADS genotypes on the amounts of LC-PUFA in umbilical cord venous plasma as an indicator of fetal fatty acid supply during pregnancy. A total of eleven cord plasma n-6 and n-3 fatty acids were analysed for association with seventeen FADS gene cluster SNP in over 2000 mothers and children from the Avon Longitudinal Study of Parents and Children. In a multivariable analysis, the maternal genotype effect was adjusted for the child genotype and vice versa to estimate which of the two has the stronger influence on cord plasma fatty acids. Both maternal and child FADS genotypes and haplotypes influenced amounts of cord plasma LC-PUFA and fatty acid ratios. Specifically, most analysed maternal SNP were associated with cord plasma levels of the precursor n-6 PUFA, whereas the child genotypes were mainly associated with more highly desaturated n-6 LC-PUFA. This first study on FADS genotypes and cord fatty acids suggests that fetal LC-PUFA status is determined to some extent by fetal fatty acid conversion. Associations of particular haplotypes suggest specific effects of SNP rs498793 and rs968567 on fatty acid metabolism.

Nutrition and neurodevelopment in children: focus on NUTRIMENTHE project.

There is growing evidence that early nutrition affects later cognitive performance. The idea that the diet of mothers, infants, and children could affect later mental performance has major implications for public health practice and policy development and for our understanding of human biology as well as for food product development, economic progress, and future wealth creation. To date, however, much of the evidence is from animal, retrospective studies and short-term nutritional intervention studies in humans. The positive effect of micronutrients on health, especially of pregnant women eating well to maximise their child's cognitive and behavioural outcomes, is commonly acknowledged. The current evidence of an association between gestational nutrition and brain development in healthy children is more credible for folate, n-3 fatty acids, and iron. Recent findings highlight the fact that single-nutrient supplementation is less adequate than supplementation with more complex formulae. However, the optimal content of micronutrient supplementation and whether there is a long-term impact on child's neurodevelopment needs to be investigated further. Moreover, it is also evident that future studies should take into account genetic heterogeneity when evaluating nutritional effects and also nutritional recommendations. The objective of the present review is to provide a background and update on the current knowledge linking nutrition to cognition and behaviour in children, and to show how the large collaborative European Project NUTRIMENTHE is working towards this aim.

Genetic variations in polyunsaturated fatty acid metabolism--implications for child health?

Sufficient nutritional supply with polyunsaturated fatty acids (PUFAs) has long been considered as beneficial for child health, especially in regard to neuronal development and allergic diseases. In recent years, genetic association studies showed that in addition to nutritional influences, the genetic background is highly important for PUFA composition in human tissues. Specifically, polymorphisms in the fatty acid desaturase genes or FADS determine the efficiency of how PUFAs are processed endogenously. Recent gene-nutrition interaction studies suggest that these polymorphisms modulate the effect of nutritional fatty acid intake on complex phenotypes such as cognitive outcomes and asthma risk in children. These early results may provide the basis for future well-specified dietary recommendations to achieve optimal health benefit for all children. This article presents results from recent gene-nutrition interaction studies, discusses its implications for child health, and gives an outlook how this association might translate into clinical practice in the future.

Genetic variation in polyunsaturated fatty acid metabolism and its potential relevance for human development and health.

Blood and tissue contents of polyunsaturated fatty acid (PUFA) and long-chain PUFA (LC-PUFA) are related to numerous health outcomes including cardiovascular health, allergies, mental health and cognitive development. Evidence has accumulated to show that in addition to diet, common polymorphisms in the fatty acid desaturase (FADS) gene cluster have very marked effects on human PUFA and LC-PUFA status. Recent results suggest that in addition to fatty acid desaturase 1 and fatty acid desaturase 2, the gene product of fatty acid desaturase 3 is associated with desaturating activity. New data have become available to show that FADS single nucleotide polymorphisms (SNPs) also modulate docosahexaenoic acid status in pregnancy as well as LC-PUFA levels in children and in human milk. There are indications that FADS SNPs modulate the risk for allergic disorders and eczema, and the effect of breastfeeding on later cognitive development. Mechanisms by which FADS SNPs modulate PUFA levels in blood, breast milk and tissues should be explored further. More studies are required to explore the effects of FADS gene variants in populations with different ethnic backgrounds, lifestyles and dietary habits, and to investigate in greater depth the interaction of gene variants, diet and clinical end points, including immune response and developmental outcomes. Analyses of FADS gene variants should be included into all sizeable cohort and intervention studies addressing biological effects of PUFA and LC-PUFA in order to consider these important confounders, and to enhance study sensitivity and precision.

Genetic variants of the FADS1 FADS2 gene cluster as related to essential fatty acid metabolism.

PURPOSE OF REVIEW: 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. RECENT FINDINGS: 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. SUMMARY: 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.

Maternal fatty acids in pregnancy, FADS polymorphisms, and child intelligence quotient at 8 y of age.

BACKGROUND: Brain tissue is selectively enriched with highly unsaturated fatty acids (FAs). Altering the maternal FA status in pregnancy may improve fetal neural development with lasting consequences for child development. OBJECTIVE: We explored whether maternal FAs in erythrocytes, either measured directly or indirectly by maternal FADS genetic variants, are associated with child intelligence quotient (IQ). DESIGN: Linear regression analyses, adjusted for 18 confounders, were used to investigate the associations in 2839 mother-child pairs from the population-based Avon Longitudinal Study of Parents and Children cohort. RESULTS: Low levels of arachidonic acid (20:4n-6) were associated with lower performance IQ (-2.0 points; 95% CI: -3.5, -0.6 points; P = 0.007, increased R² = 0.27%), high levels of osbond acid (22:5n-6) were associated with verbal IQ (-1.8 points; 95% CI: -3.2, -0.4 points; P = 0.014, R² = 0.20%), and high levels of adrenic acid (22:4n-6) were associated with verbal IQ (-1.7 points; 95% CI:-3.1, -0.3 points; P = 0.016, R² = 0.19%). There was some evidence to support a negative association of low docosahexaenoic acid (DHA; 22:6n-3) with full-scale IQ (R² = 0.15%). Novel weak associations were also observed for low levels of osbond acid (R² ≤ 0.29%) and FADS variants with opposite effects for intron variants and variants in the promoter region such as rs3834458 (R² ≤ 0.38%). CONCLUSIONS: These results support the positive role of maternal arachidonic acid and DHA on fetal neural development, although the effects on child IQ by 8 y of age were small (0.1 SD), with other factors contributing more substantially. The endogenous synthesis of these FAs by FADS genes, especially FADS2, may also be important. The replication of these results is recommended.

Tobacco smoking leads to extensive genome-wide changes in DNA methylation.

Environmental factors such as tobacco smoking may have long-lasting effects on DNA methylation patterns, which might lead to changes in gene expression and in a broader context to the development or progression of various diseases. We conducted an epigenome-wide association study (EWAs) comparing current, former and never smokers from 1793 participants of the population-based KORA F4 panel, with replication in 479 participants from the KORA F3 panel, carried out by the 450K BeadChip with genomic DNA obtained from whole blood. We observed wide-spread differences in the degree of site-specific methylation (with p-values ranging from 9.31E-08 to 2.54E-182) as a function of tobacco smoking in each of the 22 autosomes, with the percent of variance explained by smoking ranging from 1.31 to 41.02. Depending on cessation time and pack-years, methylation levels in former smokers were found to be close to the ones seen in never smokers. In addition, methylation-specific protein binding patterns were observed for cg05575921 within AHRR, which had the highest level of detectable changes in DNA methylation associated with tobacco smoking (-24.40% methylation; p = 2.54E-182), suggesting a regulatory role for gene expression. The results of our study confirm the broad effect of tobacco smoking on the human organism, but also show that quitting tobacco smoking presumably allows regaining the DNA methylation state of never smokers.

Associations of IGF-1 gene variants and milk protein intake with IGF-I concentrations in infants at age 6 months - results from a randomized clinical trial.

OBJECTIVE: The interplay of genetic and nutritional regulation of the insulin-like growth factor-I axis in children is unclear. Therefore, potential gene-nutrient effects on serum levels of the IGF-I axis in a formula feeding trial were studied. DESIGN: European multicenter randomized clinical trial of 1090 term, formula-fed infants assigned to receive cow's milk-based infant and follow-on formulae with lower (LP: 1.25 and 1.6 g/100 mL) or higher (HP: 2.05 and 3.2 g/100 mL) protein contents for the first 12 months of life; a comparison group of 588 breastfed infants (BF) was included. Eight single nucleotide polymorphisms (SNPs) of the IGF-1-(rs6214, rs1520220, rs978458, rs7136446, rs10735380, rs2195239, rs35767, and rs35766) and two of the IGFBP-3-(rs1496495, rs6670) gene were analyzed. Serum levels of total and free IGF-I, IGFBP-3 and the molar ratio IGF-1/IGFBP-3 at age 6 months were regressed on determined SNPs and feeding groups in 501 infants. RESULTS: IGF-1-SNPs rs1520220, rs978458, and rs2195239 significantly increased total-IGF-I and molar-ratio IGF-I/IGFBP-3 by ~1.3 ng/mL and ~1.3 per allele, respectively; compared to LP infants concentration and molar-ratio were increased in HP by ~1.3 ng/mL and ~1.3 and decreased in BF infants by ~0.6 ng/mL and ~0.6, respectively. IGFBP-3 was only affected by the BF group with ~450 ng/mL lower levels than the LP group. No gene-feeding-group interaction was detected for any SNP, even without correction for multiple testing. CONCLUSIONS: Variants of the IGF-1-gene play an important role in regulating serum levels of the IGF-I axis but there is no gene-protein-interaction. The predominant nutritional regulation of IGF-I and IGFBP-3 gives further evidence that higher protein intake contributes to metabolic programming of growth.

FADS1 FADS2 gene cluster, PUFA intake and blood lipids in children: results from the GINIplus and LISAplus studies.

BACKGROUND: Elevated cholesterol levels in children can be a risk factor for cardiovascular diseases in later life. In adults, it has been shown that blood lipid levels are strongly influenced by polymorphisms in the fatty acid desaturase (FADS) gene cluster in addition to nutritional and other exogenous and endogenous determinants. Our aim was to investigate whether lipid levels are determined by the FADS genotype already in children and whether this association interacts with dietary intake of n-3 fatty acids. METHODS: The analysis was based on data of 2006 children from two German prospective birth cohort studies. Total cholesterol, HDL, LDL and triglycerides were measured at 10 years of age. Six single nucleotide polymorphisms (SNPs) of the FADS gene cluster were genotyped. Dietary n-3 fatty acid intake was assessed by food frequency questionnaire. Linear regression modeling was used to assess the association between lipid levels, n-3 fatty acid intake and FADS genotype. RESULTS: Individuals carrying the homozygous minor allele had lower levels of total cholesterol [means ratio (MR) ranging from 0.96 (p = 0.0093) to 0.98 (p = 0.2949), depending on SNPs] and LDL [MR between 0.94 (p = 0.0179) and 0.97 (p = 0.2963)] compared to homozygous major allele carriers. Carriers of the heterozygous allele showed lower HDL levels [ß between -0.04 (p = 0.0074) to -0.01 (p = 0.3318)] and higher triglyceride levels [MR ranging from 1.06 (p = 0.0065) to 1.07 (p = 0.0028)] compared to homozygous major allele carriers. A higher n-3 PUFA intake was associated with higher concentrations of total cholesterol, LDL, HDL and lower triglyceride levels, but these associations did not interact with the FADS1 FADS2 genotype. CONCLUSION: Total cholesterol, HDL, LDL and triglyceride concentrations may be influenced by the FADS1 FADS2 genotype already in 10 year old children. Genetically determined blood lipid levels during childhood might differentially predispose individuals to the development of cardiovascular diseases later in life.

Human serum metabolic profiles are age dependent.

Understanding the complexity of aging is of utmost importance. This can now be addressed by the novel and powerful approach of metabolomics. However, to date, only a few metabolic studies based on large samples are available. Here, we provide novel and specific information on age-related metabolite concentration changes in human homeostasis. We report results from two population-based studies: the KORA F4 study from Germany as a discovery cohort, with 1038 female and 1124 male participants (32-81 years), and the TwinsUK study as replication, with 724 female participants. Targeted metabolomics of fasting serum samples quantified 131 metabolites by FIA-MS/MS. Among these, 71/34 metabolites were significantly associated with age in women/men (BMI adjusted). We further identified a set of 13 independent metabolites in women (with P values ranging from 4.6 × 10(-04) to 7.8 × 10(-42) , α(corr) = 0.004). Eleven of these 13 metabolites were replicated in the TwinsUK study, including seven metabolite concentrations that increased with age (C0, C10:1, C12:1, C18:1, SM C16:1, SM C18:1, and PC aa C28:1), while histidine decreased. These results indicate that metabolic profiles are age dependent and might reflect different aging processes, such as incomplete mitochondrial fatty acid oxidation. The use of metabolomics will increase our understanding of aging networks and may lead to discoveries that help enhance healthy aging.

Genetic variants of the fatty acid desaturase gene cluster predict amounts of red blood cell docosahexaenoic and other polyunsaturated fatty acids in pregnant women: findings from the Avon Longitudinal Study of Parents and Children.

BACKGROUND: Blood and tissue long-chain polyunsaturated fatty acid (LC-PUFA) amounts, which have been associated with early development and lifelong health, depend on dietary intake and endogenous conversion of precursor fatty acids (FAs) by the enzymes Δ5-desaturase and Δ6-desaturase. Polymorphisms in the desaturase encoding genes FADS1 and FADS2 have been associated with several n-6 (omega-6) and n-3 (omega-3) FAs and especially with arachidonic acid (AA) amounts. Associations with docosahexaenoic acid (DHA), which is considered particularly important for brain and retina development, are hardly existent. OBJECTIVE: We explored the relation between FADS gene cluster polymorphisms and red blood cell (RBC) FA amounts in > 4000 pregnant women participating in the Avon Longitudinal Study of Parents and Children. DESIGN: Linear regression analysis of 17 single nucleotide polymorphisms (SNPs) in the FADS gene cluster was conducted with RBC phospholipid FAs from 6711 samples from 4457 women obtained throughout pregnancy (mean ± SD gestational age: 26.8 ± 8.2 wk). RESULTS: Independent of dietary effects, the minor alleles were consistently positively associated with precursor FAs and negatively associated with LC-PUFAs and product:substrate ratios of the n-6 (AA:linoleic acid ratio) and n-3 (eicosapentaenoic acid:α-linolenic acid ratio) pathways. In contrast to previous studies, we also showed significant inverse associations with DHA. Similar but weaker associations were shown for the FADS3 SNP rs174455. CONCLUSIONS: FADS genotypes influence DHA amounts in maternal RBC phospholipids and might affect the child's DHA supply during pregnancy. It is highly likely that a gene product of FADS3 has a desaturating activity.

Genetic variants in the FADS gene cluster are associated with arachidonic acid concentrations of human breast milk at 1.5 and 6 mo postpartum and influence the course of milk dodecanoic, tetracosenoic, and trans-9-octadecenoic acid concentrations over the duration of lactation.

BACKGROUND: Breastfeeding is considered an optimal nutritional source of n-6 (omega-6) and n-3 (omega-3) fatty acids (FAs) for the proper visual and cognitive development of newborn children. In addition to maternal nutrition as an important regulator of FA concentrations, first results exist on an association of breast-milk FAs with single nucleotide polymorphisms (SNPs) in the FADS gene cluster, which encodes the rate-limiting enzymes in the elongation-desaturation pathway of long-chain polyunsaturated fatty acids (LC-PUFAs). OBJECTIVE: We analyzed the influence of FADS SNPs on breast-milk FA concentrations and their time course during lactation in the Ulm Birth Cohort study, which comprised 772 nursing mothers at 1.5 mo after giving birth, and in a subset of 463 mothers who were still breastfeeding at 6 mo postpartum. DESIGN: We conducted linear regression analysis of 8 FADS SNPs with FA concentrations at both time points separately and assessed the genotype effect over time in a longitudinal analysis by using a generalized estimating equation regression model. RESULTS: We observed significant associations of FADS genotypes with arachidonic acid (AA) concentrations and the 20:4n-6/20:3n-6 ratio at both time points but no association of FADS SNPs with the time course of AA concentrations. A longitudinal analysis of FAs other than LC-PUFAs by genotype over time showed associations for dodecanoic acid, cis-15-tetracosenoic acid, and trans-9-octadecenoic acid. CONCLUSIONS: Maternal FADS genotypes are associated with breast-milk AA concentrations and might therefore influence the supply of this FA for children. Furthermore, our data indicate an interrelation between the LC-PUFA pathway and saturated and monounsaturated FAs.

Do FADS genotypes enhance our knowledge about fatty acid related phenotypes?

Several physiological processes, such as visual and cognitive development in early life, are dependent on the availability of long-chain polyunsaturated fatty acids (LC-PUFAs). Furthermore, the concentration of LC-PUFAs in phospholipids has been associated with numerous complex diseases like cardiovascular disease, atopic disease and metabolic syndrome. The level and composition of LC-PUFAs in the human body is mainly dependent on their dietary intake or on the intake of fatty acid precursors, which are endogenously elongated and desaturated to physiologically active LC-PUFAs. The delta-5 and delta-6 desaturase are the most important enzymes in this reaction cascade. In the last few years, several studies have reported an association between single nucleotide polymorphisms (SNPs) in the two desaturase encoding genes (FADS1 and FADS2) and the concentration of omega-6 and omega-3 fatty acids. This shows that beside nutrition, genetic factors play an important role in the regulation of LC-PUFAs as well. This review focuses on current knowledge of the impact of FADS genotypes on LC-PUFA and lipid metabolism and discusses their influence on infant intellectual development, neurological conditions, metabolic disease as well as cardiovascular disease.

FADS gene cluster polymorphisms: important modulators of fatty acid levels and their impact on atopic diseases.

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.

Metabolic profiling reveals distinct variations linked to nicotine consumption in humans--first results from the KORA study.

Exposure to nicotine during smoking causes a multitude of metabolic changes that are poorly understood. We quantified and analyzed 198 metabolites in 283 serum samples from the human cohort KORA (Cooperative Health Research in the Region of Augsburg). Multivariate analysis of metabolic profiles revealed that the group of smokers could be clearly differentiated from the groups of former smokers and non-smokers. Moreover, 23 lipid metabolites were identified as nicotine-dependent biomarkers. The levels of these biomarkers are all up-regulated in smokers compared to those in former and non-smokers, except for three acyl-alkyl-phosphatidylcholines (e.g. plasmalogens). Consistently significant results were further found for the ratios of plasmalogens to diacyl-phosphatidylcolines, which are reduced in smokers and regulated by the enzyme alkylglycerone phosphate synthase (alkyl-DHAP) in both ether lipid and glycerophospholipid pathways. Notably, our metabolite profiles are consistent with the strong down-regulation of the gene for alkyl-DHAP (AGPS) in smokers that has been found in a study analyzing gene expression in human lung tissues. Our data suggest that smoking is associated with plasmalogen-deficiency disorders, caused by reduced or lack of activity of the peroxisomal enzyme alkyl-DHAP. Our findings provide new insight into the pathophysiology of smoking addiction. Activation of the enzyme alkyl-DHAP by small molecules may provide novel routes for therapy.