👤 Berthold V Koletzko

Classification of physical activity (PA) depends on the cut-point method used to allocate PA counts from accelerometer measurements. This study investigates how three validated cut-point methods affect the time spent in various levels of PA and sedentary behaviour (SB), and how they impact toddlers estimated adherence to PA guidelines. PA was assessed using an ActiGraph wGT3X-BT accelerometer in a cohort of 653 two-year-old children participating in the Toddler Milk Intervention study. Children wearing the ActiGraph for at least four days, with a minimum of six hours wear-time per day, were included. Time spent in SB and different activity levels were estimated according to three cut-point methods and were standardized to individual mean wear-time. We used one cut-point method based on the vertical axis (VA) (Trost VA), with an epoch length of 15 s and two cut-point methods based on either the VA (Costa VA) or on the vector magnitude (VM) (Costa VM) with an epoch length of five seconds. Estimates of SB and PA for each method were compared with repeated measures ANOVA. The time toddlers spent in PA was significantly different depending on the cut-point methods. Costa VM classified on average 62 min (95% CI 61, 64] more per day as SB and 57 min (95% CI -58, -56] less per day as LPA compared to Trost VA (both p < 0.0001). For MVPA, the mean difference between Costa VA and Trost VA was 6.8 min (95% CI -7, -6; p < 0.0001). Concurrently, the proportion of children meeting the WHO recommendation of 180 min of total PA differed between cut-point methods, with 86% according to Costa VM and 97% according to Trost VA. The time toddlers engage in different intensities of PA is significantly determined by the selection of cut-point method. Notably, the use of a different cut-point method leads up to a 10% difference in the estimated time spent in LPA and SB, but only a 1% difference of moderate-vigorous PA. These differences change the estimated adherence to recommendations. Future research is needed to standardize the data processing methods for better comparability between studies analysing toddlers' PA. ClinicalTrials.gov, TRN: NCT02907502, Registration Date: 31 August 2016. Show less

Fatty acids exert a range of different biological activities that could be relevant in the development of atopic dermatitis (AD). This study investigated the association of glycerophospholipid fatty acids (GPL-FA) with AD, and their interactions with single nucleotide polymorphisms (SNP) of the Show less

Both pre- and early postnatal supplementation with docosahexaenoic acid (DHA), arachidonic acid (AA) and folate have been related to neural development, but their long-term effects on later neural function remain unclear. We evaluated the long-term effects of maternal prenatal supplementation with fish-oil (FO), 5-methyltetrahydrofolate (5-MTHF), placebo or FO + 5-MTHF, as well as the role of fatty acid desaturase ( Show less

Variants in the human genes of fatty acid (FA) desaturase 1 (FADS1), 2 (FADS2) and 3 (FADS3) are associated with PUFA blood levels. We explored if maternal prenatal supplementation and children's genetic variation in seventeen SNP of the FADS1, FADS2 and FADS3 gene cluster influence twenty-one of the most relevant cheek cells' derived FA in glycerophospholipids (GPL-FA). The study was conducted in 147 Spanish and German mother-children pairs participating in the Nutraceuticals for a Healthier Life (NUHEAL) study at 8, 9 and 9·5 years. Linear and mixed model longitudinal regression analyses were performed. Maternal fish-oil (FO) or FO+5-methyltetrahydrofolate (5-MTHF) supplementation during pregnancy was associated with a significant decrease of arachidonic acid (AA) concentrations in cheek cell GPL in the offspring, from 8 to 9·5 years; furthermore, maternal FO+5-MTHF supplementation was associated with higher n-6 docosapentaenoic acid concentrations in their children at age 8 years. FADS1 rs174556 polymorphism and different FADS2 genotypes were associated with higher concentrations of linoleic and α-linolenic acids in children; moreover, some FADS2 genotypes determined lower AA concentrations in children's cheek cells. It is suggested an interaction between type of prenatal supplementation and the offspring genetic background driving GPL-FA levels at school age. Prenatal FO supplementation, and/or with 5-MTHF, seems to stimulate n-3 and n-6 FA desaturation in the offspring, increasing long-chain PUFA concentrations at school age, but depending on children's FADS1 and FADS2 genotypes. These findings suggest potential early nutrition programming of FA metabolic pathways, but interacting with children's FADS polymorphisms. Show less

The enzymes encoded by fatty acid desaturases (FADS) genes determine the desaturation of long-chain polyunsaturated fatty acids (LCPUFA). We investigated if haplotype and single nucleotide polymorphisms (SNPs) in FADS gene cluster can influence LCPUFA status in infants who received either fish oil or placebo supplementation. Children enrolled in the Infant Fish Oil Supplementation Study (IFOS) were randomly allocated to receive either fish oil or placebo from birth to 6 months of age. Blood was collected at 6 months of age for the measurement of fatty acids and for DNA extraction. A total of 276 participant DNA samples underwent genotyping, and 126 erythrocyte and 133 plasma fatty acid measurements were available for analysis. Twenty-two FADS SNPs were selected on the basis of literature and linkage disequilibrium patterns identified from the HapMap data. Haplotype construction was completed using PHASE. For participants allocated to the fish oil group who had two copies of the FADS1 haplotype consisting of SNP minor alleles, DHA levels were significantly higher compared to other haplotypes. This finding was not observed for the placebo group. Furthermore, for members of the fish oil group only, the minor homozygous carriers of all the FADS1 SNPs investigated had significantly higher DHA than other genotypes (rs174545, rs174546, rs174548, rs174553, rs174556, rs174537, rs174448, and rs174455). Overall results of this preliminary study suggest that supplementation with fish oil may only significantly increase DHA in minor allele carriers of FADS1 SNPs. Further research is required to confirm this novel finding. Show less

Atopic dermatitis (AD) is the most common skin disorder in young children worldwide, with a high impact on morbidity and quality of life. To date, no prospective study has been published on the incidence and potential predictors of AD in South East Asian populations. The Indonesian Prospective Study of Atopic Dermatitis in Infants (ISADI) will address the genetic, metabolic and dietary characteristics of mothers and their offspring, as well as potential determinants of AD within the first year of infant life. This prospective study will be undertaken in about 400 infants to investigate the direct and indirect effects of filaggrin ( The Permanent Medical Research Ethics Committee in Medicine and Health/Faculty of Medicine Universitas Indonesia/Dr Cipto Mangunkusumo Hospital (No. 47/H2.F1/ETIK/2014) approved the study protocol (extended by the letter no. 148/UN2.F1/ETIK/2015). We aim to disseminate our findings via publication in an international journal with high impact factor. Show less

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. Show less

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. 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. 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 [β 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. 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. Show less

The protective effect of breastfeeding (BF) on the development of asthma has been widely recognized, even if not all results have been consistent. Gene variants of the FADS gene cluster have a major impact on fatty acid composition in blood and in breast milk. Therefore, we evaluated the influence of the FADS1 FADS2 gene cluster polymorphisms on the association between BF and asthma. The analysis was based on data (N=2245) from two German prospective birth cohort studies. Information on asthma and BF during the first 6 months was collected using questionnaires completed by the parents. Logistic regression modelling was used to analyse the association between exclusive BF and ever having asthma stratified by genotype. In the stratified analyses, BF for 3 or 4 months after birth had a protective effect for heterozygous and homozygous carriers of the minor allele (adjusted odds ratio between 0.37 (95% CI: 0.18-0.80) and 0.42 (95% CI: 0.20-0.88). Interaction terms of BF with genotype were significant and ranged from -1.17 (P-value: 0.015) to -1.33 (0.0066). Moreover, heterozygous and homozygous carriers of the minor allele who were exclusively breastfed for 5 or 6 months after birth had a reduced risk of asthma [0.32 (0.18-0.57) to 0.47 (0.27-0.81)] in the stratified analyses. For individuals carrying the homozygous major allele, BF showed no significant effect on the development of asthma. The association between exclusive BF and asthma is modified by the genetic variants of FADS genotypes in children. Show less

The association between dietary fatty acid intake and the development of atopic diseases has been inconsistent. This could be due to inter-individual genetic differences in fatty acid metabolism. The aim of the current study was to assess the influence of FADS1 FADS2 gene cluster polymorphisms on the association between dietary fatty acid intake and atopic diseases and allergic sensitization in 10-year-old children. The analysis was based on data from two German prospective birth cohort studies. Data on margarine and fatty acid intake were collected using a food frequency questionnaire. Information on atopic diseases was collected using a questionnaire completed by the parents. Specific IgE against common food and inhalant allergens were measured. Six variants of the FADS1 FADS2 gene cluster (rs174545, rs174546, rs174556, rs174561, rs174575 and rs3834458) were tested. Logistic regression modelling, adjusted for gender, age, maternal education level and study centre, was used to analyse the association between fatty acid intake and atopic diseases stratified by genotype. No significant association was found between the six FADS single nucleotide polymorphisms (SNPs) and allergic diseases or atopic sensitization. The total n-3/total n-6 ratio was positive associated with an increased risk of hayfever in homozygous major allele carriers ranging from an adjusted odds ratios of 1.25 (95%-CI: 1.00-1.57) to 1.31 (95%-CI: 1.01-1.69) across the six tested SNPs although this association was not significant anymore after correcting for multiple testing. Daily margarine intake was significantly associated with asthma [1.17 (1.03-1.34) to 1.22 (1.06-1.40)] in individuals carrying the homozygous major allele. This association was also significant after correcting for multiple testing. The association between dietary intake of fatty acids and allergic diseases might be modulated by FADS gene variants in children. Show less

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. 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. 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). 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. 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. Show less

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. Show less

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

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

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. 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

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

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

Fatty acid composition in membranes plays an important role in cellular processes and has shown to be associated with the aetiology of several complex diseases in humans. We report strong associations between variants in the human delta-5 and delta-6 desaturase genes FADS1 FADS2 and fatty acid composition in serum phospholipids. Eighteen polymorphisms located in this gene cluster were genotyped in 727 adults from Erfurt, a German centre of the European Community Respiratory Health Survey. The cluster is located at chromosome 11q12-11q13.1, a region repeatedly found to be linked with atopy and other complex diseases. Polymorphisms and statistically reconstructed haplotypes of FADS1 and the upstream region of FADS2 showed strongest associations with the level of the direct precursor of inflammatory eicosanoids, the n-6 fatty acid arachidonic acid (C20:4n-6), also strong associations with levels of the n-6 fatty acids C18:2n-6, C18:3n-6, C20:2n-6, C20:3n-6, C22:4n-6 and of the n-3 fatty acids C18:3n-3, C20:5n-3 and C22:5n-3 (P-values < 1.0 x 10(-13)). Carriers of the rare alleles of several SNPs and their respective haplotypes had a lower prevalence of allergic rhinitis and atopic eczema. No association was found for total and specific IgE levels. Show less