Variants of the FADS1 FADS2 Gene Cluster, Blood Levels of Polyunsaturated Fatty Acids and Eczema in Children within the First 2 Years of Life

Ludwig-Maximilians-Universität München, Germany
PLoS ONE (Impact Factor: 3.23). 10/2010; 5(10):e13261. DOI: 10.1371/journal.pone.0013261
Source: PubMed


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.

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    • "Schaeffer et al found that adult minor allele carriers of several SNPs had a lower prevalence of self‐reported allergic rhinitis and atopic eczema [44]. Rzehak et al found that minor allele carriers of several SNPS in the FADS gene cluster had a higher prevalence of parental reported eczema at 2 years of age in the LISA‐ study, while no associations were found in the KOALA‐study [48]. Two studies found no association between 5 SNPs in FADS1/FADS2 and asthma, bronchitis, eczema or hay fever at 6 years of age [58] or at 10 years of age [59] in subjects from the two German LISA and GINI birth cohorts. "
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    ABSTRACT: Polyunsaturated fatty acids (PUFAs) are essential for human cell and tissue development. In foetus, PUFAs are supplied via placental transfer from maternal circulation. After birth, PUFAs are supplied via the diet. Long chain PUFAs (LCPUFAs) may also be synthesized from precursor fatty acids present in the diet. LCPUFAs have modulatory effects on the immune system. As maturation of the immune system in the neonatal period appears to be crucial for protection against allergy development, a major aim of the study was to study the impact of fatty acid composition in infant blood at birth on allergy development. Secondly, we sought to elucidate the sources of infant LCPUFAs with focus on polymorphisms in genes responsible for production of LCPUFAs in the body from shorter dietary fatty acids. Third, we studied whether LCPUFA and vitamin D metabolism differed in allergic and non-allergic adolescents. High proportions of either n-6 or n-3 LCPUFAs, among cord serum phospholipids were positively associated with the risk of developing either respiratory allergy, or atopic eczema, diagnosed at 13 years of age. We hypothesized that LCPUFAs counteract activation of the infant’s immune system in response to microbial stimuli in early life, thereby hampering the proper immune maturation necessary for healthy immune development. Regarding determinants of cord serum LCPUFA composition, we found that single nucleotide polymorphisms in the FADS gene cluster affected the proportion of the main n-6 LCPUFA, arachidonic acid, in cord serum as well as in adolescent serum. FADS gene polymorphisms that were associated with decreased proportions of arachidonic acid were also associated with a low prevalence of atopic eczema. Increased proportions of the n-3 LCPUFAs DPA and DHA in cord serum phospholipids were instead related to increased length of pregnancy. Adolescents with established allergy did not differ from non-allergic controls regarding proportions of LCPUFAs in serum phospholipids. Nor did they differ in vitamin D status. Proportions of n-3 LCPUFA in serum reflected dietary intake of fish in non-allergic adolescents, but not in adolescents with atopic eczema. The results may suggest that subjects with atopic eczema have a different LCPUFA metabolism, maybe because of enhanced usage of LCPUFAs during the allergic inflammation. In conclusion, the results suggest that LCPUFA metabolism may affects the risk of allergy development and may also be altered as a result of the allergic state. The lack of relation between allergy and vitamin D status in adolescents does not exclude that neonatal vitamin D status may affect allergy development.
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    • "As expected, the fatty acid profile of the plasma from subjects homozygous for the FADS2 rs 3834458 deletion [−/−] differed substantially from that of the other genotypes in that proportions of plasma total eicosapentaenoic acid (20:5 n-3), docosapentaenoic acid (22:5 n-3) and arachidonic acid (20:4 n-6) were significantly decreased. These findings are in line with earlier observations [3,8,9]. However, only about 8% of the dietary linoleic acid / α-linolenic acid go through the elongase/desaturase biosynthetic pathway to eicosapentaenoic acid and conversion to docosahexaenoic acid is extremely low (<0.1%) "
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    ABSTRACT: Background Oxidative modification of low-density lipoprotein (LDL) is a key event in the oxidation hypothesis of atherogenesis. We have previously shown that HDL does not protect LDL from oxidation in vitro, but is in fact oxidized fastest of all lipoproteins due to its rich polyunsaturated fatty acid (PUFA) composition, which is oxidation promoting. 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 status. There is a deletion [T/-] in the promoter region of the Δ6 –desaturase gene (FADS2, rs 3834458), which has a direct inhibitory influence on production of PUFA from linoleic and alpha-linolenic acid. To investigate the possible role of rs 3834458 in lipoprotein modification, oxidation of LDL with HDL2 or HDL3 were analyzed from plasma of 58 free-living individuals. Results Total eicosapentaenoic acid and arachidonic acid were significantly decreased in plasma from the 10 subjects homozygous for the deletion in FADS2 rs 3834458. When the isolated LDL and HDL2 were subjected to Cu2+-induced oxidation, these subjects showed decreased rate of appearance (p = 0.027) and the final concentration of conjugated dienes (p = 0.033) compared to the other genotypes. For oxidation of LDL with HDL3, the final concentration of conjugated dienes was also significantly decreased in subjects with [−/−] compared with [T/T] and [T/-] (p = 0.034). Conclusion We conclude that FADS2 genotype may play a role in peroxidation susceptibility of lipoproteins.
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