B Koletzko, E Lattka, S Zeilinger, T Illig, C Steer
Department of Pediatrics, Dr von Hauner Children’s Hospital, University of Munich Medical Center, München, Germany; Centre for Child and Adolescent Health, Department of Community Based Medicine, University of Bristol, Bristol, UK; Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany

Background: Long-chain polyunsaturated fatty acid (lcPUFA) contents in blood and tissues are associated with early development of visual, cognitive and immune functions as well as lifelong health. lcPUFA blood and tissue levels depend both on dietary intake and endogenous conversion of precursor polyunsaturated fatty acids (PUFA) by the enzymes delta-5 desaturase (D5D) and delta-6 desaturase (D6D). Previously, we and others have shown associations of polymorphisms (SNPs) of FADS1 (D5D) and FADS2 (D6D) with several n-6 and n-3 fatty acids, in particular with arachidonic acid (1-3). However, there is little evidence on genetic effects on levels of docosahexaenoic acid (DHA), which are considered particularly important for brain and retina function. Moreover, the functional role of FADS3 is unclear. We explored the relationship between polymorphisms of the FADS gene cluster and red blood cell PUFA levels in pregnant women participating in the Avon Longitudinal Study of Parents and Children.

Methods: Red blood cell phospholipid FA were determined from 6711 samples of 4457 women obtained throughout pregnancy (gestational age 26.8+ 8.2 weeks, mean+SD). We determined 3 SNPs of FADS1, 9 of FADS2, 4 intergenic SNPs and 1 of FADS3.

Results: Minor SNP alleles were consistently positively associated with the precursor FA and negatively with LC-PUFA as well as product/substrate ratios of the n-6 (AA/LA ratio) and the n-3 (EPA/ALA ratio) pathways. In contrast to previous studies, we also found strongly significant inverse associations to the DHA). A minor FADS3 polymorphism was associated with increased PUFA and decreased LC-PUFA levels.

Conclusions: The results of this largest available cohort study on the relationship between the FADS polymorphisms and PUFA status markers shows a consistent association of the minor alleles of the tested SNPs in the FADS1 FADS2 gene cluster with increased levels of desaturase substrates and decreased levels of desaturase products of both the n-6 and the n-3 pathways, compatible with a decline in desaturase expression or activity due to the polymorphisms. In contrast to previous studies, we also found a consistent significant association of the rare SNP alleles with lower levels of DHA in red blood cell phospholipids of pregnant women, which might be due to the greater statistical power of this study and/or a higher rate of DHA synthesis in pregnant women compared to men or non-pregnant women. Given the strong association of an SNP in the FADS3 gene with PUFA levels, we consider it highly likely that a gene product of FADS3 has desaturating activity.

Supported in part by the UK Medical Research Council (MRC), the Wellcome Trust, the University of Bristol, Scotia pharmaceuticals, the Commission of the European Communities, Competence Network for Adiposity funded by the German Federal Ministry of Education and Research, the Munich Center of Health Sciences, a Freedom to Discover Award of the Bristol-Myers-Squibb Foundation, and NOAA.

References:
1. Schaeffer L, Gohlke H, Müller M, Heid IM, Palmer LJ, Kompauer I, Demmelmair H, Illig T, Koletzko B, Heinrich J. Common genetic variants of the FADS1 FADS2 gene cluster and their reconstructed haplotypes are associated with the fatty acid composition in phospholipids. HumMolGenet. 2006;15:1745-56.
2. Glaser C, Heinrich J, Koletzko B. Role of FADS1 and FADS2 polymorphisms in polyunsaturated fatty acid metabolism. Metabolism 2010, in press .
3. Lattka E, Illig T, Heinrich J, Koletzko B. Do FADS genotypes enhance our knowledge about fatty acid related phenotypes? Clin Nutr. 2009 Nov 28.

Keywords: Long-chain polyunsaturated fatty acid, pregnant woman, nucleotide polymorphisms, ALSPAC study
Schlüsselwörter: DHA- und EPA-Spiegel, genetisch bedingten Desaturasemangel, Schwangerschaft