Single nucleotide polymorphisms in the FADS gene cluster are associated with delta-5 and delta-6 desaturase activities estimated by serum fatty acid ratios

Abstract

Genetic variability in the FADS1-FADS2 gene cluster [encoding delta-5 (D5D) and delta-6 (D6D) desaturases] has been associated with plasma long-chain PUFA (LCPUFA) and lipid levels in adults. To better understand these relationships, we further characterized the association between FADS1-FADS2 genetic variability and D5D and D6D activities in adolescents. Thirteen single nucleotide polymorphisms (SNPs) were genotyped in 1,144 European adolescents (mean ± SD age: 14.7 ± 1.4 y). Serum phospholipid fatty acid levels were analyzed using gas chromatography. D5D and D6D activities were estimated from the C20:4n-6/C20:3n-6 and C20:3n-6/C18:2n-6 ratios, respectively. Minor alleles of nine SNPs were associated with higher 18:2n-6 levels (1.9E-18 ≤ P ≤ 6.1E-5), lower C20:4n-6 levels (7.1E-69 ≤ P ≤ 1.2E-12), and lower D5D activity (7.2E-44 ≤ P ≤ 4.4E-5). All haplotypes carrying the rs174546 minor allele were associated with lower D5D activity, suggesting that this SNP is in linkage disequilibrium with a functional SNP within FADS1. In contrast, only the rs968567 minor allele was associated with higher D6D activity (P = 1.5E-6). This finding agrees with an earlier in vitro study showing that the minor allele of rs968567 is associated with a higher FADS2 promoter activity. These results suggest that rare alleles of several SNPs in the FADS gene cluster are associated with higher D6D activity and lower D5D activity in European adolescents. Genetic variability in the FADS1-FADS2 gene cluster [encoding delta-5 (D5D) and delta-6 (D6D) desaturases] has been associated with plasma long-chain PUFA (LCPUFA) and lipid levels in adults. To better understand these relationships, we further characterized the association between FADS1-FADS2 genetic variability and D5D and D6D activities in adolescents. Thirteen single nucleotide polymorphisms (SNPs) were genotyped in 1,144 European adolescents (mean ± SD age: 14.7 ± 1.4 y). Serum phospholipid fatty acid levels were analyzed using gas chromatography. D5D and D6D activities were estimated from the C20:4n-6/C20:3n-6 and C20:3n-6/C18:2n-6 ratios, respectively. Minor alleles of nine SNPs were associated with higher 18:2n-6 levels (1.9E-18 ≤ P ≤ 6.1E-5), lower C20:4n-6 levels (7.1E-69 ≤ P ≤ 1.2E-12), and lower D5D activity (7.2E-44 ≤ P ≤ 4.4E-5). All haplotypes carrying the rs174546 minor allele were associated with lower D5D activity, suggesting that this SNP is in linkage disequilibrium with a functional SNP within FADS1. In contrast, only the rs968567 minor allele was associated with higher D6D activity (P = 1.5E-6). This finding agrees with an earlier in vitro study showing that the minor allele of rs968567 is associated with a higher FADS2 promoter activity. These results suggest that rare alleles of several SNPs in the FADS gene cluster are associated with higher D6D activity and lower D5D activity in European adolescents. Long-chain PUFA (LCPUFA) have a key role in maintaining biological functions in humans; they are components of the cell membrane, serve as substrates for the synthesis of inflammatory eicosanoids (leukotrienes and prostaglandins), act as signaling molecules, and regulate gene expression (1.Sampath H. Ntambi J.M. Polyunsaturated fatty acid regulation of genes of lipid metabolism.Annu. Rev. Nutr. 2005; 25: 317-340Crossref PubMed Scopus (436) Google Scholar, 2.Jump D.B. Clarke S.D. Thelen A. Liimatta M. Ren B. Badin M.V. Dietary fat, genes, and human health.Adv. Exp. Med. Biol. 1997; 422: 167-176Crossref PubMed Scopus (40) Google Scholar). The FA composition of plasma and body tissues has been associated with certain pathologies, such as obesity, metabolic syndrome, cardiovascular disease, diabetes, immune system diseases, and psychiatric disorders (3.Germano M. Meleleo D. Montorfano G. Adorni L. Negroni M. Berra B. Rizzo A.M. Plasma, red blood cells phospholipids and clinical evaluation after long chain omega-3 supplementation in children with attention deficit hyperactivity disorder (ADHD).Nutr. Neurosci. 2007; 10: 1-9Crossref PubMed Scopus (58) Google Scholar, 4.Calder P.C. Polyunsaturated fatty acids and inflammation.Prostaglandins Leukot. Essent. Fatty Acids. 2006; 75: 197-202Abstract Full Text Full Text PDF PubMed Scopus (400) Google Scholar). However, the mechanisms underlying these associations have not been clearly established. Tissue LCPUFA levels are determined by both dietary intake and endogenous synthesis via the successive elongation and desaturation of dietary FA precursors (Fig. 1). Delta-5 desaturase (D5D) and delta-6 desaturase (D6D), two enzymes required for the synthesis of LCPUFA in mammals (5.Nakamura M.T. Nara T.Y. Structure, function, and dietary regulation of delta6, delta5, and delta9 desaturases.Annu. Rev. Nutr. 2004; 24: 345-376Crossref PubMed Scopus (837) Google Scholar), are respectively encoded by the FADS1 and FADS2 genes (located in a cluster on chromosome 11q12-13.1). Although both desaturases are expressed in most human tissues, the highest expression levels are observed in the liver (6.Cho H.P. Nakamura M. Clarke S.D. Cloning, expression, and fatty acid regulation of the human delta-5 desaturase.J. Biol. Chem. 1999; 274: 37335-37339Abstract Full Text Full Text PDF PubMed Scopus (437) Google Scholar). In mice, deletion of the FADS2 gene abolishes the initial step in the metabolic cascade and results in the absence of linoleic and α-linolenic acid derivatives and eicosanoid synthesis, inhibition of platelet aggregation and thrombus formation, and alterations in reproductive function (7.Stoffel W. Holz B. Jenke B. Binczek E. Gunter R.H. Kiss C. Karakesisoglou I. Thevis M. Weber A.A. Arnhold S. et al.Delta6-Desaturase (FADS2) deficiency unveils the role of omega3- and omega6-polyunsaturated fatty acids.EMBO J. 2008; 27: 2281-2292Crossref PubMed Scopus (174) Google Scholar). Many studies have reported associations between genetic variants in the FADS1-FADS2 gene cluster and plasma or erythrocyte LCPUFA levels (8.Schaeffer L. Gohlke H. Muller M. Heid I.M. Palmer L.J. 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.Hum. Mol. Genet. 2006; 15: 1745-1756Crossref PubMed Scopus (440) Google Scholar, 9.Tanaka T. Shen J. Abecasis G.R. Kisialiou A. Ordovas J.M. Guralnik J.M. Singleton A. Bandinelli S. Cherubini A. Arnett D. et al.Genome-wide association study of plasma polyunsaturated fatty acids in the InCHIANTI Study.PLoS Genet. 2009; 5: e1000338Crossref PubMed Scopus (320) Google Scholar, 10.Rzehak P. Heinrich J. Klopp N. Schaeffer L. Hoff S. Wolfram G. Illig T. Linseisen J. Evidence for an association between genetic variants of the fatty acid desaturase 1 fatty acid desaturase 2 (FADS1 FADS2) gene cluster and the fatty acid composition of erythrocyte membranes.Br. J. Nutr. 2009; 101: 20-26Crossref PubMed Scopus (169) Google Scholar, 11.Xie L. Innis S.M. Genetic variants of the FADS1 FADS2 gene cluster are associated with altered (n-6) and (n-3) essential fatty acids in plasma and erythrocyte phospholipids in women during pregnancy and in breast milk during lactation.J. Nutr. 2008; 138: 2222-2228Crossref PubMed Scopus (254) Google Scholar, 12.Truong H. DiBello J.R. Ruiz-Narvaez E. Kraft P. Campos H. Baylin A. Does genetic variation in the Delta6-desaturase promoter modify the association between alpha-linolenic acid and the prevalence of metabolic syndrome?.Am. J. Clin. Nutr. 2009; 89: 920-925Crossref PubMed Scopus (48) Google Scholar, 13.Baylin A. Ruiz-Narvaez E. Kraft P. Campos H. alpha-Linolenic acid, Delta6-desaturase gene polymorphism, and the risk of nonfatal myocardial infarction.Am. J. Clin. Nutr. 2007; 85: 554-560Crossref PubMed Scopus (107) Google Scholar, 14.Martinelli N. Girelli D. G. P. Illig T. E. M. S. Schaeffer L. et and desaturase activity estimated by the of acid linoleic acid are associated with and J. Clin. Nutr. 2008; PubMed Scopus Google Scholar, G. Schaeffer L. L. Klopp N. E. M. N. P. et of the FADS gene cluster are associated with polyunsaturated fatty acids in a of with cardiovascular 2008; PubMed Scopus Google Scholar). The observed associations between several single nucleotide polymorphisms (SNPs) on and levels of linoleic acid levels and levels of acid on the a in desaturase activity in adults. have a association between FADS1-FADS2 gene cluster SNPs and levels of and and levels of suggesting that alterations in desaturase activities plasma levels T. Shen J. Abecasis G.R. Kisialiou A. Ordovas J.M. Guralnik J.M. Singleton A. Bandinelli S. Cherubini A. Arnett D. et al.Genome-wide association study of plasma polyunsaturated fatty acids in the InCHIANTI Study.PLoS Genet. 2009; 5: e1000338Crossref PubMed Scopus (320) Google Scholar, 13.Baylin A. Ruiz-Narvaez E. Kraft P. Campos H. alpha-Linolenic acid, Delta6-desaturase gene polymorphism, and the risk of nonfatal myocardial infarction.Am. J. Clin. Nutr. 2007; 85: 554-560Crossref PubMed Scopus (107) Google Scholar, S. A. I. T. C. P. and genes for Genet. 2009; 5: PubMed Scopus Google Scholar, S. S. L. D. T. et variants Genet. 2009; PubMed Scopus Google Scholar, S. I. D. Heid I.M. T. et lipid levels and risk in European Genet. 2009; PubMed Scopus Google Scholar, C. A. S. J. T. M. et al.Genome-wide association of metabolic in a from a Genet. 2009; PubMed Scopus Google Scholar). is not desaturase or is in these To this we further characterized the association between the genetic variability in this cluster and of D5D and D6D activities in a of 1,144 European adolescents. The and of the adolescents in the study in by in have been S. M. M. D. L. M. et and of the in by in 2008; PubMed Scopus Google Scholar). a of adolescents were between and were in a of from European were from by using a cluster and of the were for blood this in a of blood The body was for 1,144 adolescents the in the were on a in with In and blood The was by the for was from and both of or in the study was The clinical are in of the of acid acid acid acid acid acid acid acid are FA are for for are in of in a are FA are for for are in of blood were after a were a the of Serum and and levels were on the clinical system for was in the the of and the the was from blood cells with the and on the phospholipid was using chromatography. The phospholipid was and the were their by with The phospholipid FA were analyzed using gas on a of were by with FA were expressed as a by the the and the results by the for The of were for FA Although is the of is of dietary acid in human and Nutr. PubMed Scopus Google in (mean = ± as E. M. 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M. B. between estimated fatty acid desaturase activities in and in and 2009; PubMed Scopus Google Scholar). were for and in a of for the and Minor alleles for SNP are are the estimated for by the the most allele and were as of D6D and D5D desaturase respectively E. M. B. between estimated fatty acid desaturase activities in and in and 2009; PubMed Scopus Google Scholar). were for and the LCPUFA not two haplotypes carrying both the rs174546 and rs968567 minor alleles and were associated with higher levels P = and P = However, only the was associated with a lower D5D activity, was associated with lower and levels P = and P = associations between FADS haplotypes and LCPUFA levels were the was lipid levels and of the haplotypes was associated with or levels or In contrast, the carrying the minor allele of the rs174546 SNP was associated with higher levels (P = The study the of associations between nine SNPs in the FADS cluster and D5D activity determined as the of C20:4n-6 in carrying the rs174546 minor allele were associated with both lower C20:4n-6 levels and lower D5D activity, suggesting that rs174546 in linkage disequilibrium with a functional SNP that FADS1. we that the minor allele of rs968567 was associated with higher levels of D6D activity determined as the of in These suggest that the genetic variability in the FADS gene cluster that LCPUFA levels is by both higher D6D activity and lower D5D activity in European adolescents. The study that the minor alleles of the and SNPs were associated with higher levels of and lower levels of studies have the as an of desaturase activity between D6D and D5D activities L. Innis S.M. Genetic variants of the FADS1 FADS2 gene cluster are associated with altered (n-6) and (n-3) essential fatty acids in plasma and erythrocyte phospholipids in women during pregnancy and in breast milk during lactation.J. Nutr. 2008; 138: 2222-2228Crossref PubMed Scopus (254) Google Scholar, 14.Martinelli N. Girelli D. G. P. Illig T. E. M. S. Schaeffer L. et and desaturase activity estimated by the of acid linoleic acid are associated with and J. Clin. Nutr. 2008; PubMed Scopus Google Scholar). the C20:3n-6/C18:2n-6 and C20:4n-6/C20:3n-6 ratios, we were the D6D and D5D activities E. M. B. between estimated fatty acid desaturase activities in and in and 2009; PubMed Scopus Google Scholar). that the minor alleles of SNPs is in linkage disequilibrium with the and were associated with lower D5D activity. rs968567 was associated with higher D6D activity. the nine SNPs associated with D5D activity, the were observed for rs174546 and rs968567 = and All the SNPs are in linkage disequilibrium and are within an both FADS1 and these associations the carrying the rs174546 minor allele were associated with lower D5D activity. is that the SNP is the only within FADS1 The rs174546 SNP in linkage disequilibrium with a functional SNP D5D activity. rs174546 is in linkage disequilibrium with the promoter SNP (8.Schaeffer L. Gohlke H. Muller M. Heid I.M. Palmer L.J. 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.Hum. Mol. Genet. 2006; 15: 1745-1756Crossref PubMed Scopus (440) Google Scholar). In an in vitro study of a with D6D the of the nucleotide was associated with a lower promoter activity and D6D activity and lower plasma C20:4n-6 levels A.A. nucleotide in the of FADS2 human fatty acid Full Text Full Text PDF PubMed Scopus Google Scholar). However, this finding was not in a study E. S. G. Weber M. D. H. Illig T. J. FADS2 promoter promoter activity and of Full Text Full Text PDF PubMed Scopus Google Scholar), suggesting that the earlier finding as by Baylin et A. Ruiz-Narvaez E. Kraft P. Campos H. alpha-Linolenic acid, Delta6-desaturase gene polymorphism, and the risk of nonfatal myocardial infarction.Am. J. Clin. Nutr. 2007; 85: 554-560Crossref PubMed Scopus (107) Google Scholar). The rs174546 SNP is in linkage disequilibrium with = a SNP within FADS1 and the minor allele of has been associated with lower FADS1 levels in the human liver S. S. L. D. T. et variants Genet. 2009; PubMed Scopus Google Scholar). In contrast, only the rs968567 minor allele was associated with higher D6D activity. This SNP is of the FADS2 are with an earlier of associations between the minor allele of rs968567 and higher and levels and lower C20:4n-6 levels on D6D activity (8.Schaeffer L. Gohlke H. Muller M. Heid I.M. Palmer L.J. 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.Hum. Mol. Genet. 2006; 15: 1745-1756Crossref PubMed Scopus (440) Google Scholar). that carrying the rs968567 minor allele was associated with higher D6D activity. This association agrees with the results of a functional study showing that the rs968567 minor allele was a higher FADS2 promoter activity in and cells E. S. G. Weber M. D. H. Illig T. J. FADS2 promoter promoter activity and of Full Text Full Text PDF PubMed Scopus Google Scholar). associations between the FADS cluster and desaturase activities estimated by FA were the of on the FA The associations between FADS SNPs and LCPUFA were with observed with the minor alleles of SNPs and were associated with higher levels of a with lower levels of of this the of dietary that and for D6D and D5D and that the dietary intake of is by higher that of the enzymes are with and this the expression of a genetic in the In contrast, the levels both the of dietary and the genetic The study agrees with the earlier showing associations between several SNPs in the FADS cluster and breast and LCPUFA levels in (8.Schaeffer L. Gohlke H. Muller M. Heid I.M. Palmer L.J. 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.Hum. Mol. Genet. 2006; 15: 1745-1756Crossref PubMed Scopus (440) Google Scholar, 9.Tanaka T. Shen J. Abecasis G.R. Kisialiou A. Ordovas J.M. Guralnik J.M. Singleton A. Bandinelli S. Cherubini A. Arnett D. et al.Genome-wide association study of plasma polyunsaturated fatty acids in the InCHIANTI Study.PLoS Genet. 2009; 5: e1000338Crossref PubMed Scopus (320) Google Scholar, 10.Rzehak P. Heinrich J. Klopp N. Schaeffer L. Hoff S. Wolfram G. Illig T. Linseisen J. Evidence for an association between genetic variants of the fatty acid desaturase 1 fatty acid desaturase 2 (FADS1 FADS2) gene cluster and the fatty acid composition of erythrocyte membranes.Br. J. Nutr. 2009; 101: 20-26Crossref PubMed Scopus (169) Google Scholar, 11.Xie L. Innis S.M. Genetic variants of the FADS1 FADS2 gene cluster are associated with altered (n-6) and (n-3) essential fatty acids in plasma and erythrocyte phospholipids in women during pregnancy and in breast milk during lactation.J. Nutr. 2008; 138: 2222-2228Crossref PubMed Scopus (254) Google Scholar, 12.Truong H. DiBello J.R. Ruiz-Narvaez E. Kraft P. Campos H. Baylin A. Does genetic variation in the Delta6-desaturase promoter modify the association between alpha-linolenic acid and the prevalence of metabolic syndrome?.Am. J. Clin. Nutr. 2009; 89: 920-925Crossref PubMed Scopus (48) Google Scholar, 13.Baylin A. Ruiz-Narvaez E. Kraft P. Campos H. alpha-Linolenic acid, Delta6-desaturase gene polymorphism, and the risk of nonfatal myocardial infarction.Am. J. Clin. Nutr. 2007; 85: 554-560Crossref PubMed Scopus (107) Google Scholar, 14.Martinelli N. Girelli D. G. P. Illig T. E. M. S. Schaeffer L. et and desaturase activity estimated by the of acid linoleic acid are associated with and J. Clin. Nutr. 2008; PubMed Scopus Google Scholar, G. Schaeffer L. L. Klopp N. E. M. N. P. et of the FADS gene cluster are associated with polyunsaturated fatty acids in a of with cardiovascular 2008; PubMed Scopus Google and these European adolescents. from association have associations between SNPs in the gene cluster on and lower levels of S. S. L. D. T. et variants Genet. 2009; PubMed Scopus Google Scholar, S. I. D. Heid I.M. T. et lipid levels and risk in European Genet. 2009; PubMed Scopus Google and T. Shen J. Abecasis G.R. Kisialiou A. Ordovas J.M. Guralnik J.M. Singleton A. Bandinelli S. Cherubini A. Arnett D. et al.Genome-wide association study of plasma polyunsaturated fatty acids in the InCHIANTI Study.PLoS Genet. 2009; 5: e1000338Crossref PubMed Scopus (320) Google Scholar, S. A. I. T. C. P. and genes for Genet. 2009; 5: PubMed Scopus Google Scholar, S. S. L. D. T. et variants Genet. 2009; PubMed Scopus Google Scholar, S. I. D. Heid I.M. T. et lipid levels and risk in European Genet. 2009; PubMed Scopus Google Scholar, C. A. S. J. T. M. et al.Genome-wide association of metabolic in a from a Genet. 2009; PubMed Scopus Google and higher levels on the A. Ruiz-Narvaez E. Kraft P. Campos H. alpha-Linolenic acid, Delta6-desaturase gene polymorphism, and the risk of nonfatal myocardial infarction.Am. J. Clin. Nutr. 2007; 85: 554-560Crossref PubMed Scopus (107) Google Scholar, S. A. I. T. C. P. and genes for Genet. 2009; 5: PubMed Scopus Google Scholar, S. S. L. D. T. et variants Genet. 2009; PubMed Scopus Google Scholar, S. I. D. Heid I.M. T. et lipid levels and risk in European Genet. 2009; PubMed Scopus Google Scholar). In the a a association between the rs174546 minor allele and higher levels in with the on A. Ruiz-Narvaez E. Kraft P. Campos H. alpha-Linolenic acid, Delta6-desaturase gene polymorphism, and the risk of nonfatal myocardial infarction.Am. J. Clin. Nutr. 2007; 85: 554-560Crossref PubMed Scopus (107) Google Scholar, S. A. I. T. C. P. and genes for Genet. 2009; 5: PubMed Scopus Google Scholar, S. S. L. D. T. et variants Genet. 2009; PubMed Scopus Google Scholar, S. I. D. Heid I.M. T. et lipid levels and risk in European Genet. 2009; PubMed Scopus Google Scholar). In contrast, we for such associations for and in adolescents a of and respectively These results suggest that the of FADS SNPs on lower in this in adults. However, that not the the plasma in these during the from A. J. in and cardiovascular risk during of risk in and 2008; PubMed Scopus Google Scholar). genetic association studies or are required the of SNPs on in This association study of FADS cluster in adolescents several and the of and is in adolescents in SNPs have a on the study was genetic we the of in the genetic the of with a the of rare alleles with the this study the association of FADS cluster polymorphisms with D6D and D5D However, we the between as of desaturase of activities are not in Although the study was in from we for of the association between the SNPs and the and not the that the dietary FA was not in the However, in an earlier study A. Ruiz-Narvaez E. Kraft P. Campos H. alpha-Linolenic acid, Delta6-desaturase gene polymorphism, and the risk of nonfatal myocardial infarction.Am. J. Clin. Nutr. 2007; 85: 554-560Crossref PubMed Scopus (107) Google Scholar), dietary not the FADS results from with an of adolescents. In results suggest that the SNPs that variability in LCPUFA levels not only D6D D5D activity. In with that have an of rs968567 in FADS2 gene results a for functional studies on the FADS1 The for with with body delta-5 desaturase delta-6 desaturase long-chain PUFA single nucleotide