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Journal of Nutrition, doi:10.3945/jn.108.096156
Vol. 138, No. 11, 2222-2228, November 2008
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© 2008 American Society for Nutrition J. Nutr. 138:2222-2228, November 2008

Nutrient Requirements and Optimal Nutrition

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 Lactation1,2

Lin Xie3 and Sheila M. Innis4,*

3 Department of Nutrition and Food Hygiene, School of Public Health, Jilin University, Changchun, People's Republic of China and 4 Child and Family Research Institute, Department of Paediatrics, University of British Columbia, Vancouver, V5Z 4H4, Canada

* To whom correspondence should be addressed. E mail: sinnis{at}interchange.ubc.ca.


   ABSTRACT
TOP
 ABSTRACT
Introduction
 Subjects and Methods
 Results
 Discussion
 LITERATURE CITED
 
The enzymes encoded by fatty acid desaturase (FADS) 1 and FADS2 are rate-limiting enzymes in the desaturation of linoleic acid [LA; 18:2(n-6)] to arachidonic acid [ARA; 20:4(n-6)], and {alpha}-linolenic acid [ALA; 18:3(n-3)] to eicosapentaenoic acid [EPA; 20:5(n-3)] and docosahexaenoic acid [DHA; 22:6(n-3)]. ARA, EPA, and DHA play central roles in infant growth, neural development, and immune function. The maternal ARA, EPA, and DHA status in gestation influences maternal-to-infant transfer and breast milk provides fatty acids for infants after birth. We determined if single nucleotide polymorphisms in FADS1 and FADS2 influence plasma phospholipid and erythrocyte ethanolamine phosphoglyceride (EPG) (n-6) and (n-3) fatty acids of women in pregnancy or their breast milk during lactation. We genotyped rs174553, rs99780, rs174575, and rs174583 in the FADS1 FADS2 gene cluster and analyzed plasma and erythrocyte fatty acids and dietary intake for 69 pregnant women and breast milk for a subset of 54 women exclusively breast-feeding at 1 mo postpartum. Minor allele homozygotes of rs174553(GG), rs99780(TT), and rs174583(TT) had lower ARA but higher LA in plasma phospholipids and erythrocyte EPG and decreased (n-6) and (n-3) fatty acid product:precursor ratios at 16 and 36 wk of gestation. Breast milk fatty acids were influenced by genotype, with significantly lower 14:0, ARA, and EPA but higher 20:2(n-6) in the minor allele homozygotes of rs174553(GG), rs99780(TT), and rs174583(TT) and lower ARA, EPA, 22:5(n-3), and DHA in the minor allele homozygotes G/G of rs174575. We showed that genetic variants of FADS1 and FADS2 influence blood lipid and breast milk essential fatty acids in pregnancy and lactation.


   Introduction
TOP
 ABSTRACT
 Introduction
Subjects and Methods
 Results
 Discussion
 LITERATURE CITED
 
The enzymes {Delta}5 desaturase and {Delta}6 desaturase, encoded by fatty acid desaturase (FADS)51 and FADS2, respectively, are the rate-limiting enzymes in synthesis of the long-chain PUFA arachidonic acid [ARA; 20:4(n-6)] and eicosapentaenoic acid [EPA; 20:5(n-3)] and docosahexaenoic acid [DHA; 22:6(n-3)] from their dietary precursors linoleic acid [LA; 18:2(n-6)] and {alpha}-linolenic acid [ALA; 18:3(n-3)], respectively (Fig. 1) (1–6). ARA, EPA, and DHA are esterified in membrane phospholipids where they contribute to membrane-dependent enzyme, receptor, and ion channel activities and provide a reservoir for the regulated release of ARA and EPA, and DHA for synthesis of eicosanoids and docosanoids, respectively, and for regulation of gene expression (1,7–10). ARA fulfills the essential role of (n-6) fatty acids in growth and is a precursor for synthesis of multiple eicosanoids, including prostaglandin E2, which is important in normal development of many organs and cells, including the central nervous system (11–16). DHA is enriched in membrane lipids of the brain and retina and plays critical roles in neurogenesis, neurotransmitter metabolism, neuroprotection, and the kinetics of the visual cycle (1,7,9,11,17–19). During gestation and breast-feeding, ARA, EPA, and DHA and their precursor (n-6) and (n-3) fatty acids are transferred from the mother by placental transfer and in breast milk, respectively (20,21), and higher levels are positively associated with pre- and postnatal growth and better development of visual, neural, and immune function (21–30).


Figure 1
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  		FIGURE 1  Schematic to illustrate the major steps in fatty acid desaturation and elongation. The sites of action of {Delta}9, {Delta}6, and {Delta}5 desaturases and e, elongation are shown. The enzymes {Delta}6 and {Delta}5 desaturases are encoded by FADS2 and FADS1, respectively. The major product of fatty acid synthesis from acetyl CoA in the liver is 16:0 and in the mammary gland, de novo fatty acid synthesis is terminated at 14:0. Those fatty acids decreased by minor allele variants of the FADS1/FADS2 gene cluster, which lower {Delta}6 and {Delta}5 desaturase activities, are in solid type in the larger box, whereas fatty acids potentially increased due to lower desaturase activity are in italics.

 
FADS1 and FADS2 are localized as a cluster, with FADS1 and FADS2 oriented head to head, exon 1 of the genes separated by an 11-kb region on chromosome 11 (11q12-q13.1), and both FADS1 and FADS2 containing 12 exons and 11 introns (2–5). Recent studies have shown that single nucleotide polymorphisms (SNP) in the FADS1 FADS2 cluster contribute to variability in plasma phospholipid and erythrocyte total lipid ARA (31,32). Further, recent large studies found that among children who had been breast-fed, those carrying the major allele in rs174575 (FADS2) scored higher on IQ tests than minor allele homozygote children, suggesting that genetic variations in FADS may confer particular benefits of breast-feeding among some children (33). To our knowledge, whether SNP in the FADS1 FADS2 gene cluster influence maternal plasma and membrane lipid (n-6) and (n-3) fatty acid levels in gestation or in breast milk has not been previously reported. Our objective in the present report, therefore, was to determine whether SNP in the FADS1 FADS2 gene contribute to differences in (n-6) and (n-3) fatty acids during pregnancy and in human breast milk, thus serving as the basis to consider whether diet-gene interactions are likely to have relevance in studies assessing the dietary needs for PUFA or their effects on early human growth and development.


   Subjects and Methods
TOP
 ABSTRACT
 Introduction
 Subjects and Methods
Results
 Discussion
 LITERATURE CITED
 
    Subjects. The present study involved pregnant women, 24–40 y of age, with no known maternal or fetal complications, all of whom were participants in a larger study of maternal fatty acid status and infant development (29). Each subject was enrolled at 16 wk of gestation and each subject was seen again at 36 wk of pregnancy and 1 mo postpartum. Women consuming a vegan diet or with any known metabolic disease, including diabetes, immune disorders, or communicable diseases, were not enrolled. In addition, women taking supplemental sources of EPA or DHA were not included in the present study. The protocol and procedures were approved by the Committee for Ethical Review of Research Involving Human Subjects at the University of British Columbia and the British Columbia's Children's and Women's Hospital. All subjects provided written informed consent prior to participation.

    Dietary assessments. Sociodemographic data, including age, parity, and highest level of education, family income, and ethnic background, were collected from each subject by questionnaire. Dietary assessments were conducted at 16 and 36 wk of gestation using an interview-administered FFQ designed to collect information on fat and fatty acid intakes and their food sources (34). Information from the dietary records was entered into a nutrient database (FOOD PROCESOR 11; ESHA Research) containing the Canadian Nutrient File, updated with the fatty acid composition of foods analyzed in our laboratory (34).

    Sample collection and fatty acid analyses. Venous blood was collected from fasting subjects in the outpatient laboratory of the British Columbia's Children's Hospital. The erythrocytes were separated from plasma by centrifugation (2000 x g; 15 min at 4°C), washed 2 times in normal saline, then the plasma and erythrocytes were frozen at –70°C until later analyses (24,28,29). Samples of breast milk, collected from a subset of 54 women who were exclusively breast-feeding their infants at 1 mo postpartum, were stored at –70°C until analysis (28,35). Total lipids were extracted from the RBC and plasma, then the plasma phospholipids and RBC ethanolamine phosphoglyceride (EPG) were separated by HPLC, recovered, and their fatty acids separated and quantified by GLC (24,28,29). The milk samples were thawed in ice-cold water, directly transmethylated to avoid potential loss of medium-chain fatty acids, and the FAME separated and quantified by GLC (28,35).

    Genotyping. We selected 6 SNP covering a 34-kb-long genomic region of the FADS1 FADS2 gene cluster in which the promoter region was included for SNP analysis. Four of the SNP analyzed by us, rs174553, rs174561, rs174583, and rs99780, have been reported to be associated with differences in the composition of serum lipid (n-6) and (n-3) fatty acids (31,32). We included analyses of 2 additional SNP, rs498793 and rs174575. SNP information was derived from NCBI dbSNP Build 128 (36). Genomic DNA was extracted from whole blood using the QIAamp DNA blood Mini kit (QIAGEN) and genotyping was performed with TaqMan SNP Genotyping assays (Applied Biosystems) using real-time PCR.

    Statistical analysis. Results are expressed as means ± SD unless otherwise specified and were analyzed with SPSS 15.0 software. The mean levels of fatty acids were compared among the major and minor allele homozygotes and heterozygotes using the Kruskal-Wallis test. We used Mann-Whitney U tests to determine differences in the {Delta}6 plus {Delta}5 desaturase fatty acid product:precursor ratios between major allele carriers and minor allele homozygotes. P-values ≤ 0.05 were considered significant. The Haploview program (version 4.0) was used to test the Hardy-Weinberg equilibrium for each genotype and linkage disequilibrium (LD) was calculated for paired SNP as described by others (32). The frequency of all haplotypes occurring among the women with a frequency >1% was calculated using the Haploview program (version 4.0).


   Results
TOP
 ABSTRACT
 Introduction
 Subjects and Methods
 Results
Discussion
 LITERATURE CITED
 
The women in the present study were 33.5 ± 3.6 y of age and 74% were Caucasian. All the subjects delivered 1 healthy, full-term infant (37–41 wk of gestation), as specified by our study inclusion criteria. The SNP in the FADS1 FADS2 gene cluster were genotyped with a success rate of 100% and, consistent with public databases, the 6 SNP we analyzed were polymorphic (Table 1). SNP rs174561 and rs498793 were not consistent with Hardy-Weinberg equilibrium and further analyses relating to these SNP to maternal or breast milk fatty acid status were not conducted. The other 4 SNP, rs174553, rs99780, rs174575, and rs174583, were consistent with the Hardy-Weinberg equilibrium and these SNP are present in a highly preserved single LD block (D' > 0.9) that covers a 34–kb-long genomic region from position 61331734 (rs174553) to position 61366326 (rs174583), in the order of rs174553, rs99780, rs174575, and rs1745843. In this LD block, for 4 locus haplotypes were 3 major haplotypes, ACCC, GTGT, and GTCT, that were present among the women in this study with a frequency of 49.3%, 31.2%, and 18.1%, respectively. The genotyping results for rs174553, rs99780, and rs174583 showed the same frequencies (Table 1). The major and minor alleles of rs174583 and rs99780 were present in the same women without exception, meaning that the results for dietary intake and plasma, erythrocyte, and breast milk fatty acids for women grouped by rs174583 and rs99780 alleles were the same. Our finding that the SNP analyses of rs174583 and rs99780 were the same is explained by the strong LD of these SNP (D' = 1; r2 = 1). Of the 20 women who were homozygous for the major allele C of rs174583 and rs99780, 19 were also homozygous for the major allele A of rs174553 and 1 woman was heterozygous; conversely, 1 woman who was homozygous for the major allele A of rs174553 was heterozygous for rs174583 and rs99780 (C/T) (Table 1). The 20 women who were homozygous for the minor allele of rs174553 were the same 20 women who were homozygous for the minor allele of rs174583. Therefore, women grouped by SNP in rs174583 and rs99780 differed from the women grouped by SNP in rs174553 by 1/20 and 1/29 of the subjects in the group of homozygote or heterozygote women, which did not affect the statistical interpretation of differences in fatty acid status due to genetic variation. The SNP rs174553 lies within intron 5 of FADS1 and is 3065 bp from exon 5 and 962 bp from exon 6, whereas rs174583 lies within intron 4 of FADS2 and is 1553 bp from exon 4 and 6006 bp from exon 5. Analysis of LD structures in the region suggests that rs174553 and rs174583 are linked (D' = 0.97) and are correlated (r2 = 0.94; P < 0.0001). Therefore, in the present report, we provide results that show the associations between the plasma, erythrocyte, and breast milk fatty acids for women grouped by the rs174553 allele, thus also reflecting common haplotypes in rs174583 and rs99780; the effects of the rarer haplotypes on (n-3) and (n-6) fatty acid status are beyond the scope of this study.


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  		TABLE 1 Characteristics of 6 SNP in the FADS1 FADS2 gene cluster

 
The women's intakes of LA, ALA, ARA, EPA and DHA were 13.1 ± 6.76 g/d, 1.86 ± 1.24 g/d, 83.3 ± 39.6 mg/d, 76.1 ± 65.6 mg/d, and 118 ± 122 mg/d, respectively (n = 69). The intakes of (n-6) and (n-3) fatty acids did not differ among the women grouped by polymorphism in rs174553 or rs174575 (data not shown). The plasma phospholipid levels of the major (n-6) and (n-3) fatty acids at 16 wk of gestation differed among the women grouped by the rs174553 allele (Table 2). Genotype influenced the plasma phospholipid levels of LA, ARA, 22:5(n-3), and 22:5(n-6) (P < 0.005) and tended to affect those of ALA (P = 0.056) and EPA (P = 0.079). For rs174575, the plasma phospholipid levels of LA did not differ among C/C (n = 33), C/G (n = 28), and G/G (n = 8) carriers and were 21.0 ± 2.94, 20.5 ± 3.29, and 22.6 ± 3.45 g/100 g fatty acids (P > 0.05), whereas concentrations of ARA were influenced by genotype with levels of 10.7 ± 1.70, 9.9 ± 1.58, and 8.5 ± 1.49 g/100 g fatty acids in the 3 groups, respectively (P = 0.003). Plasma phospholipid levels of the other (n-6) and (n-3) fatty acids did not differ among the pregnant women when grouped by rs174575 genotype (data not shown).


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  		TABLE 2 Major (n-6) and (n-3) fatty acids in plasma phospholipids of pregnant women classified by rs174553 genotype1

 
We calculated the ratio of the {Delta}6 and {Delta}5 desaturase products to their LA or ALA precursors in plasma phospholipids as indices of potential differences in desaturase activities among the women grouped as major allele carriers or minor homozygotes. However, we note that the ratios did not consider the possible effects of differences in the rate of utilization of the products. In the major allele carriers and minor allele homozygotes of rs174553 (rs99780 and rs174583), the (n-6) fatty acid product:LA ratios were 11.5 ± 1.4 (n = 49) and 8.8 ± 1.2 (n = 20) (P < 0.001) and for the (n-3) fatty acids, the desaturation product:ALA ratios were 20.4 ± 10.9 (n = 49) and 13.5 ± 5.8 (n = 20) (P = 0.007), respectively, at 16 wk of gestation. For the major allele carriers (n = 61) and minor allele homozygotes (n = 8) of rs174575, the (n-6) fatty acid desaturation product:precursor ratios were 11.0 ± 1.7 and 9.0 ± 1.5, respectively (P = 0.005), and for the (n-3) fatty acids, the desaturation product:ALA ratios were 19.0 ± 10.5 and 13.2 ± 5.1 (P = 0.119), respectively. The results thus indicate a robust association between the minor alleles of the 4 SNP we analyzed and lower levels of ARA and other long chain (n-6) fatty acids relative to the precursor, LA. Similar results were found for the (n-3) fatty acids, which were significant for rs174553, rs99780, and rs174583 but not for rs174575 (P = 0.119). Similar results were also found for the relationship between SNP and plasma phospholipid fatty acids at 36 wk and those at 16 wk of gestation, but based on our sample size, analyses for interactions between genotype and stage of gestation in influencing maternal fatty acid status were inappropriate.

The levels of the major (n-6) and (n-3) fatty acids in the erythrocyte EPG differed among the women classified by the rs174553 allele (with the same results for rs174583 and rs99780) at 16 wk of gestation (Table 3). We found a significant effect of genotype on the erythrocyte EPG levels of LA, 20:3(n-6), ARA, and 22:4(n-6), with LA being higher and its desaturation products being lower in minor allele carriers. The (n-3) fatty acids did not differ in the erythrocyte EPG of the women grouped by rs174553 allele. Calculation of the {Delta}6 and {Delta}5 desaturase products to their LA precursor ratio showed that the ratio was lower, suggesting less desaturation, for the erythrocyte EPG fatty acids of the minor allele homozygotes than major allele carriers of rs174553 (or rs99780 or rs174583) at both 16 wk (P < 0.001) and 36 wk (P = 0.001) of gestation, with a similar pattern for the (n-3) series of fatty acids at wk 16 (P = 0.086) and 36 (P = 0.046) (Table 4). For rs174575, the levels of individual (n-6) and (n-3) fatty acids did not differ in the erythrocyte EPG (data not shown) or in the ratio of 20 and 22 carbon chain (n-6) or (n-3) fatty acids to their LA or ALA precursor, respectively, between the major allele carriers and minor allele homozygotes at either 16 or 36 wk of gestation (Table 4).


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  		TABLE 3 Major (n-6) and (n-3) fatty acids in RBC EPG of pregnant women classified by rs174553 genotype1

 

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  		TABLE 4 Ratio of (n-6) and (n-3) fatty acid desaturation products to precursors in erythrocyte EPG of women classified by SNP genotype 1

 
The analysis of breast milk fatty acids provides new data to show that genetic variation in the FADS1 FADS2 gene cluster is important to the composition of fatty acids provided to breast-fed infants in mothers' milk (Tables 5 and 6). The medium chain fatty acid 14:0, which is the end product of the de novo fatty acid synthase complex in the mammary gland (21), 18:1(n-7), which is the {Delta}9 desaturation-elongation product of 16:0, and 20:2(n-6), which is the direct elongation product of LA [18:2(n-6)], (Fig. 1), as well as the levels of ARA, EPA, and 22:5(n-3) all differed due to the rs174553 allele (Table 5). The breast milk levels of 14:0 (P = 0.046) and 18:1(n-7) (P = 0.001) also differed among women grouped by the rs174553 allele. There was a pattern of lower levels of total medium chain fatty acids (10:0, 12:0, and 14:0) originating from de novo lipogenesis (P = 0.05) and higher total {Delta}9 desaturase products [16:1(n-7), 18:1(n-7) plus 18:1(n-9)] (P = 0.03), with lower {Delta}6 and {Delta}5 desaturase products in the minor allele carriers of the 3 SNP, rs174553, rs174583, and rs99780 compared with major allele carriers. The analyses for rs174575 had a similar pattern, although for this SNP, maternal allelic differences were associated with differences in the breast milk concentrations of ARA (P = 0.015), EPA (P = 0.01), 22:5(n-3) (P = 0.003), and DHA (P = 0.044), with the minor allele again associated with lower levels of the (n-6) and (n-3) long-chain fatty acids (Table 6).


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  		TABLE 5 Major fatty acids in breast milk from women classified by rs174553 genotype1

 

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  		TABLE 6 Major fatty acids in breast milk from women classified by rs174575 genotype1

 

   Discussion
TOP
 ABSTRACT
 Introduction
 Subjects and Methods
 Results
 Discussion
LITERATURE CITED
 
In the present study, among healthy women of a predominantly Caucasian background, common genetic variations in the genes encoding for the {Delta}6 and {Delta}5 desaturases are associated with differences in (n-6) and (n-3) fatty acids in plasma and erythrocyte membrane lipids in gestation and in breast milk during lactation. We provide results to show that ARA was the lowest, and its precursor LA was highest, in minor allele homozygotes of rs174553 (GG), rs99780 (TT), and rs174583 (TT) in both plasma phospholipids and erythrocyte EPG (Fig. 1). A similar pattern was found for the (n-3) fatty acids, with higher ALA and lower levels of its products in plasma phospholipids of women homozygous for the minor allele of these 3 SNP. We also show that genetic variations in the FADS1 FADS2 gene cluster are associated with differences in the saturated, monounsaturated, and (n-6) and (n-3) fatty acid composition of human milk, with the differences in (n-6) and (n-3) fatty acids similar to those in the maternal plasma phospholipids. As in the mothers' plasma phospholipids, the minor alleles of rs174553, rs99780, and rs174583 were associated with lower milk levels of the 20- and 22-carbon chain (n-6) and (n-3) fatty acid desaturation products. Furthermore, the levels of ARA, as well as the levels of all of the long-chain (n-3) fatty acids, EPA, 22:5(n-3), and DHA, were lower in breast milk of women homozygous for the minor allele of rs174575, also reflecting differences in the (n-6) and (n-3) FADS product:precursor ratios in the maternal plasma phospholipids, although not in the erythrocyte EPG.

Recently, Malerba et al. (32) reported SNP association analysis with serum phospholipid and erythrocyte total lipid fatty aids in Northern Italians and found significant associations between lower circulating ARA and minor allele variants in the region of rs174545 up to rs174570 and higher circulating ALA in the minor allele carriers of rs174545, rs3834458, and rs174583. Another study of European adults reported higher levels of LA and lower ARA, as well as higher ALA and lower EPA and 22:5(n-3), among carriers of minor variants of SNP in the FADS1 FADS2 gene cluster (31). Our results are similar, with lower plasma phospholipid and erythrocyte EPG ARA but higher LA in minor allele carriers of rs174553, rs99780, and rs174583 among pregnant women in Canada. Our work also extends the latter findings to show lower ratios of carbon chain 20 and 22 (n-6) and (n-3) fatty acids to LA and ALA, respectively, among the minor allele carriers of these SNP, as well as rs174575, suggesting less desaturation of dietary LA and ALA among the minor allele variants. Previous studies have shown a positive correlation between maternal and fetal (newborn) cord plasma phospholipid (n-6) and (n-3) fatty acids (24), and increasing the maternal intake and blood levels of DHA in gestation is known to increase maternal to fetal DHA transfer, which has also been associated with increased maturation of visual and neural systems (20,25,26,29). Higher ARA, on the other hand, is positively associated with fetal growth (22–24). Whether differences in maternal blood levels of (n-6) and (n-3) fatty acids due to genetic variations in fatty acids metabolism or diet-gene interactions contribute to differences in placental fatty acid transfer and have relevance to fetal growth and development may be worth consideration.

Human milk provides a complex array of fatty acids that contribute energy and the essential (n-6) and (n-3) fatty acids to support the growth and development of the breast-fed infant (21). To our knowledge, the effect of genetic variations in FADS on the quality of human milk fatty acids has not been reported previously, although both {Delta}6 and {Delta}5 desaturase are present in the lactating mammary gland (37). The role of medium-chain fatty acids in human milk and a biological explanation as to why the mammary fatty acid synthase complex truncates fatty acid synthesis at 14:0, rather than 16:0, as in the liver is not well understood (21). Early studies, however, suggested an important role for ketones derived from medium-chain fatty acid oxidation in sparing glucose and as a lipid precursor (38). In the latter context, we suggest that medium-chain fatty acid oxidation provides a source of malonyl CoA, which is important because lipogenesis is suppressed when a high-fat milk diet is fed yet is needed for cholesterol synthesis and fatty acid chain elongation. Our results provide novel findings for the rs174553, rs99780, and rs174583 loci to show that lower breast milk concentrations of 14:0 occur concomitantly with higher {Delta}9 desaturase products and LA and 20:2(n-6), suggesting that minor allele variants of these SNP have decreased endogenous fatty acid synthesis and lower {Delta}6 and {Delta}5 desaturase activities, with increased diversion of LA to 20:2(n-6) (Fig. 1). Whether this reflects differences in lipogenesis and desaturase activities in the mammary gland or differences in substrate flux from other organs, such as the liver, and any implications for milk total fat or metabolism in the breast-fed infant cannot be inferred from the present study, but seems worthy of more detailed study.

ARA is esterified to the sn-2 position of membrane phospholipids and is released to provide unesterified ARA for further metabolism to eicosanoids, which are important in many aspects of growth and development, including synaptic transmission and plasticity, development of the digestive tract epithelium, and immune and inflammatory responses (9,10,12–16,30). Our studies, consistent with previous studies in adults (31,32), confirm that minor allele variants of common SNP in FADS1 and FADS2 are associated with lower circulating lipid ARA, which in our study extended to similar effects in pregnant women and to the secretion of ARA in milk during lactation. Whether differences in maternal-to-infant transfer of ARA in breast milk due to genetic variation in maternal FADS are relevant to the young infant is not known. However, considerable attention has been given to the variability in DHA in human milk and the possibility that low milk levels of DHA may compromise early infant visual and neural system development (1,21,27,28,39–41). Observation and intervention studies suggest better visual and neural system development among infants receiving breast milk with >0.32 compared with 0.2 g DHA/100 g fatty acids or less (27,28,41). The present study provides new data to suggest that in addition to dietary DHA intake, genetically determined variations in FADS2 and FADS1 may influence the secretion of DHA in breast milk over a range that appears to have functional importance to the developing infant. In this regard, a recent study of large birth cohorts reported that children carrying the G/G allele in rs174575 had lower IQ scores than that those carrying the C allele (33).

In summary, we have provided new evidence that genetic variation in FADS1 and FADS2 influence maternal plasma and erythrocyte phospholipid levels of (n-6) and (n-3) fatty acids during pregnancy and levels of saturated, monounsaturated, and (n-6) and (n-3) fatty acids in breast milk during lactation. Our results suggest that genetic variation among women may influence maternal-to-infant transfer of fatty acids during pregnancy and in lactation will, via breast milk, influence fatty acid nutrition of the breast-fed infant. The extent to which maternal SNP in FADS1 and FADS2 interact with the maternal dietary fatty acid composition to contribute to maternal health and early infant growth and development need to be considered in addressing those fatty acid requirements that best support human growth and development.


   ACKNOWLEDGMENTS
 
We thank Russell W. Friesen and Janette D. King for dietary analysis and laboratory assistance, and Carmen Neufeld, Rosemary Esdaile, and Shalu Duggal for subject enrolment and collection of the dietary and sociodemographic data.


   FOOTNOTES
 
1 Supported by a grant from the Canadian Institutes of Health Research and a Freedom-to-Discover Award from the Bristol Myers Squibb Foundation. L Xie was supported by a scientist trainee grant from the China Scholarship Council. Back

2 Author disclosures: L Xie and S. Innis, no conflicts of interest. Back

5 Abbreviations used: ALA, {alpha}-linolenic acid; ARA, arachidonic acid; DHA, docosahexaenoic acid; EPG, ethanolamine phosphoglyceride; EPA, eicosapentaenoic acid; FADS, fatty acid desaturase; LA, linoleic acid; SNP, single nucleotide polymorphism. Back

Manuscript received 11 July 2008. Initial review completed 31 July 2008. Revision accepted 22 August 2008.


   LITERATURE CITED
TOP
 ABSTRACT
 Introduction
 Subjects and Methods
 Results
 Discussion
 LITERATURE CITED
 

1. Innis SM. Perinatal biochemistry and physiology of long-chain polyunsaturated fatty acids. J Pediatr. 2003;143:S1–8.[Medline]

2. Cho HP, Nakamura MT, Clarke SD. Cloning, expression, and nutritional regulation of the mammalian Delta-6 desaturase. J Biol Chem. 1999;274:471–7.[Abstract/Free Full Text]

3. Cho HP, Nakamura M, Clarke SD. Cloning, expression, and fatty acid regulation of the human delta-5 desaturase. J Biol Chem. 1999;274:37335–9.[Abstract/Free Full Text]

4. Nakamura MT, Nara TY. Structure, function, and dietary regulation of delta 6, delta 5, and delta 9 desaturases. Annu Rev Nutr. 2004;24:345–76.[Medline]

5. Marquardt A, Stohr H, White K, Weber BH. CDNA cloning, genomic structure and chromosomal localization of three members of the human fatty acid desaturase family. Genomics. 2000;66:175–83.[Medline]

6. Sprecher H, Luthria DL, Mohammed BS, Baykousheva SP. Reevaluation of the pathways for the biosynthesis of polyunsaturated fatty acids. J Lipid Res. 1995;36:2471–7.[Abstract]

7. Innis SM. Dietary (n-3) fatty acids and brain development. J Nutr. 2007;137:855–9.[Abstract/Free Full Text]

8. Jump DB, Botolin D, Wang Y, Xu J, Demeure O, Christian B. Docosahexaenoic acid (DHA) and hepatic gene transcription. Chem Phys Lipids. 2008;153:3–13.[Medline]

9. Chen C, Bazan NG. Lipid signaling: sleep, synaptic plasticity, and neuroprotection. Prostaglandins Other Lipid Mediat. 2005;77:65–76.[Medline]

10. Calder PC. N-3 polyunsaturated fatty acids, inflammation, and inflammatory diseases. Am J Clin Nutr. 2006;83:S1505–19.[Abstract/Free Full Text]

11. Innis SM. Essential fatty acids in growth and development. Prog Lipid Res. 1991;30:39–103.[Medline]

12. Cha YI, Solnica-Krezel L, DuBois RN. Fishing for prostanoids: deciphering the developmental functions of cyclooxygenase-derived prostaglandins. Dev Biol. 2006;289:263–72.[Medline]

13. Harizi H, Gualde N. The impact of eicosanoids on the crosstalk between innate and adaptive immunity: the key role of dendritic cells. Tissue Antigens. 2005;65:507–14.[Medline]

14. Leu BH, Schmidt JT. Arachidonic acid as a retrograde signal controlling growth and dynamics of retinotectal arbors. Dev Neurobiol. 2008;68:18–30.[Medline]

15. Khanapure SP, Garvey DS, Janero DR, Letts LG. Eicosanoids in inflammation: biosynthesis, pharmacology and therapeutic frontiers. Curr Top Med Chem. 2007;7:311–40.[Medline]

16. Peskar BM, Sawka N, Ehrlich K, Peskar BA. Role of cyclooxygenase-1 and -2, phospholipase C, and protein kinase C in prostaglandin-mediated gastroprotection. J Pharmacol Exp Ther. 2003;305:1233–8.[Abstract/Free Full Text]

17. Uauy R, Dangour AD. Nutrition in brain development and aging: role of essential fatty acids. Nutr Rev. 2006;64:S24–33.[Medline]

18. Grossfield A, Feller SE, Pitman MC. A role for direct interactions in the modulation of rhodopsin by omega-3 polyunsaturated lipids. Proc Natl Acad Sci USA. 2006;103:4888–93.[Abstract/Free Full Text]

19. Litman BJ, Niu SL, Polozova A, Mitchell DC. The role of docosahexaenoic acid containing phospholipids in modulating G protein-coupled signaling pathways, visual transduction. J Mol Neurosci. 2001;16:237–42.[Medline]

20. Innis SM. Essential fatty acid transfer and fetal development. Placenta. 2005;26:S70–5.[Medline]

21. Innis SM. Polyunsaturated fatty acids in human milk: an essential role in infant development. Adv Exp Med Biol. 2004;554:27–43.[Medline]

22. Koletzko B, Braun M. Arachidonic acid and early human growth: is there a relation? Ann Nutr Metab. 1991;35:128–31.[Medline]

23. Rump P, Mensink RP, Kester AD, Hornstra G. Essential fatty acid composition of plasma phospholipids and birth weight: a study in term neonates. Am J Clin Nutr. 2001;73:797–806.[Abstract/Free Full Text]

24. Elias SL, Innis SM. Infant plasma trans, n-6, and n-3 fatty acids and conjugated linoleic acids are related to maternal plasma fatty acids, length of gestation, and birth weight and length. Am J Clin Nutr. 2001;73:807–14.[Abstract/Free Full Text]

25. Helland IB, Saugstad OD, Smith L, Saarem K, Soluoll R, Ganes T, Drevon CA. Similar effects on infants of n-3 and n-6 fatty acids supplementation to pregnant and lactating women. Pediatrics. 2001;108:E82–92.[Medline]

26. Helland IB, Smith L, Saarem K, Saugstad OD, Drevon CA. Maternal supplementation with very-long-chain n-3 fatty acids during pregnancy and lactation augments children's IQ at 4 years of age. Pediatrics. 2003;111:e39–44.[Abstract/Free Full Text]

27. Jensen CL, Voigt RG, Prager TC, Zou YL, Fraley JK, Rozelle JC, Turcich MR, Llorente AM, Anderson RE, Heird WC. Effects of maternal docosahexaenoic acid intake on visual function and neurodevelopment in breastfed term infants. Am J Clin Nutr. 2005;82:125–32.[Abstract/Free Full Text]

28. Innis SM, Gilley J, Werker J. Are human milk long-chain polyunsaturated fatty acids related to visual and neural development in breast-fed term infants? J Pediatr. 2001;139:532–8.[Medline]

29. Innis SM, Friesen RW. Essential n-3 fatty acids in pregnant women and early visual acuity maturation in term infants. Am J Clin Nutr. 2008;87:548–57.[Abstract/Free Full Text]

30. Prescott SL, Dunstan JA. Prenatal fatty acid status and immune development: the pathways and the evidence. Lipids. 2007;42:801–10.[Medline]

31. Schaeffer L, Gohlke H, Muller M, Heid IM, Palmer LJ, et al. 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;15:1745–56.[Abstract/Free Full Text]

32. Malerba G, Schaeffer L, Xumerle L, Klopp N, Trabetti E, et al. SNPs of the FADS gene cluster are associated with polyunsaturated fatty acids in a cohort of patients with cardiovascular disease. Lipids. 2008;43:288–99.

33. Caspi A, Williams B, Kim-Cohen J, Craig IW, Milne BJ, et al. Moderation of breastfeeding effects on the IQ by genetic variation in fatty acid metabolism. Proc Natl Acad Sci USA. 2007;104:18860–5.[Abstract/Free Full Text]

34. Innis SM, Elias SL. Intakes of essential n-6 and n-3 polyunsaturated fatty acids among pregnant Canadian Women. Am J Clin Nutr. 2003;77:473–8.[Abstract/Free Full Text]

35. Innis SM, King DJ. Trans fatty acids in human milk are inversely associated with concentrations of essential all-cis n-6 and n-3, fatty acids, and determine trans, but not n-6 and n-3 fatty acids in plasma of breast-fed infants. Am J Clin Nutr. 1999;70:383–90.[Abstract/Free Full Text]

36. National Center for Biotechnology Information. Single nucleotide polymorphism [cited October 2007]. Available from: http://www.ncbi.nlm.nih.gov/SNP/.

37. Rodriguez-Cruz M, Tovar AR, Palacios-González B, Del Prado M, Torres N. Synthesis of long-chain polyunsaturated fatty acids in lactating mammary gland: role of Delta5 and Delta6 desaturases, SREBP-1, PPARalpha, and PGC-1. J Lipid Res. 2006;47:553–60.[Abstract/Free Full Text]

38. Williamson DH. Ketone body metabolism during development. Fed Proc. 1985;44:2342–6.[Medline]

39. Innis SM. Human milk and formula fatty acids. J Pediatr. 1992;120:S56–61.[Medline]

40. Brenna JT, Varamini B, Jensen RE, Diersen-Schade DA, Boettcher JA, Arterburn LM. Docosahexaenoic and arachidonic acid concentrations in human milk worldwide. Am J Clin Nutr. 2007;85:1457–64.[Abstract/Free Full Text]

41. Innis SM. Human milk: maternal dietary lipids and infant development. Proc Nutr Soc. 2007;66:397–404.[Medline]




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Long Chain PUFA Transport in Human Term Placenta
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