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New Study: The Effect of Infant Formula Supplemented with ARA and DHA on Fatty Acid Levels of Infants with Different FADS Genotypes

NUTRI-FACTS Editors

May 1, 2019

Breast milk is the nutritional gold standard for feeding a term infant and is used as a reference for the formulation of breast milk substitutes. Infant nutrition products are designed to mimic, as closely as possible, the composition and functionality of breast milk. Arachidonic acid (ARA) and docosahexaenoic acid (DHA) are always found in breast milk. These fatty acids have important roles in brain and eye development and function, as well as immune function during early life (2-4).  

Fatty Acid Desaturase Genes (FADS) 

Although DHA and ARA can be synthesized endogenously from the essential fatty acids alpha-linolenic acid (ALA) and linoleic acid (LA) respectively, a preformed source of DHA and ARA is necessary to achieve a status more closely resembling that of a breast fed infant, as endogenous synthesis is limited and influenced by genetic background (5,6).  Fatty acid desaturase genes FADS 1 and FADS 2 encode D5 and D6 desaturase enzymes, which along with elongase enzymes, result in the conversion of ALA and LA to DHA and ARA respectively. The D5 and D6 desaturase enzymes are thus considered to be a rate limiting step in the conversion process (7). 

The impact of FADS polymorphisms on DHA and ARA

Single nucleotide polymorphisms (SNPs) in the FADS genes have previously been shown to reduce DHA and ARA synthesis by reducing the activity of the D5 and D6 desaturase enzymes (8-10). Minor FADS polymorphism alleles exhibit lower desaturase activity than major FADS alleles (an allele is an alternative form of a gene). ARA is most affected with up to 28 percent of the variation in ARA blood levels attributed to FADS polymorphisms (11). Reduced synthesis of DHA and ARA associated with such genetic variants are reported in approximately 30 percent of the EU population and may be even higher in Asia and Mexico (11-13). What’s more, several studies have described the effects of FADS polymorphisms on fatty acid status and their associations with the development of intelligence, immune function and the risk of allergies during childhood (14).

COGNIS Study 

The COGNIS study investigated neurocognitive and immunological effects of a new formula for healthy infants. Additionally, in a subset of these infants, the researchers looked specifically at the effect of diet and FADS polymorphisms on the long-chain polyunsaturated fatty acid (LCPUFA) levels of formula fed and breastfed infants (1). There were 176 Spanish infants in this assessment, less than 6-months of age. The infants were randomly allocated to one of two infant formula groups. The standard infant formula (SF) did not contain DHA and ARA (n=61), and the new infant formula (EF) contained 11.2 mg DHA per 100 ml of formula (16mg DHA /100 kcal) and 15.8 mg ARA per 100 ml of formula (23mg ARA/100 kcal) (n=70)* (15). Both formulas followed the guidelines of the Committee on Nutrition of the European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN), and the international and national recommendations for the composition of infant formulas. Breastfed infants (n=45) served as a reference group. Fatty acid levels and FADS polymorphisms were analyzed from cheek cells collected at 3-months of age. 

Statistically different cellular levels of DHA and ARA were reported in some of the feeding groups when classifying infants by FADS polymorphism alleles.  In breastfed infants, the DHA and ARA levels did not differ between carriers of the FADS major and minor alleles. The authors believe the higher DHA and ARA concentrations present in breast milk may have overcome the FADS polymorphisms-related reductions in D5 and D6 desaturase enzyme activity. Indeed, this also may have been the case in a study by Miklavcic et al, who randomized infants to receive a formula with 17 mg/100 kcal DHA, and 0, 25, or 34 mg/100 kcal ARA (34 mg/100 kcal being substantially higher than in the COGNIS study), (16).  In FADS minor allele carriers, plasma ARA was higher than the 0 ARA group only at the highest level of ARA supplementation.

In contrast, Salas-Lorenzo et al reported that FADS minor allele carriers in the new infant formula group (EF) had an ARA level significantly lower than the breastfed group.  In other words, while the minor FADS alleles did not impact ARA status in breastfed infants, the presence of these alleles decreased ARA status in babies receiving the supplemented formula. Strikingly, their ARA level was not different from that of the infants in the standard formula group, whose formula was not supplemented with DHA and ARA. Cellular DHA levels of minor allele carriers in the EF group were also lower than in the breastfed group but were higher than in the standard formula group.  

FADS major allele carriers in the EF group did not exhibit a decrease in desaturase activity, and levels of DHA and ARA in these infants were not statistically different from those of the breastfed group; however, they were significantly higher than those of the SF group.   

Regardless of the genotype, DHA and ARA levels in this study showed a gradient of SF< EF< BF. Nevertheless, the authors concluded these results identify a group of infants, the FADS minor allele carriers, who may be vulnerable to a lower DHA and ARA status and thus might require higher levels of DHA and ARA supplementation to achieve a status more closely resembling those of the breast fed infant. 

*The Commission Delegated Regulation (EU) 2016/127 of 25 September 2015 regarding infant formula and follow-on formula, now mandates the addition of 20 – 50 mg DHA/100 kcal, with the addition of ARA being optional. This EU regulation becomes mandatory as of February 2020. 

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References

  1. Salas- Lorenzo I, Tonato AMC, de la Garza Puentes A, Nieto A. Herrmann F, Dieguez E, Castellote AI, Lopez-Sabater MC, Rodriguez-Palmero M, Campoy C. (2019). The Effect of an Infant Formula Supplemented with AA and DHA on Fatty Acid Levels of Infants with Different FADS Genotypes: The COGNIS Study.yNutrients. Mar 12 11(3).
  2. Richard C, Lewis ED, Field CJ. (2016) Evidence for the essentiality of arachidonic and docosahexaenoic acid in the postnatal maternal and infant diet for the development of the infant's immune system early in life. Appl Physiol Nutr Metab, 41(5):461-75.
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  5. Pawlosky RJ. (2007) n-6 fatty acid metabolism in the newborn infant: is linoleic acid sufficient to meet the demand for arachidonic acid? Oilseeds Fats, Crops Lipids. 14:159–163.
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  7. Janssen CI, Kiliaan A.J (2014) Long-chain polyunsaturated fatty acids (LCPUFA) from genesis to senescence: The influence of LCPUFA on neural development, aging, and neurodegeneration. Prog. Lipid Res. 53,1–17.
  8. Barman M, Nilsson S, Torinsson Naluai Å, Sandin A, Wold AE & Sandberg A-S. (2015) Single nucleotide polymorphisms in the FADS gene cluster but not the ELOVL2 gene are associated with serum polyunsaturated fatty acid composition and development of allergy (in a Swedish birth cohort). Nutrients, 7: 10100–10115.
  9. Ding Z, Liu GL, Li X, Chen XY, Wu YX, Cui CC, Zhang X, Yang G, Xie, L. (2016) Association of polyunsaturated fatty acids in breast milk with fatty acid desaturase gene polymorphisms among Chinese lactating mothers. Prostaglandins Leukot. Essent. Fat. Acids 109, 66–71.
  10. Zietemann V, Kröger J, Enzenbach C, Jansen E, Fritsche A, Weikert C, Boeing H, Schulze MB. (2010) Genetic variation of the FADS1 FADS2 gene cluster and n-6 PUFA composition in erythrocyte membranes in the European Prospective Investigation into Cancer and Nutrition-Potsdam study. Br. J. Nutr. 104,748–1759.
  11. Schaeffer L, Gohlke H, Müller M, Heid IM, Palmer LJ, Kompauer I, Demmelmair H, Illig T, Koletzko B, Heinrich J (2006) Common genetic variants of the FADS1 FADS2 gene cluster and their reconstructed haplotypes are associated with the fatty acid composition in phospholipids. Human Molecular Genetics, 15: 1745–1756.
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