Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Lipids and cardiovascular health

Associations between fatty acids and low-grade inflammation in children from the LISAplus birth cohort study

Abstract

Background/Objectives:

Assessing fatty acid (FA) composition in relation to inflammatory markers can shed light on the role of different FA and their metabolism in low-grade inflammation. Existing exploratory studies in children are scarce, and findings inconsistent. We hence aim to analyse associations of FA with common inflammatory markers, high-sensitivity C-reactive protein (hs-CRP) and interleukin-6 (IL-6), in 10-year-old children.

Subjects/Methods:

Complete data were available for 958 participants from the 10-year follow-up of the LISAplus (Influence of Lifestyle-Related Factors on the Immune System and the Development of Allergies in Childhood plus the Influence of Traffic Emissions and Genetics) birth cohort study. FA composition was assessed in serum glycerophospholipids. Hs-CRP and IL-6 were categorised into three levels. Associations of FA with inflammatory markers were assessed using multinomial logistic regression, adjusting for potential confounders. Additionally, sex-stratified analyses were carried out.

Results:

FA exposures associated with significantly higher low-grade inflammation, as indicated by higher hs-CRP or IL-6 levels, included: palmitic acid (PA) (IL-6: P<0.001, 95% confidence interval: 1.30; 2.43), arachidonic acid (AA) (hs-CRP: P=0.002, 1.07; 1.31), n-6 highly unsaturated FA (HUFA) (hs-CRP: P=0.002, 1.06; 1.27), ratio of AA to linoleic acid (AA/LA) (hs-CRP: P<0.001, 1.16; 1.62) and total saturated FA (SFA) (IL-6: P<0.001, 1.77; 3.15). FA exposures associated with reduced levels of inflammatory markers included LA (hs-CRP: P=0.001, 0.84; 0.96; IL-6: P<0.001, 0.69; 0.90) and total polyunsaturated FA (PUFA) (IL-6: P<0.001, 0.57; 0.78).

Conclusions:

These findings suggest that higher SFA and minor n-6 HUFA, namely PA and AA, are associated with increased low-grade inflammation in children, whereas the major dietary n-6 PUFA and total PUFA are associated with reduced inflammation. Elevated desaturase activity, estimated by the ratio AA/LA, may be associated with higher inflammation, particularly in boys.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Get just this article for as long as you need it

$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2

References

  1. Libby P . Inflammation in atherosclerosis. Arterioscler Thromb Vasc Biol 2012; 32: 2045–2051.

    Article  CAS  Google Scholar 

  2. Libby P, Ridker PM . Inflammation and atherosclerosis: role of C-reactive protein in risk assessment. Am J Med 2004; 116: 9s–16s.

    Article  Google Scholar 

  3. Tilg H, Moschen AR . Adipocytokines: mediators linking adipose tissue, inflammation and immunity. Nat Rev Immunol 2006; 6: 772–783.

    Article  CAS  Google Scholar 

  4. Visser M, Bouter LM, McQuillan GM, Wener MH, Harris TB . Elevated C-reactive protein levels in overweight and obese adults. JAMA 1999; 282: 2131–2135.

    Article  CAS  Google Scholar 

  5. Pepys MB, Hirschfield GM . C-reactive protein: a critical update. J Clin Invest 2003; 111: 1805–1812.

    Article  CAS  Google Scholar 

  6. Jarvisalo MJ, Harmoinen A, Hakanen M, Paakkunainen U, Viikari J, Hartiala J et al. Elevated serum C-reactive protein levels and early arterial changes in healthy children. Arterioscler Thromb Vasc Biol 2002; 22: 1323–1328.

    Article  CAS  Google Scholar 

  7. Kapiotis S, Holzer G, Schaller G, Haumer M, Widhalm H, Weghuber D et al. A proinflammatory state is detectable in obese children and is accompanied by functional and morphological vascular changes. Arterioscler Thromb Vasc Biol 2006; 26: 2541–2546.

    Article  CAS  Google Scholar 

  8. Calder PC, Albers R, Antoine JM, Blum S, Bourdet-Sicard R, Ferns GA et al. Inflammatory disease processes and interactions with nutrition. Br J Nutr 2009; 101 (Suppl 1), S1–45.

    PubMed  Google Scholar 

  9. Calder PC . Polyunsaturated fatty acids and inflammatory processes: new twists in an old tale. Biochimie 2009; 91: 791–795.

    Article  CAS  Google Scholar 

  10. Calder PC . Omega-3 polyunsaturated fatty acids and inflammatory processes: nutrition or pharmacology? Br J Clin Pharmacol 2013; 75: 645–662.

    Article  CAS  Google Scholar 

  11. Fekete K, Marosvölgyi T, Jakobik V, Decsi T . Methods of assessment of n-3 long-chain polyunsaturated fatty acid status in humans: a systematic review. Am J Clin Nutr 2009; 89: 2070S–2084SS.

    Article  CAS  Google Scholar 

  12. Zeleniuch-Jacquotte A, Chajes V, Van Kappel AL, Riboli E, Toniolo P . Reliability of fatty acid composition in human serum phospholipids. Eur J Clin Nutr 2000; 54: 367–372.

    Article  CAS  Google Scholar 

  13. Nakamura MT, Nara TY . Structure, function, and dietary regulation of Δ6, Δ5, and Δ9 desaturases. Annu Rev Nutr 2004; 24: 345–376.

    Article  CAS  Google Scholar 

  14. Ferrucci L, Cherubini A, Bandinelli S, Bartali B, Corsi A, Lauretani F et al. Relationship of plasma polyunsaturated fatty acids to circulating inflammatory markers. J Clin Endocrinol Metab 2006; 91: 439–446.

    Article  CAS  Google Scholar 

  15. Steffen BT, Steffen LM, Tracy R, Siscovick D, Hanson NQ, Nettleton J et al. Obesity modifies the association between plasma phospholipid polyunsaturated fatty acids and markers of inflammation: the Multi-Ethnic Study of Atherosclerosis. Int J Obes (Lond) 2012; 36: 797–804.

    Article  CAS  Google Scholar 

  16. Kaikkonen JE, Kresanov P, Ahotupa M, Jula A, Mikkila V, Viikari JS et al. High serum n6 fatty acid proportion is associated with lowered LDL oxidation and inflammation: the Cardiovascular Risk in Young Finns Study. Free Radic Res 2014; 48: 420–426.

    Article  CAS  Google Scholar 

  17. Muka T, Kiefte-de Jong JC, Hofman A, Dehghan A, Rivadeneira F, Franco OH . Polyunsaturated fatty acids and serum C-reactive protein: the Rotterdam study. Am J Epidemiol 2015; 181: 846–856.

    Article  Google Scholar 

  18. Klein-Platat C, Drai J, Oujaa M, Schlienger JL, Simon C . Plasma fatty acid composition is associated with the metabolic syndrome and low-grade inflammation in overweight adolescents. Am J Clin Nutr 2005; 82: 1178–1184.

    Article  CAS  Google Scholar 

  19. González-Gil EM, Santabárbara J, Siani A, Ahrens W, Sioen I, Eiben G et al. Whole-blood fatty acids and inflammation in European children: the IDEFICS Study. Eur J Clin Nutr 2016; 70: 819–823.

    Article  Google Scholar 

  20. Heinrich J, Bolte G, Holscher B, Douwes J, Lehmann I, Fahlbusch B et al. Allergens and endotoxin on mothers' mattresses and total immunoglobulin E in cord blood of neonates. Eur Respir J 2002; 20: 617–623.

    Article  CAS  Google Scholar 

  21. Glaser C, Rzehak P, Demmelmair H, Klopp N, Heinrich J, Koletzko B et al. Influence of FADS polymorphisms on tracking of serum glycerophospholipid fatty acid concentrations and percentage composition in children. PLoS One 2011; 6: e21933.

    Article  CAS  Google Scholar 

  22. Glaser C, Demmelmair H, Sausenthaler S, Herbarth O, Heinrich J, Koletzko B . Fatty acid composition of serum glycerophospholipids in children. J Pediatr 2010; 157: 826–831. e1.

    Article  CAS  Google Scholar 

  23. Standl M, Thiering E, Demmelmair H, Koletzko B, Heinrich J . Age-dependent effects of cord blood long-chain PUFA composition on BMI during the first 10 years of life. Br J Nutr 2014; 111: 2024–2031.

    Article  CAS  Google Scholar 

  24. Glaser C, Demmelmair H, Koletzko B . High-throughput analysis of fatty acid composition of plasma glycerophospholipids. J Lipid Res 2010; 51: 216–221.

    Article  Google Scholar 

  25. Lands B . Consequences of essential fatty acids. Nutrients 2012; 4: 1338–1357.

    Article  CAS  Google Scholar 

  26. Simopoulos AP . The importance of the omega-6/omega-3 fatty acid ratio in cardiovascular disease and other chronic diseases. Exp Biol Med (Maywood) 2008; 233: 674–688.

    Article  CAS  Google Scholar 

  27. Marventano S, Kolacz P, Castellano S, Galvano F, Buscemi S, Mistretta A et al. A review of recent evidence in human studies of n-3 and n-6 PUFA intake on cardiovascular disease, cancer, and depressive disorders: does the ratio really matter? Int J Food Sci Nutr 2015; 66: 611–622.

    Article  Google Scholar 

  28. Harris WS, Mozaffarian D, Rimm E, Kris-Etherton P, Rudel LL, Appel LJ et al. Omega-6 fatty acids and risk for cardiovascular disease. A Science Advisory From the American Heart Association Nutrition Subcommittee of the Council on Nutrition, Physical Activity, and Metabolism; Council on Cardiovascular Nursing; and Council on Epidemiology and Prevention. Circulation 2009; 119: 902–907.

    Article  Google Scholar 

  29. Ohnishi H, Saito Y . Eicosapentaenoic acid (EPA) reduces cardiovascular events: relationship with the EPA/arachidonic acid ratio. J Atheroscler Thromb 2013; 20: 861–877.

    Article  Google Scholar 

  30. Cotogni P, Trombetta A, Muzio G, Maggiora M, Canuto RA . The omega-3 fatty acid docosahexaenoic acid modulates inflammatory mediator release in human alveolar cells exposed to bronchoalveolar lavage fluid of ARDS patients. Biomed Res Int 2015; 2015: 642520.

    Article  Google Scholar 

  31. Martinelli N, Girelli D, Malerba G, Guarini P, Illig T, Trabetti E et al. FADS genotypes and desaturase activity estimated by the ratio of arachidonic acid to linoleic acid are associated with inflammation and coronary artery disease. Am J Clin Nutr 2008; 88: 941–949.

    Article  CAS  Google Scholar 

  32. Vessby B, Gustafsson IB, Tengblad S, Boberg M, Andersson A . Desaturation and elongation of fatty acids and insulin action. Ann NY Acad Sci 2002; 967: 183–195.

    Article  CAS  Google Scholar 

  33. R Core Team. R: A Language and Environment for Statistical Computing. R Foundation for Statistical Computing. Vienna, Austria, 2016.

  34. Venables WN, Ripley BD . Modern Applied Statistics with S, 4th edn. Springer: New York, NY, USA, 2002.

    Book  Google Scholar 

  35. Shine B, de Beer FC, Pepys MB . Solid phase radioimmunoassays for human C-reactive protein. Clin Chim Acta 1981; 117: 13–23.

    Article  CAS  Google Scholar 

  36. Kleiner G, Marcuzzi A, Zanin V, Monasta L, Zauli G . Cytokine levels in the serum of healthy subjects. Mediat Inflamm 2013; 2013: 6.

  37. Vittinghoff E, McCulloch CE . Relaxing the rule of ten events per variable in logistic and Cox regression. Am J Epidemiol 2007; 165: 710–718.

    Article  Google Scholar 

  38. Peduzzi P, Concato J, Kemper E, Holford TR, Feinstein AR . A simulation study of the number of events per variable in logistic regression analysis. J Clin Epidemiol 1996; 49: 1373–1379.

    Article  CAS  Google Scholar 

  39. Black S, Kushner I, Samols D . C-reactive protein. J Biol Chem 2004; 279: 48487–48490.

    Article  CAS  Google Scholar 

  40. Castell JV, Gómez-Lechón MJ, David M, Andus T, Geiger T, Trullenque R et al. Interleukin-6 is the major regulator of acute phase protein synthesis in adult human hepatocytes. FEBS Lett 1989; 242: 237–239.

    Article  CAS  Google Scholar 

  41. Bode JG, Albrecht U, Häussinger D, Heinrich PC, Schaper F . Hepatic acute phase proteins—regulation by IL-6-and IL-1-type cytokines involving STAT3 and its crosstalk with NF-κB-dependent signaling. Eur J Cell Biol 2012; 91: 496–505.

    Article  CAS  Google Scholar 

  42. Ganter U, Arcone R, Toniatti C, Morrone G, Ciliberto G . Dual control of C-reactive protein gene expression by interleukin-1 and interleukin-6. EMBO J 1989; 8: 3773–3779.

    Article  CAS  Google Scholar 

  43. Ford ES . C-reactive protein concentration and cardiovascular disease risk factors in children: findings from the National Health and Nutrition Examination Survey 1999–2000. Circulation 2003; 108: 1053–1058.

    Article  CAS  Google Scholar 

  44. Decsi T, Kennedy K . Sex-specific differences in essential fatty acid metabolism. Am J Clin Nutr 2011; 94 (Suppl), 1914S–1919SS.

    Article  CAS  Google Scholar 

  45. Burdge GC, Wootton SA . Conversion of alpha-linolenic acid to eicosapentaenoic, docosapentaenoic and docosahexaenoic acids in young women. Br J Nutr 2002; 88: 411–420.

    Article  CAS  Google Scholar 

  46. James MJ, Gibson RA, Cleland LG . Dietary polyunsaturated fatty acids and inflammatory mediator production. Am J Clin Nutr 2000; 71 (Suppl), 343s–348s.

    Article  CAS  Google Scholar 

  47. King DE, Egan BM, Geesey ME . Relation of dietary fat and fiber to elevation of C-reactive protein. Am J Cardiol 2003; 92: 1335–1339.

    Article  CAS  Google Scholar 

  48. Weigert C, Brodbeck K, Staiger H, Kausch C, Machicao F, Haring HU et al. Palmitate, but not unsaturated fatty acids, induces the expression of interleukin-6 in human myotubes through proteasome-dependent activation of nuclear factor-kappaB. J Biol Chem 2004; 279: 23942–23952.

    Article  CAS  Google Scholar 

  49. Ajuwon KM, Spurlock ME . Palmitate activates the NF-κB transcription factor and induces IL-6 and TNFα expression in 3T3-L1 adipocytes. J Nutr 2005; 135: 1841–1846.

    Article  CAS  Google Scholar 

  50. Enzenbach C, Kroger J, Zietemann V, Jansen EH, Fritsche A, Doring F et al. Erythrocyte membrane phospholipid polyunsaturated fatty acids are related to plasma C-reactive protein and adiponectin in middle-aged German women and men. Eur J Nutr 2011; 50: 625–636.

    Article  CAS  Google Scholar 

  51. De Caterina R, Liao JK, Libby P . Fatty acid modulation of endothelial activation. Am J Clin Nutr 2000; 71 (Suppl), 213s–223ss.

    Article  CAS  Google Scholar 

  52. Lands B . Historical perspectives on the impact of n-3 and n-6 nutrients on health. Prog Lipid Res 2014; 55: 17–29.

    Article  CAS  Google Scholar 

  53. Johnson GH, Fritsche K . Effect of dietary linoleic acid on markers of inflammation in healthy persons: a systematic review of randomized controlled trials. J Acad Nutr Diet 2012; 112: 1029–1041, 41.e1–41.e15.

    Article  CAS  Google Scholar 

  54. Mohrhauer H, Holman RT . The effect of dose level of essential fatty acids upon fatty acid composition of the rat liver. J Lipid Res 1963; 4: 151–159.

    CAS  PubMed  Google Scholar 

  55. Rett BS, Whelan J . Increasing dietary linoleic acid does not increase tissue arachidonic acid content in adults consuming Western-type diets: a systematic review. Nutr Metab (Lond) 2011; 8: 36.

    Article  CAS  Google Scholar 

  56. Bjermo H, Iggman D, Kullberg J, Dahlman I, Johansson L, Persson L et al. Effects of n-6 PUFAs compared with SFAs on liver fat, lipoproteins, and inflammation in abdominal obesity: a randomized controlled trial. Am J Clin Nutr 2012; 95: 1003–1012.

    Article  CAS  Google Scholar 

  57. Liou YA, King DJ, Zibrik D, Innis SM . Decreasing linoleic acid with constant alpha-linolenic acid in dietary fats increases (n-3) eicosapentaenoic acid in plasma phospholipids in healthy men. J Nutr 2007; 137: 945–952.

    Article  CAS  Google Scholar 

  58. Brenna JT . Efficiency of conversion of alpha-linolenic acid to long chain n-3 fatty acids in man. Curr Opin Clin Nutr Metab Care 2002; 5: 127–132.

    Article  CAS  Google Scholar 

  59. FAOFats and fatty acids in human nutrition. Report of an expert consultation. FAO food and nutrition paper no. 19, 2010, pp 1–166.

  60. Riboli E, Ronnholm H, Saracci R . Biological markers of diet. Cancer Surv 1987; 6: 685–718.

    CAS  PubMed  Google Scholar 

  61. Rise P, Eligini S, Ghezzi S, Colli S, Galli C . Fatty acid composition of plasma, blood cells and whole blood: relevance for the assessment of the fatty acid status in humans. Prostaglandins Leukot Essent Fatty Acids 2007; 76: 363–369.

    Article  CAS  Google Scholar 

  62. Sergeant S, Ruczinski I, Ivester P, Lee TC, Morgan TM, Nicklas BJ et al. Impact of methods used to express levels of circulating fatty acids on the degree and direction of associations with blood lipids in humans. Br J Nutr 2016; 115: 251–261.

    Article  CAS  Google Scholar 

  63. Schaeffer L, Gohlke H, Muller M, Heid IM, Palmer LJ, Kompauer I 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: 1745–1756.

    Article  CAS  Google Scholar 

  64. Steffen LM, Vessby B, Jacobs DR Jr, Steinberger J, Moran A, Hong CP et al. Serum phospholipid and cholesteryl ester fatty acids and estimated desaturase activities are related to overweight and cardiovascular risk factors in adolescents. Int J Obes (Lond) 2008; 32: 1297–1304.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank all the families for their participation in the LISAplus studies. Furthermore, we thank all members of the LISAplus study groups for their excellent work.The LISAplus study was mainly supported by grants from the Federal Ministry for Education, Science, Research and Technology and in addition from Helmholtz Zentrum Munich (former GSF), Helmholtz Centre for Environmental Research—UFZ, Leipzig, Research Institute at Marien-Hospital Wesel, Paediatric Practice, Bad Honnef for the first 2 years. The 4-, 6- and 10-year follow-up examinations of the LISAplus study were covered from the respective budgets of the involved partners (Helmholtz Zentrum Munich (former GSF), Helmholtz Centre for Environmental Research—UFZ, Leipzig, Research Institute at Marien-Hospital Wesel, Paediatric Practice, Bad Honnef, IUF—Leibniz-Research Institute for Environmental Medicine at the University of Düsseldorf) and in addition by a grant from the Federal Ministry for Environment (IUF Düsseldorf, FKZ 20462296). The work of BK is financially supported in part by the European Research Council Advanced Grant META-GROWTH (ERC-2012-AdG—no.322605).

Author contributions

CH, JH and MS were involved in the conception and design of the study; BK, HD, IL, AvB and JH in the data acquisition; CH, MS and CF in the statistical analyses; CH, MS, HD and JH in the interpretation; CH drafted the manuscript; all authors revised it critically for important intellectual content, and approved the final version to be published.

Author information

Authors and Affiliations

Authors

Consortia

Corresponding author

Correspondence to M Standl.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies this paper on European Journal of Clinical Nutrition website

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Harris, C., Demmelmair, H., von Berg, A. et al. Associations between fatty acids and low-grade inflammation in children from the LISAplus birth cohort study. Eur J Clin Nutr 71, 1303–1311 (2017). https://doi.org/10.1038/ejcn.2017.73

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ejcn.2017.73

This article is cited by

Search

Quick links