The associations of serum n-6 polyunsaturated fatty acids with serum C-reactive protein in men: the Kuopio Ischaemic Heart Disease Risk Factor Study

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There are concerns that high intake of n-6 polyunsaturated fatty acids (PUFA) may promote inflammation, because the end-product of n-6 PUFA metabolism, arachidonic acid, is a precursor for pro-inflammatory eicosanoids. Our aim was to investigate cross-sectional associations of the serum n-6 PUFAs, objective biomarkers for exposure, with serum high-sensitivity C-reactive protein (CRP), a key inflammation marker.


The study included 1287 generally healthy men aged 42–60 years from the population-based Kuopio Ischaemic Heart Disease Risk Factor Study, examined in 1984–1989. ANCOVA and logistic regression were used for analyses.


In the multivariable-adjusted analyses, both serum total n-6 PUFA and linoleic acid, the predominant n-6 PUFA, were associated with lower CRP. The mean CRP concentrations in quartiles of linoleic acid were 1.86, 1.51, 1.53, and 1.37 mg/L (P-trend = 0.001). The odds ratio for elevated CRP (>3 mg/L) in the highest vs. the lowest quartile was 0.47 (95% confidence interval (CI) 0.25–0.87, P-trend = 0.01). Arachidonic acid or the mainly endogenously produced n-6 PUFAs, gamma-linolenic acid and dihomo-gamma-linolenic acid, were not associated with higher CRP, either. Age, body mass index, or serum long-chain n-3 PUFA concentration did not modify the associations (P-interactions > 0.14).


Serum n-6 PUFAs were not associated with increased inflammation in men. In contrast, the main n-6 PUFA linoleic acid had a strong inverse association with the key inflammation marker, CRP.

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  1. 1.

    Dandona P, Aljada A, Bandyopadhyay A. Inflammation: the link between insulin resistance, obesity and diabetes. Trends Immunol. 2004;25:4–7.

  2. 2.

    Perry VH, Cunningham C, Holmes C. Systemic infections and inflammation affect chronic neurodegeneration. Nat Rev Immunol. 2007;7:161–7.

  3. 3.

    Grivennikov SI, Greten FR, Karin M. Immunity, inflammation, and cancer. Cell. 2010;140:883–99.

  4. 4.

    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;233:674–88.

  5. 5.

    Calder PC. Polyunsaturated fatty acids and inflammation. Prostaglandins Leukot Essent Fatty Acids. 2006;75:197–202.

  6. 6.

    Harris WS, Shearer GC. Omega-6 fatty acids and cardiovascular disease: friend, not foe? Circulation. 2014;130:1562–4.

  7. 7.

    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;112:1029–41, 1041.e1-15.

  8. 8.

    Pischon T, Hankinson SE, Hotamisligil GS, Rifai N, Willett WC, Rimm EB. Habitual dietary intake of n-3 and n-6 fatty acids in relation to inflammatory markers among US men and women. Circulation. 2003;108:155–60.

  9. 9.

    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;91:439–46.

  10. 10.

    Yoneyama S, Miura K, Sasaki S, Yoshita K, Morikawa Y, Ishizaki M, et al. Dietary intake of fatty acids and serum C-reactive protein in Japanese. J Epidemiol. 2007;17:86–92.

  11. 11.

    Petersson H, Basu S, Cederholm T, Riserus U. Serum fatty acid composition and indices of stearoyl-CoA desaturase activity are associated with systemic inflammation: longitudinal analyses in middle-aged men. Br J Nutr. 2008;99:1186–9.

  12. 12.

    Tomiyama H, Matsumoto C, Odaira M, Yamada J, Yoshida M, Shiina K, et al. Relationships among the serum omega fatty acid levels, serum C-reactive protein levels and arterial stiffness/wave reflection in Japanese men. Atherosclerosis. 2011;217:433–6.

  13. 13.

    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;50:625–36.

  14. 14.

    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.

  15. 15.

    Julia C, Touvier M, Meunier N, Papet I, Galan P, Hercberg S, et al. Intakes of PUFAs were inversely associated with plasma C-reactive protein 12 years later in a middle-aged population with vitamin E intake as an effect modifier. J Nutr. 2013;143:1760–6.

  16. 16.

    de Oliveira Otto MC, Wu JH, Baylin A, Vaidya D, Rich SS, Tsai MY, et al. Circulating and dietary omega-3 and omega-6 polyunsaturated fatty acids and incidence of CVD in the Multi-Ethnic Study of Atherosclerosis. J Am Heart Assoc. 2013;2:e000506.

  17. 17.

    Takkunen MJ, de Mello VD, Schwab US, Agren JJ, Kuusisto J, Uusitupa MI. Associations of erythrocyte membrane fatty acids with the concentrations of C-reactive protein, interleukin 1 receptor antagonist and adiponectin in 1373 men. Prostaglandins Leukot Essent Fatty Acids. 2014;91:169–74.

  18. 18.

    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;48:420–6.

  19. 19.

    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;181:846–56.

  20. 20.

    Kubota Y, Higashiyama A, Imano H, Sugiyama D, Kawamura K, Kadota A, et al. Serum polyunsaturated fatty acid composition and serum high-sensitivity C-reactive protein levels in healthy Japanese residents: the KOBE Study. J Nutr Health Aging. 2015;19:719–28.

  21. 21.

    Ebbesson SO, Voruganti VS, Higgins PB, Fabsitz RR, Ebbesson LO, Laston S, et al. Fatty acids linked to cardiovascular mortality are associated with risk factors. Int J Circumpolar Health. 2015;74:28055.

  22. 22.

    El-Saed A, Masaki K, Okamura T, Evans RW, Nakamura Y, Willcox BJ, et al. The associations of C-reactive protein with serum levels of polyunsaturated fatty acids and trans fatty acids among middle-aged men from three populations. J Nutr Health Aging. 2016;20:16–21.

  23. 23.

    Salonen JT. Is there a continuing need for longitudinal epidemiologic research? The Kuopio Ischaemic Heart disease risk factor study. Ann Clin Res. 1988;20:46–50.

  24. 24.

    Reinders I, Virtanen JK, Brouwer IA, Tuomainen TP. Association of serum n-3 polyunsaturated fatty acids with C-reactive protein in men. Eur J Clin Nutr. 2012;66:736–41.

  25. 25.

    Salonen JT, Nyyssonen K, Korpela H, Tuomilehto J, Seppanen R, Salonen R. High stored iron levels are associated with excess risk of myocardial infarction in eastern Finnish men. Circulation. 1992;86:803–11.

  26. 26.

    Lakka TA, Venäläinen JM, Rauramaa R, Salonen R, Tuomilehto J, Salonen JT. Relation of leisure-time physical activity and cardiorespiratory fitness to the risk of acute myocardial infarction. N Engl J Med. 1994;330:1549–54.

  27. 27.

    Voutilainen S, Rissanen TH, Virtanen J, Lakka TA, Salonen JT. Low dietary folate intake is associated with an excess incidence of acute coronary events: the Kuopio Ischemic Heart Disease Risk Factor Study. Circulation. 2001;103:2674–80.

  28. 28.

    Levy JC, Matthews DR, Hermans MP. Correct homeostasis model assessment (HOMA) evaluation uses the computer program. Diabetes Care. 1998;21:2191–2.

  29. 29.

    Laaksonen DE, Lakka TA, Lakka HM, Nyyssonen K, Rissanen T, Niskanen LK, et al. Serum fatty acid composition predicts development of impaired fasting glycaemia and diabetes in middle-aged men. Diabet Med. 2002;19:456–64.

  30. 30.

    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;8:36–7075-8-36.

  31. 31.

    Kelley DS, Taylor PC, Nelson GJ, Mackey BE. Arachidonic acid supplementation enhances synthesis of eicosanoids without suppressing immune functions in young healthy men. Lipids. 1998;33:125–30.

  32. 32.

    Thies F, Miles EA, Nebe-von-Caron G, Powell JR, Hurst TL, Newsholme EA, et al. Influence of dietary supplementation with long-chain n-3 or n-6 polyunsaturated fatty acids on blood inflammatory cell populations and functions and on plasma soluble adhesion molecules in healthy adults. Lipids. 2001;36:1183–93.

  33. 33.

    Vachier I, Chanez P, Bonnans C, Godard P, Bousquet J, Chavis C. Endogenous anti-inflammatory mediators from arachidonate in human neutrophils. Biochem Biophys Res Commun. 2002;290:219–24.

  34. 34.

    Inceoglu B, Zolkowska D, Yoo HJ, Wagner KM, Yang J, Hackett E, et al. Epoxy fatty acids and inhibition of the soluble epoxide hydrolase selectively modulate GABA mediated neurotransmission to delay onset of seizures. PLoS ONE. 2013;8:e80922.

  35. 35.

    Fritsche KL. The science of fatty acids and inflammation. Adv Nutr. 2015;6:293S–301S.

  36. 36.

    Sergeant S, Rahbar E, Chilton FH. Gamma-linolenic acid, dihommo-gamma linolenic, eicosanoids and inflammatory processes. Eur J Pharmacol. 2016;785:77–86.

  37. 37.

    Hodson L, Skeaff CM, Fielding BA. Fatty acid composition of adipose tissue and blood in humans and its use as a biomarker of dietary intake. Prog Lipid Res. 2008;47:348–80.

  38. 38.

    Hodson L, Eyles HC, McLachlan KJ, Bell ML, Green TJ, Skeaff CM. Plasma and erythrocyte fatty acids reflect intakes of saturated and n-6 PUFA within a similar time frame. J Nutr. 2014;144:33–41.

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  1. University of Eastern Finland, Institute of Public Health and Clinical Nutrition, P.O. Box 1627, 70211, Kuopio, Finland

    • Jyrki K. Virtanen
    • , Jaakko Mursu
    • , Sari Voutilainen
    •  & Tomi-Pekka Tuomainen


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The authors declare that they have no competing interests.

Corresponding author

Correspondence to Jyrki K. Virtanen.