Biomarkers of Dietary Omega-6 Fatty Acids and Incident Cardiovascular Disease and Mortality: An Individual-Level Pooled Analysis of 30 Cohort Studies

Matti Marklund*, Jason H.Y. Wu, Fumiaki Imamura, Liana C. Del Gobbo, Amanda Fretts, Janette De Goede, Peilin Shi, Nathan Tintle, Maria Wennberg, Stella Aslibekyan, Tzu An Chen, Marcia C. De Oliveira Otto, Yoichiro Hirakawa, Helle Højmark Eriksen, Janine Kröger, Federica Laguzzi, Maria Lankinen, Rachel A. Murphy, Kiesha Prem, Cécilia SamieriJyrki Virtanen, Alexis C. Wood, Kerry Wong, Wei Sin Yang, Xia Zhou, Ana Baylin, Jolanda M.A. Boer, Ingeborg A. Brouwer, Hannia Campos, Paulo H.M. Chaves, Kuo Liong Chien, Ulf De Faire, Luc Djoussé, Gudny Eiriksdottir, Naglaa El-Abbadi, Nita G. Forouhi, J. Michael Gaziano, Johanna M. Geleijnse, Bruna Gigante, Graham Giles, Eliseo Guallar, Vilmundur Gudnason, Tamara Harris, William S. Harris, Catherine Helmer, Mai Lis Hellenius, Allison Hodge, Frank B. Hu, Paul F. Jacques, Jan Håkan Jansson, Anya Kalsbeek, Kay Tee Khaw, Woon Puay Koh, Markku Laakso, Karin Leander, Hung Ju Lin, Lars Lind, Robert Luben, Juhua Luo, Barbara Mcknight, Jaakko Mursu, Toshiharu Ninomiya, Kim Overvad, Bruce M. Psaty, Eric Rimm, Matthias B. Schulze, David Siscovick, Michael Skjelbo Nielsen, Albert V. Smith, Brian T. Steffen, Lyn Steffen, Qi Sun, Johan Sundström, Michael Y. Tsai, Hugh Tunstall-Pedoe, Matti I.J. Uusitupa, Rob M. Van Dam, Jenna Veenstra, W. M. Monique Verschuren, Nick Wareham, Walter Willett, Mark Woodward, Jian Min Yuan, Renata Micha, Rozenn N. Lemaitre, Dariush Mozaffarian, Ulf Risérus

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

87 Citations (Scopus)


Background: Global dietary recommendations for and cardiovascular effects of linoleic acid, the major dietary omega-6 fatty acid, and its major metabolite, arachidonic acid, remain controversial. To address this uncertainty and inform international recommendations, we evaluated how in vivo circulating and tissue levels of linoleic acid (LA) and arachidonic acid (AA) relate to incident cardiovascular disease (CVD) across multiple international studies. Methods: We performed harmonized, de novo, individual-level analyses in a global consortium of 30 prospective observational studies from 13 countries. Multivariable-adjusted associations of circulating and adipose tissue LA and AA biomarkers with incident total CVD and subtypes (coronary heart disease, ischemic stroke, cardiovascular mortality) were investigated according to a prespecified analytic plan. Levels of LA and AA, measured as the percentage of total fatty acids, were evaluated linearly according to their interquintile range (ie, the range between the midpoint of the first and fifth quintiles), and categorically by quintiles. Study-specific results were pooled using inverse-variance-weighted meta-analysis. Heterogeneity was explored by age, sex, race, diabetes mellitus, statin use, aspirin use, omega-3 levels, and fatty acid desaturase 1 genotype (when available). Results: In 30 prospective studies with medians of follow-up ranging 2.5 to 31.9 years, 15 198 incident cardiovascular events occurred among 68 659 participants. Higher levels of LA were significantly associated with lower risks of total CVD, cardiovascular mortality, and ischemic stroke, with hazard ratios per interquintile range of 0.93 (95% CI, 0.88-0.99), 0.78 (0.70-0.85), and 0.88 (0.79-0.98), respectively, and nonsignificantly with lower coronary heart disease risk (0.94; 0.88-1.00). Relationships were similar for LA evaluated across quintiles. AA levels were not associated with higher risk of cardiovascular outcomes; in a comparison of extreme quintiles, higher levels were associated with lower risk of total CVD (0.92; 0.86-0.99). No consistent heterogeneity by population subgroups was identified in the observed relationships. Conclusions: In pooled global analyses, higher in vivo circulating and tissue levels of LA and possibly AA were associated with lower risk of major cardiovascular events. These results support a favorable role for LA in CVD prevention.

Original languageEnglish
Pages (from-to)2422-2436
Number of pages15
Issue number21
Publication statusPublished - 21 May 2019

Bibliographical note

Publisher Copyright:
© 2019 American Heart Association, Inc.

Other keywords

  • arachidonic acid
  • biomarkers
  • cardiovascular diseases
  • diet
  • epidemiology
  • linoleic acid
  • primary prevention


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