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

Research output: Contribution to journalArticlepeer-review

190 Scopus citations


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 (US)
Pages (from-to)2422-2436
Number of pages15
Issue number21
StatePublished - May 21 2019

Bibliographical note

Funding Information:
Drs Wu and Micha report research support from Unilever for this work. Dr Mo-zaffarian reports research funding from the National Institutes of Health and the Gates Foundation; personal fees from Global Organization for EPA and DHA Omega-3, DSM, Nutrition Impact, Pollock Communications, Bunge, Indigo Agriculture, Amarin, Acasti Pharma, and America’s Test Kitchen; scientific advisory board, Elysium Health (with stock options), Omada Health, and DayTwo; and chapter royalties from UpToDate; all outside the submitted work. Dr Psaty serves on the Data and Safety Monitoring Board of a clinical trial funded by the manufacturer (Zoll LifeCor) and on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. The other authors report no conflicts.

Funding Information:
Funding for the Fatty acids & Outcomes Research Consortium (FORCE): Cohortspecific funding is outlined in Table II in the online-only Data Supplement. Unilever provided Tufts University with a restricted grant ('Epidemiological research on circulating polyunsaturated fatty acids in relation to cardiometabolic health within the CHARGE-consortium') to partly support this analysis. Unilever had no role in study design, study conduct, data analysis, manuscript preparation, or decision to submit. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Publisher Copyright:
© 2019 American Heart Association, Inc.


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


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