Biomarkers of Dietary Omega-6 Fatty Acids and Incident Cardiovascular Disease and Mortality
Authors: Marklund Matti , Wu Jason H.Y. , Imamura Fumiaki , Del Gobbo Liana C. , Fretts Amanda , de Goede Janette , Shi Peilin , Tintle Nathan , Wennberg Maria , Aslibekyan Stella , Chen Tzu-An , de Oliveira Otto Marcia C. , Hirakawa Yoichiro , Eriksen Helle Højmark , Kröger Janine , Laguzzi Federica , Lankinen Maria , Murphy Rachel A. , Prem Kiesha , Samieri Cécilia , Virtanen Jyrki , Wood Alexis C. , Wong Kerry , Yang Wei-Sin , Zhou Xia , Baylin Ana , Boer Jolanda M.A. , Brouwer Ingeborg A. , Campos Hannia , Chaves Paulo H. M. , Chien Kuo-Liong , de Faire Ulf , Djoussé Luc , Eiriksdottir Gudny , El-Abbadi Naglaa , Forouhi Nita G. , Michael Gaziano J. , Geleijnse Johanna M. , Gigante Bruna , Giles Graham , Guallar Eliseo , Gudnason Vilmundur , Harris Tamara , Harris William S. , Helmer Catherine , Hellenius Mai-Lis , Hodge Allison , Hu Frank B. , Jacques Paul F. , Jansson Jan-Håkan , Kalsbeek Anya , Khaw Kay-Tee , Koh Woon-Puay , Laakso Markku , Leander Karin , Lin Hung-Ju , Lind Lars , Luben Robert , Luo Juhua , McKnight Barbara , Mursu Jaakko , Ninomiya Toshiharu , Overvad Kim , Psaty Bruce M. , Rimm Eric , Schulze Matthias B. , Siscovick David , Skjelbo Nielsen Michael , Smith Albert V. , Steffen Brian T. , Steffen Lyn , Sun Qi , Sundström Johan , Tsai Michael Y. , Tunstall-Pedoe Hugh , Uusitupa Matti I. J. , van Dam Rob M. , Veenstra Jenna , Monique Verschuren W.M. , Wareham Nick , Willett Walter , Woodward Mark , Yuan Jian-Min , Micha Renata , Lemaitre Rozenn N. , Mozaffarian Dariush , Risérus Ulf ,   For the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Fatty Acids and Outcomes Research Consortium (FORCE)
Published: April 2019

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.