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Title: Biomarkers of dietary omega-6 fatty acids and incident cardiovascular disease and mortality: an individual-level pooled analysis of 30 cohort studies

Author
item MARKLUND, MATTI - University Of New South Wales
item WU, JASON - University Of New South Wales
item IMAMURA, FUMIAKI - University Of Cambridge
item DEL GOBBO, LIANA - Stanford University
item FRETTS, AMANDA - University Of Washington
item DE GOEDE, JANETTE - University Of Wageningen
item SHI, PEILIN - Tufts University
item TINTLE, NATHAN - Dordt College
item WENNBERG, MARIA - University Of Umea
item ASLIBEKYAN, STELLA - University Of Alabama
item CHEN, TZU-AN - Baylor University
item DE OLIVEIRA OTTO, MARCIA - University Of Texas
item HIRAKAWA, YOICHIRO - Kyushu University
item ERIKSEN, HELLE - Aalborg University
item KROGER, JANINE - German Institute Of Human Nutrition
item LAGUZZI, FEDERICA - Karolinska Institute
item LANKINEN, MARIA - University Of Eastern Finland
item MURPHY, RACHEL - University Of British Columbia
item PREM, KIESHA - National University Of Singapore
item SAMIERI, CECILIA - University Of Bordeaux
item VIRTANEN, JYRKI - University Of Eastern Finland
item WOOD, ALEXIS - Children'S Nutrition Research Center (CNRC)
item WONG, KERRY - University Of Melbourne
item YANG, WEI-SIN - National Taiwan University
item ZHOU, XIA - University Of Minnesota
item BAYLIN, ANA - University Of Michigan
item BOER, JOLANDA - National Institute For Public Health And The Environment (RIVM)
item BROUWER, INGEBORG - Vrije University
item CAMPOS, HANNIA - Harvard University
item CHAVES, PAULO - Florida International University
item CHIEN, KUO-LIONG - National Taiwan University
item DE FAIRE, ULF - Karolinska Institute
item DJOUSSE, LUC - Brigham & Women'S Hospital
item EIRIKSDOTTIR, GUDNY - Icelandic Heart Association
item EL-ABBADI, NAGLAA - Jean Mayer Human Nutrition Research Center On Aging At Tufts University
item FOROUHI, NITA - University Of Cambridge
item GAZIANO, J - Brigham & Women'S Hospital
item GELEIJNSE, JOHANNA - University Of Wageningen
item GIGANTE, BRUNA - Karolinska Institute
item GILES, GRAHAM - University Of Melbourne
item GUALLAR, ELISEO - Johns Hopkins University
item GUDNASON, VILMUNDUR - University Of Iceland
item HARRIS, TAMARA - National Institute On Aging (NIA, NIH)
item HARRIS, WILLIAM - University Of South Dakota
item HELMER, CATHERINE - University Of Bordeaux
item HELLENIUS, MAI-LIS - Karolinska Institute
item HODGE, ALLISON - University Of Melbourne
item HU, FRANK - Harvard University
item JACQUES, PAUL - Jean Mayer Human Nutrition Research Center On Aging At Tufts University
item JANSSON, JAN-HAKAN - University Of Umea
item KALSBEEK, ANYA - Dordt College
item KHAW, KAY-TEE - University Of Cambridge
item KOH, WOON-PUAY - National University Of Singapore
item LAAKSO, MARKKU - University Of Eastern Finland
item LEANDER, KARIN - Karolinska Institute
item LIN, HUNG-JU - National Taiwan University
item LIND, LARS - Uppsala University
item LUBEN, ROBERT - University Of Cambridge
item LUO, JUHUA - Indiana University
item MCKNIGHT, BARBARA - University Of Washington
item MURSU, JAAKKO - University Of Eastern Finland
item NINOMIYA, TOSHIHARU - Kyushu University
item OVERVAD, KIM - Aarhus University
item PSATY, BRUCE - University Of Washington
item RIMM, ERIC - Harvard University
item SCHULZE, MATTHIAS - German Institute Of Human Nutrition
item SISCOVICK, DAVID - New York Academy Of Medicine
item SKJELBO NIELSEN, MICHAEL - Aalborg University
item SMITH, ALBERT - University Of Iceland
item STEFFEN, BRIAN - University Of Minnesota
item STEFFEN, LYN - University Of Minnesota
item SUN, QI - Harvard University
item SUNDSTROM, JOHAN - Uppsala University
item TSAI, MICHAEL - University Of Minnesota
item TUNSTALL-PEDOE, HUGH - University Of Dundee
item UUSITUPA, MATTI - University Of Eastern Finland
item VAN DAM, ROB - National University Of Singapore
item VEENSTRA, JENNA - Dordt College
item VERSCHUREN, W.M. - National Institute For Public Health And The Environment (RIVM)
item WAREHAM, NICK - University Of Cambridge
item WILLETT, WALTER - Harvard University
item WOODWARD, MARK - University Of New South Wales
item YUAN, JIAN-MIN - University Of Pittsburgh
item MICHA, RENATA - Tufts University
item LEMAITRE, ROZENN - University Of Washington
item MOZAFFARIAN, DARIUSH - Tufts University
item RISERUS, ULF - Uppsala University

Submitted to: Circulation
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 2/7/2019
Publication Date: 5/21/2019
Citation: Marklund, M., Wu, J.H., Imamura, F., Del Gobbo, L.C., Fretts, A., De Goede, J., Shi, P., Tintle, N., Wennberg, M., Aslibekyan, S., Chen, T., De Oliveira Otto, M.C., Hirakawa, Y., Eriksen, H.H., Kroger, J., Laguzzi, F., Lankinen, M., Murphy, R.A., Prem, K., Samieri, C., Virtanen, J., Wood, A.C., Wong, K., Yang, W., Zhou, X., Baylin, A., Boer, J.M., Brouwer, I.A., Campos, H., Chaves, P.H., Chien, K., De Faire, U., Djousse, L., Eiriksdottir, G., El-Abbadi, N., Forouhi, N.G., Gaziano, J., Geleijnse, J.M., Gigante, B., Giles, G., Guallar, E., Gudnason, V., Harris, T., Harris, W.S., Helmer, C., Hellenius, M., Hodge, A., Hu, F.B., Jacques, P.F., Jansson, J., Kalsbeek, A., Khaw, K., Koh, W., Laakso, M., Leander, K., Lin, H., Lind, L., Luben, R., Luo, J., Mcknight, B., Mursu, J., Ninomiya, T., Overvad, K., Psaty, B.M., Rimm, E., Schulze, M.B., Siscovick, D., Skjelbo Nielsen, M., Smith, A.V., Steffen, B.T., Steffen, L., Sun, Q., Sundstrom, J., Tsai, M.Y., Tunstall-Pedoe, H., Uusitupa, M.I., Van Dam, R.M., Veenstra, J., Verschuren, W.M., Wareham, N., Willett, W., Woodward, M., Yuan, J., Micha, R., Lemaitre, R.N., Mozaffarian, D., Riserus, U. 2019. Biomarkers of dietary omega-6 fatty acids and incident cardiovascular disease and mortality: an individual-level pooled analysis of 30 cohort studies. Circulation. 139(21):2422-2436. https://doi.org/10.1161/CIRCULATIONAHA.118.038908.
DOI: https://doi.org/10.1161/CIRCULATIONAHA.118.038908

Interpretive Summary: Controversy exists around the effect of consuming omega-6 polyunsaturated fatty acids, a type of polyunsaturated fatty acid found in vegetable oils, seeds and nuts, on cardiovascular disease risk. As such, our study aimed to examine the association between blood levels of two types of omega-6 fatty acids, linoleic acid (LA) and arachidonic acid (AA), and new cases of CVD. To do this, we conducted a meta-analysis, which is a study that combines data from many individual studies on the topic. Our meta-analysis includes results from 30 studies conducted in 13 different countries and is the largest meta-analysis to examine the link between LA, AA, and CVD. The results showed that a higher blood level of LA was associated with lower risk of total CVD, ischemic stroke, and death from cardiovascular disease. AA was not associated with cardiovascular risk. These findings are novel in that they suggest that omega-6 fatty acids, specifically LA, may be beneficial for preventing CVD. This study does not support previous beliefs that omega-6 fatty acids may be harmful to CVD risk, and the results can be used to help inform global dietary recommendations about omega-6 fatty acid consumption.

Technical Abstract: 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.