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

Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Fatty Acids and Outcomes Research Consortium (FORCE)

doi:10.1161/CIRCULATIONAHA.118.038908

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

Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Fatty Acids and Outcomes Research Consortium (FORCE)

Research output: Contribution to Journal › Article › Academic › peer-review

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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.

Original language	English
Pages (from-to)	2422-2436
Number of pages	15
Journal	Circulation
Volume	139
Issue number	21
Early online date	11 Apr 2019
DOIs	https://doi.org/10.1161/CIRCULATIONAHA.118.038908
Publication status	Published - 21 May 2019

Funding

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\u2019s 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 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.

Funders	Funder number
DayTwo
Fatty acids & Outcomes Research Consortium
Omada Health
National Institutes of Health
Bill and Melinda Gates Foundation
National Center for Advancing Translational Sciences	UL1TR000040
Unilever
Tufts University
Dipartimento di Scienze Mediche, Università degli Studi di Torino

Keywords

arachidonic acid
biomarkers
cardiovascular diseases
diet
epidemiology
linoleic acid
primary prevention

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1161/CIRCULATIONAHA.118.038908

Biomarkers of Dietary Omega-6 Fatty Acids and Incident Cardiovascular Disease and MortalityFinal published version, 1.15 MBLicence: Article 25fa Dutch Copyright Act

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@article{0b1414334a114053a505c2ed9696b5cf,

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

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.",

keywords = "arachidonic acid, biomarkers, cardiovascular diseases, diet, epidemiology, linoleic acid, primary prevention",

author = "Matti Marklund and Wu, {Jason H.Y.} and Fumiaki Imamura and {Del Gobbo}, {Liana C.} and Amanda Fretts and {de Goede}, Janette and Peilin Shi and Nathan Tintle and Maria Wennberg and Stella Aslibekyan and Chen, {Tzu An} and {de Oliveira Otto}, {Marcia C.} and Yoichiro Hirakawa and Eriksen, {Helle H{\o}jmark} and Janine Kr{\"o}ger and Federica Laguzzi and Maria Lankinen and Murphy, {Rachel A.} and Kiesha Prem and C{\'e}cilia Samieri and Jyrki Virtanen and Wood, {Alexis C.} and Kerry Wong and Yang, {Wei Sin} and Xia Zhou and Ana Baylin and Boer, {Jolanda M.A.} and Brouwer, {Ingeborg A.} and Hannia Campos and Chaves, {Paulo H.M.} and Chien, {Kuo Liong} and {de Faire}, Ulf and Luc Djouss{\'e} and Gudny Eiriksdottir and Naglaa El-Abbadi and Forouhi, {Nita G.} and {Michael Gaziano}, J. and Geleijnse, {Johanna M.} and Bruna Gigante and Graham Giles and Eliseo Guallar and Vilmundur Gudnason and Tamara Harris and Harris, {William S.} and Catherine Helmer and Hellenius, {Mai Lis} and Allison Hodge and Hu, {Frank B.} and Jacques, {Paul F.} and Jansson, {Jan H{\aa}kan} and Anya Kalsbeek and Khaw, {Kay Tee} and Koh, {Woon Puay} and Markku Laakso and Karin Leander and Lin, {Hung Ju} and Lars Lind and Robert Luben and Juhua Luo and Barbara McKnight and Jaakko Mursu and Toshiharu Ninomiya and Kim Overvad and Psaty, {Bruce M.} and Eric Rimm and Schulze, {Matthias B.} and David Siscovick and {Skjelbo Nielsen}, Michael and Smith, {Albert V.} and Steffen, {Brian T.} and Lyn Steffen and Qi Sun and Johan Sundstr{\"o}m and Tsai, {Michael Y.} and Hugh Tunstall-Pedoe and Uusitupa, {Matti I.J.} and {van Dam}, {Rob M.} and Jenna Veenstra and {Monique Verschuren}, {W. M.} and Nick Wareham and Walter Willett and Mark Woodward and Yuan, {Jian Min} and Renata Micha and Lemaitre, {Rozenn N.} and Dariush Mozaffarian and Ulf Ris{\'e}rus and {Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Fatty Acids and Outcomes Research Consortium (FORCE)}",

year = "2019",

month = may,

day = "21",

doi = "10.1161/CIRCULATIONAHA.118.038908",

language = "English",

volume = "139",

pages = "2422--2436",

journal = "Circulation",

issn = "1524-4539",

publisher = "Lippincott Williams and Wilkins",

number = "21",

}

Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Fatty Acids and Outcomes Research Consortium (FORCE) 2019, 'Biomarkers of Dietary Omega-6 Fatty Acids and Incident Cardiovascular Disease and Mortality: An Individual-Level Pooled Analysis of 30 Cohort Studies', Circulation, vol. 139, no. 21, pp. 2422-2436. https://doi.org/10.1161/CIRCULATIONAHA.118.038908

Biomarkers of Dietary Omega-6 Fatty Acids and Incident Cardiovascular Disease and Mortality: An Individual-Level Pooled Analysis of 30 Cohort Studies. / Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Fatty Acids and Outcomes Research Consortium (FORCE).
In: Circulation, Vol. 139, No. 21, 21.05.2019, p. 2422-2436.

Research output: Contribution to Journal › Article › Academic › peer-review

TY - JOUR

T1 - Biomarkers of Dietary Omega-6 Fatty Acids and Incident Cardiovascular Disease and Mortality

T2 - An Individual-Level Pooled Analysis of 30 Cohort Studies

AU - Marklund, Matti

AU - Wu, Jason H.Y.

AU - Imamura, Fumiaki

AU - Del Gobbo, Liana C.

AU - Fretts, Amanda

AU - de Goede, Janette

AU - Shi, Peilin

AU - Tintle, Nathan

AU - Wennberg, Maria

AU - Aslibekyan, Stella

AU - Chen, Tzu An

AU - de Oliveira Otto, Marcia C.

AU - Hirakawa, Yoichiro

AU - Eriksen, Helle Højmark

AU - Kröger, Janine

AU - Laguzzi, Federica

AU - Lankinen, Maria

AU - Murphy, Rachel A.

AU - Prem, Kiesha

AU - Samieri, Cécilia

AU - Virtanen, Jyrki

AU - Wood, Alexis C.

AU - Wong, Kerry

AU - Yang, Wei Sin

AU - Zhou, Xia

AU - Baylin, Ana

AU - Boer, Jolanda M.A.

AU - Brouwer, Ingeborg A.

AU - Campos, Hannia

AU - Chaves, Paulo H.M.

AU - Chien, Kuo Liong

AU - de Faire, Ulf

AU - Djoussé, Luc

AU - Eiriksdottir, Gudny

AU - El-Abbadi, Naglaa

AU - Forouhi, Nita G.

AU - Michael Gaziano, J.

AU - Geleijnse, Johanna M.

AU - Gigante, Bruna

AU - Giles, Graham

AU - Guallar, Eliseo

AU - Gudnason, Vilmundur

AU - Harris, Tamara

AU - Harris, William S.

AU - Helmer, Catherine

AU - Hellenius, Mai Lis

AU - Hodge, Allison

AU - Hu, Frank B.

AU - Jacques, Paul F.

AU - Jansson, Jan Håkan

AU - Kalsbeek, Anya

AU - Khaw, Kay Tee

AU - Koh, Woon Puay

AU - Laakso, Markku

AU - Leander, Karin

AU - Lin, Hung Ju

AU - Lind, Lars

AU - Luben, Robert

AU - Luo, Juhua

AU - McKnight, Barbara

AU - Mursu, Jaakko

AU - Ninomiya, Toshiharu

AU - Overvad, Kim

AU - Psaty, Bruce M.

AU - Rimm, Eric

AU - Schulze, Matthias B.

AU - Siscovick, David

AU - Skjelbo Nielsen, Michael

AU - Smith, Albert V.

AU - Steffen, Brian T.

AU - Steffen, Lyn

AU - Sun, Qi

AU - Sundström, Johan

AU - Tsai, Michael Y.

AU - Tunstall-Pedoe, Hugh

AU - Uusitupa, Matti I.J.

AU - van Dam, Rob M.

AU - Veenstra, Jenna

AU - Monique Verschuren, W. M.

AU - Wareham, Nick

AU - Willett, Walter

AU - Woodward, Mark

AU - Yuan, Jian Min

AU - Micha, Renata

AU - Lemaitre, Rozenn N.

AU - Mozaffarian, Dariush

AU - Risérus, Ulf

AU - Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Fatty Acids and Outcomes Research Consortium (FORCE)

PY - 2019/5/21

Y1 - 2019/5/21

N2 - 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.

AB - 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.

KW - arachidonic acid

KW - biomarkers

KW - cardiovascular diseases

KW - diet

KW - epidemiology

KW - linoleic acid

KW - primary prevention

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U2 - 10.1161/CIRCULATIONAHA.118.038908

DO - 10.1161/CIRCULATIONAHA.118.038908

M3 - Article

C2 - 30971107

AN - SCOPUS:85066456162

SN - 1524-4539

VL - 139

SP - 2422

EP - 2436

JO - Circulation

JF - Circulation

IS - 21

ER -

Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Fatty Acids and Outcomes Research Consortium (FORCE). Biomarkers of Dietary Omega-6 Fatty Acids and Incident Cardiovascular Disease and Mortality: An Individual-Level Pooled Analysis of 30 Cohort Studies. Circulation. 2019 May 21;139(21):2422-2436. Epub 2019 Apr 11. doi: 10.1161/CIRCULATIONAHA.118.038908

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

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