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 Samieri; Jyrki 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 Hellénius; Allison Hodge; Frank B. Hu; Hugh Tunstall-Pedoe; Mark Woodward

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

, Matti Marklund (Lead / Corresponding author), 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 PremCécilia Samieri, Jyrki 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 Hellénius, Allison Hodge, Frank B. Hu, Hugh Tunstall-Pedoe, Mark Woodward

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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

Keywords

arachidonic acid
biomarkers
cardiovascular diseases
diet
epidemiology
linoleic acid
primary prevention

ASJC Scopus subject areas

Cardiology and Cardiovascular Medicine
Physiology (medical)

UN SDGs

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

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10.1161/CIRCULATIONAHA.118.038908

Author Accepted ManuscriptAccepted author manuscript, 2.02 MB

Cite this

, Marklund, M., Wu, J. H. Y., Imamura, F., Del Gobbo, L. C., Fretts, A., de Goede, J., Shi, P., Tintle, N., Wennberg, M., Aslibekyan, S., Chen, T.-A., de Oliveira Otto, M. C., Hirakawa, Y., Eriksen, H. H., Kröger, J., Laguzzi, F., Lankinen, M., Murphy, R. A., ... Woodward, M. (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

@article{40929cc7486b4e9fafaf7367b77fc3e8,

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 Tzu-An Chen 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 Wei-Sin Yang and Xia Zhou and Ana Baylin and Boer, {Jolanda M. A.} and Brouwer, {Ingeborg A.} and Hannia Campos and Chaves, {Paulo H. M.} and Kuo-Liong Chien and {de Faire}, Ulf and Luc Djouss{\'e} and Gudny Eiriksdottir and Naglaa El-Abbadi and Forouhi, {Nita G.} and Gaziano, {J. Michael} 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 Mai-Lis Hell{\'e}nius and Allison Hodge and Hu, {Frank B.} and Hugh Tunstall-Pedoe and Mark Woodward",

year = "2019",

month = may,

day = "21",

doi = "10.1161/CIRCULATIONAHA.118.038908",

language = "English",

volume = "139",

pages = "2422--2436",

journal = "Circulation",

issn = "0009-7322",

publisher = "Lippincott Williams and Wilkins",

number = "21",

}

Marklund, M, Wu, JHY, Imamura, F, Del Gobbo, LC, Fretts, A, de Goede, J, Shi, P, Tintle, N, Wennberg, M, Aslibekyan, S, Chen, T-A, de Oliveira Otto, MC, Hirakawa, Y, Eriksen, HH, Kröger, J, Laguzzi, F, Lankinen, M, Murphy, RA, Prem, K, Samieri, C, Virtanen, J, Wood, AC, Wong, K, Yang, W-S, Zhou, X, Baylin, A, Boer, JMA, Brouwer, IA, Campos, H, Chaves, PHM, Chien, K-L, de Faire, U, Djoussé, L, Eiriksdottir, G, El-Abbadi, N, Forouhi, NG, Gaziano, JM, Geleijnse, JM, Gigante, B, Giles, G, Guallar, E, Gudnason, V, Harris, T, Harris, WS, Helmer, C, Hellénius, M-L, Hodge, A, Hu, FB & Tunstall-Pedoe, H & Woodward, M 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

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 - Gaziano, J. Michael

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 - Hellénius, Mai-Lis

AU - Hodge, Allison

AU - Hu, Frank B.

AU - Tunstall-Pedoe, Hugh

AU - Woodward, Mark

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

UR - http://www.scopus.com/inward/record.url?scp=85066456162&partnerID=8YFLogxK

U2 - 10.1161/CIRCULATIONAHA.118.038908

DO - 10.1161/CIRCULATIONAHA.118.038908

M3 - Article

C2 - 30971107

SN - 0009-7322

VL - 139

SP - 2422

EP - 2436

JO - Circulation

JF - Circulation

IS - 21

ER -

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

Abstract

Keywords

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UN SDGs

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