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

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

Research output: Contribution to JournalArticleAcademicpeer-review

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 languageEnglish
Pages (from-to)2422-2436
Number of pages15
JournalCirculation
Volume139
Issue number21
DOIs
Publication statusPublished - 21 May 2019

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Omega-6 Fatty Acids
Linoleic Acid
Cardiovascular Diseases
Biomarkers
Arachidonic Acid
Mortality
Coronary Disease
Prospective Studies
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Population Characteristics
Aspirin
Uncertainty
Observational Studies
Meta-Analysis
Adipose Tissue
Diabetes Mellitus
Fatty Acids
Stroke
Myocardial Infarction
Genotype

Keywords

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

Cite this

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. Circulation, 139(21), 2422-2436. https://doi.org/10.1161/CIRCULATIONAHA.118.038908
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. In: Circulation. 2019 ; Vol. 139, No. 21. pp. 2422-2436.
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title = "Biomarkers of Dietary Omega-6 Fatty Acids and Incident Cardiovascular Disease and Mortality",
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",
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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' 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. / 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 JournalArticleAcademicpeer-review

TY - JOUR

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

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

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JO - Circulation

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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. Circulation. 2019 May 21;139(21):2422-2436. https://doi.org/10.1161/CIRCULATIONAHA.118.038908