Meta-Analysis

. 2019 May 21;139(21):2422-2436.

doi: 10.1161/CIRCULATIONAHA.118.038908.

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

Matti Marklund^{1

2}, Jason H Y Wu², Fumiaki Imamura³, Liana C Del Gobbo⁴, Amanda Fretts⁵, Janette de Goede⁶, Peilin Shi⁷, Nathan Tintle⁸, Maria Wennberg⁹, Stella Aslibekyan¹⁰, Tzu-An Chen¹¹, Marcia C de Oliveira Otto¹², Yoichiro Hirakawa¹³, Helle Højmark Eriksen¹⁴, Janine Kröger¹⁵, Federica Laguzzi¹⁶, Maria Lankinen¹⁷, Rachel A Murphy¹⁸, Kiesha Prem¹⁹, Cécilia Samieri²⁰, Jyrki Virtanen¹⁷, Alexis C Wood¹¹, Kerry Wong²¹, Wei-Sin Yang²², Xia Zhou²³, Ana Baylin²⁴, Jolanda M A Boer²⁵, Ingeborg A Brouwer²⁶, Hannia Campos²⁷, Paulo H M Chaves²⁸, Kuo-Liong Chien^{22

29}, Ulf de Faire¹⁶, Luc Djoussé³⁰, Gudny Eiriksdottir³¹, Naglaa El-Abbadi^{7

32}, Nita G Forouhi³, J Michael Gaziano³⁰, Johanna M Geleijnse⁶, Bruna Gigante¹⁶, Graham Giles²¹, Eliseo Guallar³³, Vilmundur Gudnason³¹, Tamara Harris³⁴, William S Harris^{35

36}, Catherine Helmer²⁰, Mai-Lis Hellenius³⁷, Allison Hodge²¹, Frank B Hu^{27

38

39}, Paul F Jacques^{7

32}, Jan-Håkan Jansson⁴⁰, Anya Kalsbeek⁸, Kay-Tee Khaw⁴¹, Woon-Puay Koh^{19

42}, Markku Laakso⁴³, Karin Leander¹⁶, Hung-Ju Lin²⁹, Lars Lind⁴⁴, Robert Luben⁴¹, Juhua Luo⁴⁵, Barbara McKnight⁴⁶, Jaakko Mursu¹⁷, Toshiharu Ninomiya⁴⁷, Kim Overvad^{48

49}, Bruce M Psaty^{50

51}, Eric Rimm^{27

38

39}, Matthias B Schulze¹⁵, David Siscovick⁵², Michael Skjelbo Nielsen⁴⁹, Albert V Smith³¹, Brian T Steffen⁵³, Lyn Steffen²³, Qi Sun^{27

39}, Johan Sundström⁴⁴, Michael Y Tsai⁵³, Hugh Tunstall-Pedoe⁵⁴, Matti I J Uusitupa¹⁷, Rob M van Dam¹⁹, Jenna Veenstra⁸, W M Monique Verschuren^{25

55}, Nick Wareham³, Walter Willett^{27

38

39}, Mark Woodward^{2

54

56}, Jian-Min Yuan⁵⁷, Renata Micha⁷, Rozenn N Lemaitre⁵, Dariush Mozaffarian⁷, Ulf Risérus¹; Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Fatty Acids and Outcomes Research Consortium (FORCE)

Affiliations

¹ Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism, Uppsala University, Sweden (M.M., U.R.).
² The George Institute for Global Health and the Faculty of Medicine, University of New South Wales, Sydney, Australia (M.M., J.H.Y.W., M. Woodward).
³ Medical Research Council Epidemiology Unit, University of Cambridge, United Kingdom (F.I., N.G.F., N.W.).
⁴ Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, CA (L.C.D.G.).
⁵ Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle (A.F., R.N.L.).
⁶ Division of Human Nutrition, Wageningen University, The Netherlands (J.d.G., J.M. Geleijnse).
⁷ Friedman School of Nutrition Science and Policy, Tufts University, Boston, MA (P.S., N.E.-A., P.F.J., R.M., D.M.).
⁸ Department of Mathematics and Statistics, Dordt College, Sioux Centre, IA (N.T., A.K., J. Veenstra).
⁹ Department of Public Health and Clinical Medicine, Nutritional Research, Umeå University, Sweden (M. Wennberg).
¹⁰ Department of Epidemiology, University of Alabama at Birmingham (S.A.).
¹¹ USDA/ARS Children's Nutrition Research Center, Baylor College of Medicine, Houston, TX (T.-A.C., A.C.W.).
¹² Division of Epidemiology, Human Genetics and Environmental Sciences, the University of Texas Health Science Center, School of Public Health, Houston (M.C.d.O.O.).
¹³ Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan (Y.H.).
¹⁴ Unit of Epidemiology and Biostatistics, Aalborg University Hospital, Denmark (H.H.E.).
¹⁵ Department of Molecular Epidemiology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany (J.K., M.B.S.).
¹⁶ Unit of Cardiovascular Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden (F.L., U.d.F., B.G., K.L.).
¹⁷ Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio (N. Lankinen, J. Virtanen, J.M., M.I.J.U.).
¹⁸ University of British Columbia, Vancouver, British Columbia, Canada (R.A.M.).
¹⁹ Saw Swee Hock School of Public Health, National University of Singapore (K.P., W.-P.K., R.M.v.D.).
²⁰ Univ. Bordeaux, Inserm, Bordeaux Population Health Research Center, TUMR 1219, France (C.S., C.H.).
²¹ Centre for Epidemiology and Biostatistics, The University of Melbourne, Australia (K.W., G.G., A.H.).
²² Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei (W.-S.Y., K.-L.C.).
²³ Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis (X.Z., L.S.).
²⁴ Departments of Nutritional Sciences and Epidemiology, School of Public Health, University of Michigan, Ann Arbor (A.B.).
²⁵ Centre for Nutrition, Prevention and Health Services, National Institute of Public Health and the Environment, Bilthoven, The Netherlands (J.M.A.B., W.M.M.V.).
²⁶ Health Sciences, Vrije Universiteit, Amsterdam, The Netherlands (I.A.B.).
²⁷ Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA (H.C., F.B.H., E.R., Q.S., W.W.).
²⁸ Benjamin Leon for Geriatrics Research and Education, Herbert Wertheim College of Medicine, Florida International University, Miami (P.H.M.C.).
²⁹ Department of Internal Medicine, National Taiwan University Hospital, Taipei (K.-L.C., H.-J.L.).
³⁰ Brigham and Women's Hospital, Boston Veterans Affairs Healthcare System, MA (L.D., J.M. Gaziano).
³¹ Icelandic Heart Association, Kópavogur, Iceland; and Faculty of Medicine, University of Iceland, Reykjavik (G.E., V.G., A.V.S.).
³² USDA Jean Mayer Human Nutrition Research Center, Boston, MA (N.E.-A., P.F.J.).
³³ Division of Environmental Epidemiology, Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD (E.G.).
³⁴ National Institute on Aging, Bethesda, MD (T.H.).
³⁵ Department of Internal Medicine, Sanford School of Medicine, University of South Dakota, Sioux Falls (W.S.H.).
³⁶ OmegaQuant Analytics, LLC, Sioux Falls, SD (W.S.H.).
³⁷ Department of Medicine, Cardiology Unit, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden (M.-L.H.).
³⁸ Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA (F.B.H., E.R., W.W.).
³⁹ Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA (F.B.H., E.R., Q.S., W.W.).
⁴⁰ Department of Public Health and Clinical Medicine, Research Unit Skellefteå, Umeå University, Umeå, Sweden (J.-H.J.).
⁴¹ Department of Public Health and Primary Care, University of Cambridge School of Clinical Medicine, United Kingdom (K.-T.K., R.L.).
⁴² Duke-NUS Medical School, Singapore (W.-P.K.).
⁴³ Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland, Kuopio, Finland (M. Laakso).
⁴⁴ Department of Medical Sciences, Uppsala University, Sweden (L.L., J.S.).
⁴⁵ Department of Epidemiology and Biostatistics, Indiana University, Bloomington (J.L.).
⁴⁶ Department of Biostatistics, School of Public Health, University of Washington, Seattle (B.M.).
⁴⁷ Department of Epidemiology and Public Health, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan (T.N.).
⁴⁸ Department of Public Health, Section for Epidemiology, Aarhus University, Denmark (K.O.).
⁴⁹ Department of Cardiology, Aalborg University Hospital, Denmark (K.O., M.S.N.).
⁵⁰ Cardiovascular Health Study, Departments of Medicine, Epidemiology, and Health Services, University of Washington, Seattle (B.M.P.).
⁵¹ Kaiser Permanente Washington Health Research Institute, Seattle (B.M.P.).
⁵² The New York Academy of Medicine (D.S.).
⁵³ Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis (B.T.S., M.Y.T.).
⁵⁴ Cardiovascular Epidemiology Unit, Institute of Cardiovascular Research, University of Dundee, United Kingdom (H.T.-P., M. Woodward).
⁵⁵ Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, The Netherlands (W.M.M.V.).
⁵⁶ The George Institute for Global Health, University of Oxford, United Kingdom (M. Woodward).
⁵⁷ Division of Cancer Control and Population Sciences, UPMC Hillman Cancer, and Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, PA (J.-M.Y.).

PMID: 30971107
PMCID: PMC6582360
DOI: 10.1161/CIRCULATIONAHA.118.038908

Meta-Analysis

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

Matti Marklund et al. Circulation. 2019.

. 2019 May 21;139(21):2422-2436.

doi: 10.1161/CIRCULATIONAHA.118.038908.

Authors

Affiliations

¹ Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism, Uppsala University, Sweden (M.M., U.R.).
² The George Institute for Global Health and the Faculty of Medicine, University of New South Wales, Sydney, Australia (M.M., J.H.Y.W., M. Woodward).
³ Medical Research Council Epidemiology Unit, University of Cambridge, United Kingdom (F.I., N.G.F., N.W.).
⁴ Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, CA (L.C.D.G.).
⁵ Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle (A.F., R.N.L.).
⁶ Division of Human Nutrition, Wageningen University, The Netherlands (J.d.G., J.M. Geleijnse).
⁷ Friedman School of Nutrition Science and Policy, Tufts University, Boston, MA (P.S., N.E.-A., P.F.J., R.M., D.M.).
⁸ Department of Mathematics and Statistics, Dordt College, Sioux Centre, IA (N.T., A.K., J. Veenstra).
⁹ Department of Public Health and Clinical Medicine, Nutritional Research, Umeå University, Sweden (M. Wennberg).
¹⁰ Department of Epidemiology, University of Alabama at Birmingham (S.A.).
¹¹ USDA/ARS Children's Nutrition Research Center, Baylor College of Medicine, Houston, TX (T.-A.C., A.C.W.).
¹² Division of Epidemiology, Human Genetics and Environmental Sciences, the University of Texas Health Science Center, School of Public Health, Houston (M.C.d.O.O.).
¹³ Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan (Y.H.).
¹⁴ Unit of Epidemiology and Biostatistics, Aalborg University Hospital, Denmark (H.H.E.).
¹⁵ Department of Molecular Epidemiology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany (J.K., M.B.S.).
¹⁶ Unit of Cardiovascular Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden (F.L., U.d.F., B.G., K.L.).
¹⁷ Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio (N. Lankinen, J. Virtanen, J.M., M.I.J.U.).
¹⁸ University of British Columbia, Vancouver, British Columbia, Canada (R.A.M.).
¹⁹ Saw Swee Hock School of Public Health, National University of Singapore (K.P., W.-P.K., R.M.v.D.).
²⁰ Univ. Bordeaux, Inserm, Bordeaux Population Health Research Center, TUMR 1219, France (C.S., C.H.).
²¹ Centre for Epidemiology and Biostatistics, The University of Melbourne, Australia (K.W., G.G., A.H.).
²² Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei (W.-S.Y., K.-L.C.).
²³ Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis (X.Z., L.S.).
²⁴ Departments of Nutritional Sciences and Epidemiology, School of Public Health, University of Michigan, Ann Arbor (A.B.).
²⁵ Centre for Nutrition, Prevention and Health Services, National Institute of Public Health and the Environment, Bilthoven, The Netherlands (J.M.A.B., W.M.M.V.).
²⁶ Health Sciences, Vrije Universiteit, Amsterdam, The Netherlands (I.A.B.).
²⁷ Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA (H.C., F.B.H., E.R., Q.S., W.W.).
²⁸ Benjamin Leon for Geriatrics Research and Education, Herbert Wertheim College of Medicine, Florida International University, Miami (P.H.M.C.).
²⁹ Department of Internal Medicine, National Taiwan University Hospital, Taipei (K.-L.C., H.-J.L.).
³⁰ Brigham and Women's Hospital, Boston Veterans Affairs Healthcare System, MA (L.D., J.M. Gaziano).
³¹ Icelandic Heart Association, Kópavogur, Iceland; and Faculty of Medicine, University of Iceland, Reykjavik (G.E., V.G., A.V.S.).
³² USDA Jean Mayer Human Nutrition Research Center, Boston, MA (N.E.-A., P.F.J.).
³³ Division of Environmental Epidemiology, Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD (E.G.).
³⁴ National Institute on Aging, Bethesda, MD (T.H.).
³⁵ Department of Internal Medicine, Sanford School of Medicine, University of South Dakota, Sioux Falls (W.S.H.).
³⁶ OmegaQuant Analytics, LLC, Sioux Falls, SD (W.S.H.).
³⁷ Department of Medicine, Cardiology Unit, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden (M.-L.H.).
³⁸ Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA (F.B.H., E.R., W.W.).
³⁹ Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA (F.B.H., E.R., Q.S., W.W.).
⁴⁰ Department of Public Health and Clinical Medicine, Research Unit Skellefteå, Umeå University, Umeå, Sweden (J.-H.J.).
⁴¹ Department of Public Health and Primary Care, University of Cambridge School of Clinical Medicine, United Kingdom (K.-T.K., R.L.).
⁴² Duke-NUS Medical School, Singapore (W.-P.K.).
⁴³ Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland, Kuopio, Finland (M. Laakso).
⁴⁴ Department of Medical Sciences, Uppsala University, Sweden (L.L., J.S.).
⁴⁵ Department of Epidemiology and Biostatistics, Indiana University, Bloomington (J.L.).
⁴⁶ Department of Biostatistics, School of Public Health, University of Washington, Seattle (B.M.).
⁴⁷ Department of Epidemiology and Public Health, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan (T.N.).
⁴⁸ Department of Public Health, Section for Epidemiology, Aarhus University, Denmark (K.O.).
⁴⁹ Department of Cardiology, Aalborg University Hospital, Denmark (K.O., M.S.N.).
⁵⁰ Cardiovascular Health Study, Departments of Medicine, Epidemiology, and Health Services, University of Washington, Seattle (B.M.P.).
⁵¹ Kaiser Permanente Washington Health Research Institute, Seattle (B.M.P.).
⁵² The New York Academy of Medicine (D.S.).
⁵³ Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis (B.T.S., M.Y.T.).
⁵⁴ Cardiovascular Epidemiology Unit, Institute of Cardiovascular Research, University of Dundee, United Kingdom (H.T.-P., M. Woodward).
⁵⁵ Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, The Netherlands (W.M.M.V.).
⁵⁶ The George Institute for Global Health, University of Oxford, United Kingdom (M. Woodward).
⁵⁷ Division of Cancer Control and Population Sciences, UPMC Hillman Cancer, and Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, PA (J.-M.Y.).

PMID: 30971107
PMCID: PMC6582360
DOI: 10.1161/CIRCULATIONAHA.118.038908

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.

PubMed Disclaimer

Conflict of interest statement

DISCLOSURES

Drs. Wu and Micha report research support from Unilever for this work. Dr. Mozaffarian reports research funding from the National Institutes of Health and the Gates Foundation; personal fees from GOED, DSM, Nutrition Impact, Pollock Communications, Bunge, Indigo Agriculture, Amarin, Acasti Pharma, and America’s 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 DSMB 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. No other conflicts were reported.

Figures

**Figure 1.. Concentration of A) linoleic acid (LA; 18:2n6) and B) arachidonic acid (AA; 20:4n6) across different biomarker compartments measured in the 31 contributing studies.**
Concentrations of arachidonic acid and linoleic acid concentrations are expressed as % of total fatty acids (FA), and indicated as median (circles) and interquintile range (lines; defined as the range between the midpoint of the bottom quintile [10^th percentile] and the top quintile [90^th percentile]), respectively. For MPCDRF and the MORGEN, values are only shown for controls.*Total number of individual FA measured in the biomarker compartment. ^†Not reported.

**Figure 2.. Associations of linoleic acid (LA; 18:2n6) with total CVD (A) and CVD mortality (B) in pooled analysis of 30 prospective studies.**
Study-specific estimates for hazard ratio (HR) per interquintile range (i.e., range between the midpoint of the bottom quintile [10^th percentile] and the top quintile [90^th percentile]) of biomarker linoleic acid were pooled based on the following order: 1) adipose tissue, 2) erythrocyte phospholipid, 3) plasma phospholipid 4) cholesterol ester, and 5) total plasma. Study weights are indicated (grey squares) by individual biomarker compartment and overall. Study-specific analyses were conducted using models that included the following covariates: age (years), sex (male/female), race (Caucasian/non-Caucasian, or study-specific), field center if applicable (categories), body-mass index (BMI, kg/m²), education (less than high school graduate, high school graduate, some college or vocational school, college graduate), smoking (current, former, never; if history not assessed, then current/not current), physical activity (quintiles of metabolic equivalents (METs)/week), alcohol intake (none, 1–6 drinks/week, 1–2 drinks/day, >2 drinks/day), prevalent diabetes mellitus (defined as treatment with oral antihyperglycemic agents, insulin, or fasting plasma glucose >126 mg/dL), treated hypertension (defined as hypertension drug use; or if unavailable, as diagnosed/history of hypertension), treated hypercholesterolemia (defined as LDL-lowering drug use; if unavailable, as diagnosed/history of hypercholesterolemia), regular aspirin use (defined as ≥2 times/week), levels of α-linolenic acid (ALA; 18:3n-3), eicosapentaenoic acid (EPA; 20:5n-3), sum of *trans* isomers of oleic acid (trans18:1), and sum of *trans* isomers of LA (trans-18:2) (each expressed as % total FAs). If data did not allow such categorization, study-specific categories were used. See Table 1 footnote for abbreviations of cohorts.

**Figure 3.. Associations of linoleic acid (LA; 18:2n6) with total CHD (A) and ischemic stroke (B) in pooled analysis of 30 prospective studies.**
Study-specific estimates for hazard ratio (HR) per interquintile range (i.e., range between the midpoint of the bottom quintile [10^th percentile] and the top quintile [90^th percentile]) of biomarker linoleic acid were pooled based on the following order: 1) adipose tissue, 2) erythrocyte phospholipid, 3) plasma phospholipid 4) cholesterol ester, and 5) total plasma. Study weights are indicated (grey squares) by individual biomarker compartment and overall. Study-specific analyses were conducted using models that included the following covariates: age (years), sex (male/female), race (Caucasian/non-Caucasian, or study-specific), field center if applicable (categories), body-mass index (BMI, kg/m²), education (less than high school graduate, high school graduate, some college or vocational school, college graduate), smoking (current, former, never; if history not assessed, then current/not current), physical activity (quintiles of metabolic equivalents (METs)/week), alcohol intake (none, 1–6 drinks/week, 1–2 drinks/day, >2 drinks/day), prevalent diabetes mellitus (defined as treatment with oral antihyperglycemic agents, insulin, or fasting plasma glucose >126 mg/dL), treated hypertension (defined as hypertension drug use; or if unavailable, as diagnosed/history of hypertension), treated hypercholesterolemia (defined as LDL-lowering drug use; if unavailable, as diagnosed/history of hypercholesterolemia), regular aspirin use (defined as ≥2 times/week), levels of α-linolenic acid (ALA; 18:3n-3), eicosapentaenoic acid (EPA; 20:5n-3), sum of *trans* isomers of oleic acid (trans18:1), and sum of *trans* isomers of LA (trans-18:2) (each expressed as % total FAs). If data did not allow such categorization, study-specific categories were used. See Table 1 footnote for abbreviations of cohorts.

**Figure 4.. Associations of arachidonic acid (AA; 20:4n6) with total CVD (A) and CVD mortality (B) in pooled analysis of 30 prospective studies.**
Study-specific estimates for hazard ratio (HR) per interquintile range (i.e., range between the midpoint of the bottom quintile [10^th percentile] and the top quintile [90^th percentile]) of biomarker linoleic acid were pooled based on the following order: 1) adipose tissue, 2) erythrocyte phospholipid, 3) plasma phospholipid 4) cholesterol ester, and 5) total plasma. Study weights are indicated (grey squares) by individual biomarker compartment and overall. Study-specific analyses were conducted using models that included the following covariates: age (years), sex (male/female), race (Caucasian/non-Caucasian, or study-specific), field center if applicable (categories), body-mass index (BMI, kg/m²), education (less than high school graduate, high school graduate, some college or vocational school, college graduate), smoking (current, former, never; if history not assessed, then current/not current), physical activity (quintiles of metabolic equivalents (METs)/week), alcohol intake (none, 1–6 drinks/week, 1–2 drinks/day, >2 drinks/day), prevalent diabetes mellitus (defined as treatment with oral antihyperglycemic agents, insulin, or fasting plasma glucose >126 mg/dL), treated hypertension (defined as hypertension drug use; or if unavailable, as diagnosed/history of hypertension), treated hypercholesterolemia (defined as LDL-lowering drug use; if unavailable, as diagnosed/history of hypercholesterolemia), regular aspirin use (defined as ≥2 times/week), levels of α-linolenic acid (ALA; 18:3n-3), eicosapentaenoic acid (EPA; 20:5n-3), sum of *trans* isomers of oleic acid (trans18:1), and sum of *trans* isomers of LA (trans-18:2) (each expressed as % total FAs). If data did not allow such categorization, study-specific categories were used. See Table 1 footnote for abbreviations of cohorts.

**Figure 5.. Associations of arachidonic acid (AA; 20:4n6) with total CHD (A) and ischemic stroke (B) in pooled analysis of 30 prospective studies.**
Study-specific estimates for hazard ratio (HR) per interquintile range (i.e., range between the midpoint of the bottom quintile [10^th percentile] and the top quintile [90^th percentile]) of biomarker linoleic acid were pooled based on the following order: 1) adipose tissue, 2) erythrocyte phospholipid, 3) plasma phospholipid 4) cholesterol ester, and 5) total plasma. Study weights are indicated (grey squares) by individual biomarker compartment and overall. Study-specific analyses were conducted using models that included the following covariates: age (linear), sex (male/female), race (binary: Caucasian/non-Caucasian, or study-specific), field or clinical center if applicable (study-specific categories), body-mass index (BMI, linear), education (less than high school graduate, high school graduate, some college or vocational school, college graduate), smoking (current, former, or never; if former not assessed, then current or not current), physical activity (quintiles of metabolic equivalents (METs) per week; or if METs unavailable, quintiles of study-specific definitions of physical or leisure activity), alcohol intake (none, 1–6 drinks/week, 1–2 drink/day, >2 drink/day [14 g alcohol=1 standard drink]), diabetes mellitus (yes or no; defined as treatment with oral hypoglycemic agents, insulin, or fasting plasma glucose >126 mg/dL), treated hypertension (yes or no; defined as hypertension drug use; or if unavailable, as diagnosed/history of hypertension according to study-specific definitions), treated hypercholesterolemia (yes or no; defined as lipid-lowering drug use; if unavailable, as diagnosed/history of hypercholesterolemia according to study-specific definitions), regular aspirin use (yes or no), biomarker concentrations of α-linolenic acid (ALA; 18:3n-3), eicosapentaenoic acid (EPA; 20:5n-3), sum of trans-18:1 fatty acids, and sum of trans-18:2 fatty acids (all linear; expressed as % total fatty acids). If data did not allow such categorization, study-specific categories were used. See Table 1 footnote for abbreviations of cohorts.

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Comment in

Omega-6 Fatty Acids and Cardiovascular Disease.
Sanders TAB. Sanders TAB. Circulation. 2019 May 21;139(21):2437-2439. doi: 10.1161/CIRCULATIONAHA.119.040331. Circulation. 2019. PMID: 31107617 No abstract available.

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

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

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