. 2016 Aug 1;176(8):1155-66.

doi: 10.1001/jamainternmed.2016.2925.

ω-3 Polyunsaturated Fatty Acid Biomarkers and Coronary Heart Disease: Pooling Project of 19 Cohort Studies

Liana C Del Gobbo¹, Fumiaki Imamura², Stella Aslibekyan³, Matti Marklund⁴, Jyrki K Virtanen⁵, Maria Wennberg⁶, Mohammad Y Yakoob¹, Stephanie E Chiuve⁷, Luicito Dela Cruz⁸, Alexis C Frazier-Wood⁹, Amanda M Fretts¹⁰, Eliseo Guallar¹¹, Chisa Matsumoto¹², Kiesha Prem¹³, Tosh Tanaka¹⁴, Jason H Y Wu¹⁵, Xia Zhou¹⁶, Catherine Helmer¹⁷, Erik Ingelsson¹⁸, Jian-Min Yuan¹⁹, Pascale Barberger-Gateau¹⁷, Hannia Campos²⁰, Paulo H M Chaves²¹, Luc Djoussé²², Graham G Giles⁸, Jose Gómez-Aracena²³, Allison M Hodge⁸, Frank B Hu²⁴, Jan-Håkan Jansson⁶, Ingegerd Johansson²⁵, Kay-Tee Khaw²⁶, Woon-Puay Koh²⁷, Rozenn N Lemaitre²⁸, Lars Lind²⁹, Robert N Luben²⁶, Eric B Rimm²⁴, Ulf Risérus⁴, Cecilia Samieri¹⁷, Paul W Franks³⁰, David S Siscovick³¹, Meir Stampfer²⁴, Lyn M Steffen¹⁶, Brian T Steffen¹⁶, Michael Y Tsai³², Rob M van Dam³³, Sari Voutilainen⁵, Walter C Willett²⁴, Mark Woodward³⁴, Dariush Mozaffarian³⁵; Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Fatty Acids and Outcomes Research Consortium (FORCe)

Affiliations

¹ Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, California.
² Medical Research Council Epidemiology Unit, Institute of Metabolic Science, University of Cambridge School of Clinical Medicine, Cambridge University, Cambridge, United Kingdom.
³ Department of Epidemiology, University of Alabama at Birmingham School of Public Health, Birmingham.
⁴ Department of Public Health and Caring Sciences, Uppsala University, Uppsala, Sweden.
⁵ Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Joensuu, Finland.
⁶ Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden.
⁷ Division of Preventive Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts8Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, Massachusetts.
⁸ Cancer Epidemiology Centre, Cancer Council Victoria, Victoria, Australia.
⁹ USDA/ARS Children's Nutrition Research Center, Baylor College of Medicine, Houston, Texas.
¹⁰ Department of Epidemiology, University of Washington, Seattle.
¹¹ Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland.
¹² Division of Cardiology, Tokyo Medical University, Tokyo, Japan14Division of Aging, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
¹³ Saw Swee Hock School of Public Health, National University of Singapore, Singapore.
¹⁴ Translational Gerontology Branch, National Institute on Aging, Bethesda, Maryland.
¹⁵ The George Institute for Global Health, Sydney Medical School, University of Sydney, Sydney, Australia.
¹⁶ Division of Epidemiology and Community Health, University of Minnesota School of Public Health, Minneapolis.
¹⁷ Institut National de la Santé et de la Recherche Médicale, Institut de Santé Publique, d'Épidémiologie et de Développement, Centre IInstitut National de la Santé et de la Recherche Médicale U897-Epidemiologie-Biostatistique, Bordeaux, France20University B.
¹⁸ Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, California21Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
¹⁹ Division of Cancer Control and Population Sciences, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania23Department of Epidemiology, University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania.
²⁰ Department of Nutrition, Harvard T. H. Chan School of Public Health, Boston, Massachusetts.
²¹ Benjamin Leon Center for Geriatric Research and Education, Florida International University, Miami.
²² Division of Aging, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
²³ Department of Preventive Medicine, Universidad de Malaga, Malaga, Spain.
²⁴ Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, Massachusetts24Department of Nutrition, Harvard T. H. Chan School of Public Health, Boston, Massachusetts27Channing Division of Network Medicine, Department of Medicine, Brigh.
²⁵ Department of Odontology, Umeå University, Umeå, Sweden.
²⁶ Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom.
²⁷ Saw Swee Hock School of Public Health, National University of Singapore, Singapore30Duke-NUS Graduate Medical School Singapore, Singapore.
²⁸ Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle.
²⁹ Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
³⁰ Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden24Department of Nutrition, Harvard T. H. Chan School of Public Health, Boston, Massachusetts32Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Lund Un.
³¹ The New York Academy of Medicine, New York.
³² Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis.
³³ Saw Swee Hock School of Public Health, National University of Singapore, Singapore24Department of Nutrition, Harvard T. H. Chan School of Public Health, Boston, Massachusetts35Department of Medicine, Yong Loo Lin School of Medicine, National University of.
³⁴ Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland17The George Institute for Global Health, Sydney Medical School, University of Sydney, Sydney, Australia36The George Institute for Global Health, Nuffield Depa.
³⁵ Friedman School of Nutrition Science and Policy, Tufts University, Boston, Massachusetts.

PMID: 27357102
PMCID: PMC5183535
DOI: 10.1001/jamainternmed.2016.2925

ω-3 Polyunsaturated Fatty Acid Biomarkers and Coronary Heart Disease: Pooling Project of 19 Cohort Studies

Liana C Del Gobbo et al. JAMA Intern Med. 2016.

. 2016 Aug 1;176(8):1155-66.

doi: 10.1001/jamainternmed.2016.2925.

Authors

Affiliations

¹ Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, California.
² Medical Research Council Epidemiology Unit, Institute of Metabolic Science, University of Cambridge School of Clinical Medicine, Cambridge University, Cambridge, United Kingdom.
³ Department of Epidemiology, University of Alabama at Birmingham School of Public Health, Birmingham.
⁴ Department of Public Health and Caring Sciences, Uppsala University, Uppsala, Sweden.
⁵ Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Joensuu, Finland.
⁶ Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden.
⁷ Division of Preventive Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts8Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, Massachusetts.
⁸ Cancer Epidemiology Centre, Cancer Council Victoria, Victoria, Australia.
⁹ USDA/ARS Children's Nutrition Research Center, Baylor College of Medicine, Houston, Texas.
¹⁰ Department of Epidemiology, University of Washington, Seattle.
¹¹ Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland.
¹² Division of Cardiology, Tokyo Medical University, Tokyo, Japan14Division of Aging, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
¹³ Saw Swee Hock School of Public Health, National University of Singapore, Singapore.
¹⁴ Translational Gerontology Branch, National Institute on Aging, Bethesda, Maryland.
¹⁵ The George Institute for Global Health, Sydney Medical School, University of Sydney, Sydney, Australia.
¹⁶ Division of Epidemiology and Community Health, University of Minnesota School of Public Health, Minneapolis.
¹⁷ Institut National de la Santé et de la Recherche Médicale, Institut de Santé Publique, d'Épidémiologie et de Développement, Centre IInstitut National de la Santé et de la Recherche Médicale U897-Epidemiologie-Biostatistique, Bordeaux, France20University B.
¹⁸ Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, California21Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
¹⁹ Division of Cancer Control and Population Sciences, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania23Department of Epidemiology, University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania.
²⁰ Department of Nutrition, Harvard T. H. Chan School of Public Health, Boston, Massachusetts.
²¹ Benjamin Leon Center for Geriatric Research and Education, Florida International University, Miami.
²² Division of Aging, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
²³ Department of Preventive Medicine, Universidad de Malaga, Malaga, Spain.
²⁴ Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, Massachusetts24Department of Nutrition, Harvard T. H. Chan School of Public Health, Boston, Massachusetts27Channing Division of Network Medicine, Department of Medicine, Brigh.
²⁵ Department of Odontology, Umeå University, Umeå, Sweden.
²⁶ Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom.
²⁷ Saw Swee Hock School of Public Health, National University of Singapore, Singapore30Duke-NUS Graduate Medical School Singapore, Singapore.
²⁸ Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle.
²⁹ Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
³⁰ Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden24Department of Nutrition, Harvard T. H. Chan School of Public Health, Boston, Massachusetts32Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Lund Un.
³¹ The New York Academy of Medicine, New York.
³² Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis.
³³ Saw Swee Hock School of Public Health, National University of Singapore, Singapore24Department of Nutrition, Harvard T. H. Chan School of Public Health, Boston, Massachusetts35Department of Medicine, Yong Loo Lin School of Medicine, National University of.
³⁴ Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland17The George Institute for Global Health, Sydney Medical School, University of Sydney, Sydney, Australia36The George Institute for Global Health, Nuffield Depa.
³⁵ Friedman School of Nutrition Science and Policy, Tufts University, Boston, Massachusetts.

PMID: 27357102
PMCID: PMC5183535
DOI: 10.1001/jamainternmed.2016.2925

Erratum in

Explanation of Errors in Abstract and Supplement and in the Reporting of Analyses.
Mozaffarian D. Mozaffarian D. JAMA Intern Med. 2016 Nov 1;176(11):1727-1728. doi: 10.1001/jamainternmed.2016.6508. JAMA Intern Med. 2016. PMID: 27695819 No abstract available.
Errors in Abstract and Supplement and in Reporting of Analyses.
[No authors listed] [No authors listed] JAMA Intern Med. 2016 Nov 1;176(11):1728. doi: 10.1001/jamainternmed.2016.6514. JAMA Intern Med. 2016. PMID: 27695848 No abstract available.
Error in Author Affiliation.
[No authors listed] [No authors listed] JAMA Intern Med. 2019 Mar 1;179(3):457. doi: 10.1001/jamainternmed.2019.0135. JAMA Intern Med. 2019. PMID: 30742209 No abstract available.

Abstract

Importance: The role of ω-3 polyunsaturated fatty acids for primary prevention of coronary heart disease (CHD) remains controversial. Most prior longitudinal studies evaluated self-reported consumption rather than biomarkers.

Objective: To evaluate biomarkers of seafood-derived eicosapentaenoic acid (EPA; 20:5ω-3), docosapentaenoic acid (DPA; 22:5ω-3), and docosahexaenoic acid (DHA; 22:6ω-3) and plant-derived α-linolenic acid (ALA; 18:3ω-3) for incident CHD.

Data sources: A global consortium of 19 studies identified by November 2014.

Study selection: Available prospective (cohort, nested case-control) or retrospective studies with circulating or tissue ω-3 biomarkers and ascertained CHD.

Data extraction and synthesis: Each study conducted standardized, individual-level analysis using harmonized models, exposures, outcomes, and covariates. Findings were centrally pooled using random-effects meta-analysis. Heterogeneity was examined by age, sex, race, diabetes, statins, aspirin, ω-6 levels, and FADS desaturase genes.

Main outcomes and measures: Incident total CHD, fatal CHD, and nonfatal myocardial infarction (MI).

Results: The 19 studies comprised 16 countries, 45 637 unique individuals, and 7973 total CHD, 2781 fatal CHD, and 7157 nonfatal MI events, with ω-3 measures in total plasma, phospholipids, cholesterol esters, and adipose tissue. Median age at baseline was 59 years (range, 18-97 years), and 28 660 (62.8%) were male. In continuous (per 1-SD increase) multivariable-adjusted analyses, the ω-3 biomarkers ALA, DPA, and DHA were associated with a lower risk of fatal CHD, with relative risks (RRs) of 0.91 (95% CI, 0.84-0.98) for ALA, 0.90 (95% CI, 0.85-0.96) for DPA, and 0.90 (95% CI, 0.84-0.96) for DHA. Although DPA was associated with a lower risk of total CHD (RR, 0.94; 95% CI, 0.90-0.99), ALA (RR, 1.00; 95% CI, 0.95-1.05), EPA (RR, 0.94; 95% CI, 0.87-1.02), and DHA (RR, 0.95; 95% CI, 0.91-1.00) were not. Significant associations with nonfatal MI were not evident. Associations appeared generally stronger in phospholipids and total plasma. Restricted cubic splines did not identify evidence of nonlinearity in dose responses.

Conclusions and relevance: On the basis of available studies of free-living populations globally, biomarker concentrations of seafood and plant-derived ω-3 fatty acids are associated with a modestly lower incidence of fatal CHD.

PubMed Disclaimer

Conflict of interest statement

Disclosures: Dr Barberger-Gateau reported receiving grants and nonfinancial support from Danone Research, Vifor Pharma, and Groupe Lipides et Nutrition; personal fees and nonfinancial support from Nutricia, ILSI Europe, and PiLeJe; and a grant from the Centre National Interprofessionnel de l’Industrie Laitière. Dr Del Gobbo reported receiving ad hoc consulting fees from the Life Sciences Research Organization. Dr Djoussé reported receiving investigator-initiated grants from Merck, Amarin Pharma Inc, California Walnut Commission, and the National Institutes of Health and serving as ad hoc consultant for Amarin Pharma Inc. Dr Helmer reported receiving fees for a conference from Novartis. Dr Mozaffarian reported receiving ad hoc honoraria from Bunge, Pollock Institute, and Quaker Oats; ad hoc consulting for Foodminds, Life Sciences Research Organization, Nutrition Impact, Amarin, AstraZeneca, Winston, and Strawn LLP; membership in Unilever North America Scientific Advisory Board; and chapter royalties from UpToDate. Dr Woodward reported receiving consulting fees from Amgen and Novartis and research funding from Sanofi. No other disclosures were reported.

Figures

**Figure 1**
Relative Risk (RR) of Fatal Coronary Heart Disease (CHD) per 1-SD Increase in the Biomarkers α-Linolenic Acid (ALA; 18:3ω-3) and Eicosapentaenoic Acid (EPA; 20:5ω-3) Estimates were pooled using random effects meta-analysis. See eFigure 1 in the Supplement for results using inverse-variance weights. CHS indicates Cardiovascular Health Study; EPIC-Norfolk, European Prospective Investigation of Cancer (Norfolk); HPFS, Health Professionals Follow-up Study; KIHD, Kuopio Ischaemic Heart Disease Risk Factor Study; MCCS, Melbourne Collaborative Cohort Study; MESA, Multi-Ethnic Study of Atherosclerosis; NHS, Nurses’ Health Study; NSHDS, Northern Sweden Health and Disease Study^,; PHS, Physician’s Health Study; SCHS, Singapore Chinese Health Study; and ULSAM, Uppsala Longitudinal Study of Adult Men.

**Figure 2**
Relative Risk (RR) of Fatal Coronary Heart Disease (CHD) per 1-SD Increase in the Biomarkers Docosapentaenoic Acid (DPA; 22:5ω-3) and Docosahexaenoic Acid (DHA; 22:6ω-3) Estimates were pooled using random effects meta-analysis. See eFigure 1 in the Supplement for results using inverse-variance weights. CHS indicates Cardiovascular Health Study; EPIC-Norfolk, European Prospective Investigation of Cancer (Norfolk); HPFS, Health Professionals Follow-up Study; KIHD, Kuopio Ischaemic Heart Disease Risk Factor Study; MCCS, Melbourne Collaborative Cohort Study; MESA, Multi-Ethnic Study of Atherosclerosis; NHS, Nurses’ Health Study; NSHDS, Northern Sweden Health and Disease Study^,; PHS, Physician’s Health Study; SCHS, Singapore Chinese Health Study; SHHEC, Scottish Heart Health Extended Chart; and ULSAM, Uppsala Longitudinal Study of Adult Men.

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Comment in

Long-Chain Omega-3 Fatty Acid Bioavailability: Implications for Understanding the Effects of Supplementation on Heart Disease Risk.
Maki KC. Maki KC. J Nutr. 2018 Nov 1;148(11):1701-1703. doi: 10.1093/jn/nxy205. J Nutr. 2018. PMID: 30383282 No abstract available.

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ω-3 Polyunsaturated Fatty Acid Biomarkers and Coronary Heart Disease: Pooling Project of 19 Cohort Studies

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ω-3 Polyunsaturated Fatty Acid Biomarkers and Coronary Heart Disease: Pooling Project of 19 Cohort Studies

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