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Original Investigation
August 2016

ω-3 Polyunsaturated Fatty Acid Biomarkers and Coronary Heart DiseasePooling Project of 19 Cohort Studies

Liana C. Del Gobbo, PhD1; Fumiaki Imamura, PhD2; Stella Aslibekyan, PhD3; et al Matti Marklund, PhD4; Jyrki K. Virtanen, PhD5; Maria Wennberg, PhD6; Mohammad Y. Yakoob, PhD1; Stephanie E. Chiuve, ScD7,8; Luicito dela Cruz, PhD9; Alexis C. Frazier-Wood, PhD10; Amanda M. Fretts, MPH, PhD11; Eliseo Guallar, PhD12; Chisa Matsumoto, PhD, MD13,14; Kiesha Prem, MSc15; Tosh Tanaka, PhD16; Jason H. Y. Wu, PhD17; Xia Zhou, PhD18; Catherine Helmer, MD, PhD19,20; Erik Ingelsson, MD, PhD1,21; Jian-Min Yuan, MD, PhD22,23; Pascale Barberger-Gateau, PhD19,20; Hannia Campos, PhD24; Paulo H. M. Chaves, MD, PhD25; Luc Djoussé, MD, ScD14; Graham G. Giles, PhD9; Jose Gómez-Aracena, PhD26; Allison M. Hodge, PhD9; Frank B. Hu, PhD, MD, MPH8,24,27; Jan-Håkan Jansson, MD, PhD6; Ingegerd Johansson, PhD28; Kay-Tee Khaw, PhD, MD29; Woon-Puay Koh, PhD15,30; Rozenn N. Lemaitre, PhD, MPH31; Lars Lind, PhD21; Robert N. Luben, PhD29; Eric B. Rimm, ScD8,24,27; Ulf Risérus, PhD, MD4; Cecilia Samieri, PhD19,20; Paul W. Franks, PhD6,24,32; David S. Siscovick, MPH, MD33; Meir Stampfer, DrPH, MD8,24,27; Lyn M. Steffen, PhD, MPH18; Brian T. Steffen, PhD18; Michael Y. Tsai, PhD34; Rob M. van Dam, PhD15,24,35; Sari Voutilainen, PhD5; Walter C. Willett, DrPH, MD8,24,27; Mark Woodward, PhD12,17,36; Dariush Mozaffarian, MD, DrPH37; for the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Fatty Acids and Outcomes Research Consortium (FORCe)
Author Affiliations
  • 1Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, California
  • 2Medical Research Council Epidemiology Unit, Institute of Metabolic Science, University of Cambridge School of Clinical Medicine, Cambridge University, Cambridge, United Kingdom
  • 3Department of Epidemiology, University of Alabama at Birmingham School of Public Health, Birmingham
  • 4Department of Public Health and Caring Sciences, Uppsala University, Uppsala, Sweden
  • 5Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Joensuu, Finland
  • 6Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden
  • 7Division of Preventive Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts
  • 8Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, Massachusetts
  • 9Cancer Epidemiology Centre, Cancer Council Victoria, Victoria, Australia
  • 10USDA/ARS Children’s Nutrition Research Center, Baylor College of Medicine, Houston, Texas
  • 11Department of Epidemiology, University of Washington, Seattle
  • 12Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland
  • 13Division of Cardiology, Tokyo Medical University, Tokyo, Japan
  • 14Division of Aging, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
  • 15Saw Swee Hock School of Public Health, National University of Singapore, Singapore
  • 16Translational Gerontology Branch, National Institute on Aging, Bethesda, Maryland
  • 17The George Institute for Global Health, Sydney Medical School, University of Sydney, Sydney, Australia
  • 18Division of Epidemiology and Community Health, University of Minnesota School of Public Health, Minneapolis
  • 19Institut 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, France
  • 20University Bordeaux, Institut de Santé Publique, d'Épidémiologie et de Développement, Centre Institut National de la Santé et de la Recherche Médicale U897-Epidemiologie-Biostatistique, Bordeaux, France
  • 21Department of Medical Sciences, Uppsala University, Uppsala, Sweden
  • 22Division of Cancer Control and Population Sciences, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania
  • 23Department of Epidemiology, University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania
  • 24Department of Nutrition, Harvard T. H. Chan School of Public Health, Boston, Massachusetts
  • 25Benjamin Leon Center for Geriatric Research and Education, Florida International University, Miami
  • 26Department of Preventive Medicine, Universidad de Malaga, Malaga, Spain
  • 27Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
  • 28Department of Odontology, Umeå University, Umeå, Sweden
  • 29Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom
  • 30Duke-NUS Graduate Medical School Singapore, Singapore
  • 31Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle
  • 32Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Lund University, Lund, Sweden
  • 33The New York Academy of Medicine, New York
  • 34Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis
  • 35Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore and National University Health System, Singapore
  • 36The George Institute for Global Health, Nuffield Department of Public Health, Oxford University, Oxford, United Kingdom
  • 37Friedman School of Nutrition Science and Policy, Tufts University, Boston, Massachusetts

Copyright 2016 American Medical Association. All Rights Reserved. Applicable FARS/DFARS Restrictions Apply to Government Use.

JAMA Intern Med. 2016;176(8):1155-1166. doi:10.1001/jamainternmed.2016.2925

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 per 1 SD. Across quintiles, lower risk of nonfatal MI was evident with EPA (RR, 0.71; 95% CI, 0.56-0.90) and ALA (RR, 0.87; 95% CI, 0.78-0.97), and lower risk of fatal CHD was evident with DPA (RR, 0.76; 95% CI, 0.65-0.90) and DHA (RR, 0.77; 95% CI, 0.64-0.89). 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 lower incidence of fatal CHD.