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Original Investigation |

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

Liana C. Del Gobbo, PhD1; Fumiaki Imamura, PhD2; Stella Aslibekyan, PhD3; 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
JAMA Intern Med. 2016;176(8):1155-1166. doi:10.1001/jamainternmed.2016.2925.
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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.

Figures in this Article

Figures

Place holder to copy figure label and caption
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. CHS indicates Cardiovascular Health Study20; EPIC-Norfolk, European Prospective Investigation of Cancer (Norfolk)21; HPFS, Health Professionals Follow-up Study23; KIHD, Kuopio Ischaemic Heart Disease Risk Factor Study25; MCCS, Melbourne Collaborative Cohort Study26; MESA, Multi-Ethnic Study of Atherosclerosis27; NHS, Nurses’ Health Study30; NSHDS, Northern Sweden Health and Disease Study28,29; PHS, Physician’s Health Study31; SCHS, Singapore Chinese Health Study33; and ULSAM, Uppsala Longitudinal Study of Adult Men.35

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Place holder to copy figure label and caption
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. CHS indicates Cardiovascular Health Study20; EPIC-Norfolk, European Prospective Investigation of Cancer (Norfolk)21; HPFS, Health Professionals Follow-up Study23; KIHD, Kuopio Ischaemic Heart Disease Risk Factor Study25; MCCS, Melbourne Collaborative Cohort Study26; MESA, Multi-Ethnic Study of Atherosclerosis27; NHS, Nurses’ Health Study30; NSHDS, Northern Sweden Health and Disease Study28,29; PHS, Physician’s Health Study31; SCHS, Singapore Chinese Health Study33; SHHEC, Scottish Heart Health Extended Chart32; and ULSAM, Uppsala Longitudinal Study of Adult Men.35

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