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; 20:5 ω-3), docosapentaenoic acid (DPA; 22:5 ω-3), and docosahexaenoic acid (DHA; 22:6 ω-3) and plant-derived α-linolenic acid (ALA; 18:3 ω-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 baselinewas 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 DHAwere 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 MIwere 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.
Bibliographical noteFunding Information:
The Atherosclerosis Risk in Communities study was performed as a collaborative study supported by contracts HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, HHSN268201100012C, R01HL087641, R01HL59367, and R01HL086694 from the National Heart, Lung, and Blood Institute; contract U01HG004402 from the National Human Genome Research Institute; and contract HHSN268200625226C from the National Institutes of Health. We thank the staff and participants of the Atherosclerosis Risk in Communities study for their important contributions. Infrastructure was partly supported by grant UL1RR025005, a component of the National Institutes of Health and National Institutes of Health Roadmap for Medical Research. The Cardiovascular Health Study (CHS) was supported by contracts HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, and N01HC85086 and grant U01HL080295 from the National Heart, Lung, and Blood Institute, with additional contribution from the National Institute of Neurological Disorders and Stroke. Additional support was provided by grant R01AG023629 from the National Institute on Aging. A full list of principal CHS investigators and institutions can be found at CHS-NHLBI.org. The Costa Rican adult study was supported by grant R01HL081549 from the National Institutes of Health. The European Study on Antioxidants, Myocardial Infarction and Cancer was supported by the Commission of the European Communities, as a Concerted Action within Directorate General-XII, with additional support from Directorate General-V Europe against Cancer. The national studies were financed by the Dutch Ministry of Health. Ulster Cancer Foundation and Milk Intervention Board, grant AKT76 from Cancer Research Switzerland, grant 32-9257-87 from the Swiss National Science Foundation, The Spanish Fondo de Investigaciones Sanitarias and Ministry of Science and Education, and German Federal Health Office. EPIC-Norfolk was funded by grants from Medical Research Council and Cancer Research UK. Dr Imamura received support from grant MC-UU-12015/5 from the Medical Research Council Epidemiology Unit. The Health Professionals Follow-up Study (HPFS) was supported by grants UM1 CA167552, R01 HL35464, AA11181, HL35464, CA55075, HL60712, and P30 DK46200 from the National Institutes of Health. The InChianti study was supported by grant ICS 110.1\RS97.71 as a targeted project by the ItalianMinistry of Health and in part by contracts N01-AG-916413, N01-AG- 821336, 263 MD 9164 13, and 263MD 821336 from the Intramural Research Program of the National Institutes of Health. The Kuopio Ischaemic Heart Disease Risk Factor Study was supported by grants 41471 and 1041086 from the Academy of Finland, Helsinki, Finland. The Melbourne Collaborative Cohort Study recruitment was funded by VicHealth and Cancer Council Victoria and was further supported by grants 209057, 251553, and 504711 from Australia's National Health and Medical Research Council and by infrastructure provided by Cancer Council Victoria. Cases and their vital status were ascertained through the Victorian Cancer Registry and the Australian Institute of Health and Welfare, including the National Death Index and the Australian Cancer Database. The Multi-Ethnic Study of Atherosclerosis (MESA) and the MESA SHARe project are conducted and supported by the National Heart, Lung, and Blood Institute in collaboration with MESA investigators. Support for MESA is provided by contracts N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169, UL1-TR-001079, and UL1-TR- 000040 from the National Heart, Lung, and Blood Institute. Funding for SHARe genotyping was provided by contract N02-HL-64278 from the National Heart, Lung, and Blood Institute. Genotyping was performed at Affymetrix and the Broad Institute of Harvard and MIT using the Affymetrix Genome-Wide Human SNP Array 6.0. The Northern Sweden Health and Disease Studies I and II were supported by the Swedish Cancer Society and the Swedish Research Council. The Nurses Health Study was supported by research grants UM1 CA186107, R01 CA49449, R01 HL034594, P01CA87969, R01HL034594, and R01HL088521 from the National Institutes of Health. The Physician's Health Study was supported by grants R21 HL088081, CA-34944, CA-40360, and CA-097193 from the National Cancer Institute and grants HL-26490 and HL-34595 from the National Heart, Lung, and Blood Institute. The Three-City study was conducted under a partnership agreement between the Institut National de la Sant? et de la Recherche M?dicale, the University Bordeaux 2 Victor Segalen, and Sanofi. The Fondation pour la Recherche M?dicale funded the preparation and initiation of the study. The Three-City study was also supported by the Caisse Nationale Maladie des Travailleurs Salari?s, Direction G?n?rale de la Sant?, MGEN, Institut de la Long?vit?, Conseils R?gionaux d'Aquitaine et Bourgogne, Fondation de France, Ministry of Research-Institut National de la Sant? et de la Recherche M?dicale Programme Cohortes et collections de donn?es biologiques, grant COGINUT ANR-06-PNRA-005 from the Agence Nationale de la Recherche, grant FCS 2009-2012 from the Fondation Plan Alzheimer, and the Caisse Nationale pour la Solidarit? et l'Autonomie. Dr Samieri was sponsored by a grant from the Fondation Plan Alzheimer. The Scottish Heart Health Extended Cohort study was funded by the Scottish Health Department Chief Scientist Organization, British Heart Foundation, and FP Fleming Trust. The Singapore Chinese Health Study was supported by grant NMRC 1270/2010 fromthe Singapore National Medical Research Council and grants R01CA 144034 and UM1 CA182876 from the National Institutes of Health. The Uppsala Longitudinal Studies of Adult Men 50 and 70 were funded by the Swedish Research Council for Health, Working Life and Welfare, Uppsala City Council, and Swedish Research Council.