ω-3 Polyunsaturated Fatty Acid Biomarkers and Coronary Heart Disease

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.ARIC was carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201100012C), R01HL087641, R01HL59367 and R01HL086694; National Human Genome Research Institute contract U01HG004402; and National Institutes of Health contract HHSN268200625226C. The authors thank the staff and participants of the ARIC study for their important contributions. Infrastructure was partly supported by Grant Number UL1RR025005, a component of the National Institutes of Health and NIH Roadmap for Medical Research. 
CHS was supported by contracts HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, and grant U01HL080295 from the National Heart, Lung, and Blood Institute (NHLBI), with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided by R01AG023629 from the National Institute on Aging (NIA). A full list of principal CHS investigators and institutions can be found at CHS-NHLBI.org. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health
The Costa-Rican adult study was supported by grant R01HL081549 from the National Institutes of Health.
EURAMIC 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. Swiss National Science Foundation Grant 32-9257-87. Spanish FIS 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 also received support from the Medical Research Council Epidemiology Unit Core Support (MC_UU_12015/5).
HPFS was supported by the NIH grants UM1 CA167552, R01 HL35464, AA11181, HL35464, CA55075, HL60712 and P30 DK46200
The InChianti study was supported as a ‘targeted project’ (ICS 110.1\RS97.71) by the Italian Ministry of Health and in part by the Intramural Research Program of the NIH (Contracts N01-AG-916413 and N01-AG-821336 and Contracts 263 MD 9164 13 and 263 MD 821336)
KIND (Kuopio Ischaemic Heart Disease Risk Factor Study) was supported by grants from the Academy of Finland, Helsinki, Finland (grants 41471, 1041086)
MCCS (Melbourne Collaborative Cohort Study) recruitment was funded by VicHealth and Cancer Council Victoria. The MCCS was further supported by Australian NHMRC grants 209057, 251553 and 504711 and by infrastructure provided by Cancer Council Victoria. Cases and their vital status were ascertained through the Victorian Cancer Registry (VCR) and the Australian Institute of Health and Welfare (AIHW), including the National Death Index and the Australian Cancer Database.
MESA and the MESA SHARe project are conducted and supported by the National Heart, Lung, and Blood Institute (NHLBI) 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-MEHC-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. Funding for SHARe genotyping was provided by NHLBI Contract N02-HL-64278. Genotyping was performed at Affymetrix (Santa Clara, California, USA) and the Broad Institute of Harvard and MIT (Boston, Massachusetts, USA) using the Affymetric Genome-Wide Human SNP Array 6.0. 
NSHDS I & II (The Northern Sweden Health & Disease Study I & II) was supported by the Swedish Cancer Society and the Swedish Research Council
NHS (Nurses’ Health Study) was supported by research grants UM1 CA186107, R01 CA49449, R01 HL034594, P01CA87969, R01HL034594, and R01HL088521 of the National Institutes of Health 
The PHS (Physician’s Health Study) was supported by grant R21 HL088081, CA-34944 and CA-40360, and CA-097193 from the National Cancer Institute and grants HL-26490 and HL-34595from the National Heart, Lung, and Blood Institute, Bethesda, MD.
The 3C (Three-City) study was conducted under a partnership agreement between the Institut National de la Santé et de la Recherche Médicale (INSERM), the University Bordeaux 2 Victor Segalen and Sanofi-Aventis. The Fondation pour la Recherche Médicale funded the preparation and initiation of the study. The Three-City study was also supported by the Caisse Nationale Maladie des Travailleurs Salariés, Direction Générale de la Santé, MGEN, Institut de la Longévité, Conseils Régionaux d’Aquitaine et Bourgogne, Fondation de France, Ministry of Research-INSERM Programme “Cohortes et collections de données biologiques”,  Agence Nationale de la Recherche (grant number COGINUT ANR-06-PNRA-005), the Fondation Plan Alzheimer (grant number FCS 2009-2012), and the Caisse Nationale pour la Solidarité et l’Autonomie (CNSA) . Dr Samieri was on a grant from the “Fondation Plan Alzheimer”
SHHEC (Scottish Heart Health Extended Cohort) study was funded by the Scottish Health Department Chief Scientist Organization; British Heart Foundation; FP Fleming Trust. The authors would like to acknowledge Dr. Roger Tavendale for his work with the Scottish Heart Health Study.
SCHS (Singapore Chinese Health Study) was supported by the Singapore National Medical Research Council (grant number: NMRC 1270/2010) and the U.S. NIH (grant numbers: R01CA 144034 and UM1 CA182876)
ULSAM 50 and 70 were funded by the Swedish Research Council for Health, Working Life and Welfare (FORTE) Uppsala City Council (ALF) and Swedish Research CouncilThis is the final version of the article. It first appeared from American Medical Association via http://dx.doi.org/10.1001/jamainternmed.2016.292