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Cited by 244Fatty Acid Research and HealthNutritional Studies and DietAquaculture Nutrition and Growth

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Blood n-3 fatty acid levels and total and cause-specific mortality from 17 prospective studies

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Harris, William S., Tintle, Nathan L., Imamura, Fumiaki, Qian, Frank, Korat, Andres V. Ardisson, Marklund, Matti, Djoussé, Luc, Bassett, Julie K., Carmichael, Pierre-Hugues, Chen, Yun-Yu, Hirakawa, Yoichiro, Küpers, Leanne K., Laguzzi, Federica, Lankinen, Maria, Murphy, Rachel A., Samieri, Cécilia, Senn, Mackenzie K., Shi, Peilin, Virtanen, Jyrki K., Brouwer, Ingeborg A., Chien, Kuo-Liong, Eiriksdottir, Gudny, Forouhi, Nita G., Geleijnse, Johanna M., Giles, Graham G., Gudnason, Vilmundur, Helmer, Catherine, Hodge, Allison, Jackson, Rebecca, Khaw, Kay-Tee, Laakso, Markku, Lai, Heidi, Laurin, Danielle, Leander, Karin, Lindsay, Joan, Micha, Renata, Mursu, Jaako, Ninomiya, Toshiharu, Post, Wendy, Psaty, Bruce M., Risérus, Ulf, Robinson, Jennifer G., Shadyab, Aladdin H., Snetselaar, Linda, Sala-Vila, Aleix, Sun, Yangbo, Steffen, Lyn M., Tsai, Michael Y., Wareham, Nicholas J., Wood, Alexis C., Wu, Jason H. Y., Hu, Frank, Sun, Qi, Siscovick, David S., Lemaitre, Rozenn N., Mozaffarian, Dariush, The Fatty Acids and Outcomes Research Consortium (FORCE)·2021·Nature Communications
DOI 10.1038/s41467-021-22370-2PMC PMC8062567
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Abstract

The health effects of omega-3 fatty acids have been controversial. Here we report the results of a de novo pooled analysis conducted with data from 17 prospective cohort studies examining the associations between blood omega-3 fatty acid levels and risk for all-cause mortality. Over a median of 16 years of follow-up, 15,720 deaths occurred among 42,466 individuals. We found that, after multivariable adjustment for relevant risk factors, risk for death from all causes was significantly lower (by 15–18%, at least p < 0.003) in the highest vs the lowest quintile for circulating long chain (20–22 carbon) omega-3 fatty acids (eicosapentaenoic, docosapentaenoic, and docosahexaenoic acids). Similar relationships were seen for death from cardiovascular disease, cancer and other causes. No associations were seen with the 18-carbon omega-3, alpha-linolenic acid. These findings suggest that higher circulating levels of marine n-3 PUFA are associated with a lower risk of premature death.

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Fig. 1 Adjusted hazard ratios (HR, 95% CI) for total mortality for circulating eicosapentaenoic (EPA) plus docosahexaenoic acid (DHA) in the 17 contributing studies of the Fatty Acids and Outcomes Research Consortium. Study-specific estimates for HRs (dark squares) are shown per interquartile range (comparing the midpoint of the top to the bottom quintiles) their sizes indicate study weights (column 3). The horizontal line through each HR is 95% CI. Compartments included erythrocyte phospholipids, plasma phospholipids, cholesteryl esters, and total plasma. All HRs are adjusted for age, sex, race, field center, body-mass index, education, occupation, marital status, smoking, physical activity, alcohol intake, prevalent diabetes, hypertension, and dyslipidemia, self-reported general health, and the sum of circulating n-6 PUFA (linoleic plus arachidonic acids). See Table 1 footnote for abbreviations of cohorts.
Fig. 1 Adjusted hazard ratios (HR, 95% CI) for total mortality for circulating eicosapentaenoic (EPA) plus docosahexaenoic acid (DHA) in the 17 contributing studies of the Fatty Acids and Outcomes Research Consortium. Study-specific estimates for HRs (dark squares) are shown per interquartile range (comparing the midpoint of the top to the bottom quintiles) their sizes indicate study weights (column 3). The horizontal line through each HR is 95% CI. Compartments included erythrocyte phospholipids, plasma phospholipids, cholesteryl esters, and total plasma. All HRs are adjusted for age, sex, race, field center, body-mass index, education, occupation, marital status, smoking, physical activity, alcohol intake, prevalent diabetes, hypertension, and dyslipidemia, self-reported general health, and the sum of circulating n-6 PUFA (linoleic plus arachidonic acids). See Table 1 footnote for abbreviations of cohorts.CC BY · PubMed Central
Fig. 2 Associations of circulating long-chain n-3 PUFA levels with all-cause mortality: nonlinear dose-response meta-analysis in the Fatty Acids and Outcomes Research Consortium. Hazard ratios and cohort-specific quantiles are presented in the vertical and horizontal axis, respectively. The best estimates and their confidence intervals are presented as black lines and gray-shaded areas, respectively. The 10th percentile was selected as a reference level and the x-axis depicts 5th to 95th percentiles. Potential nonlinearity was identified for EPA (p = 0.0004) but not for the others (p > 0.05). All HRs are adjusted for age, sex, race, field center, body-mass index, education, occupation, marital status, smoking, physical activity, alcohol intake, prevalent diabetes, hypertension, and dyslipidemia, self-reported general health, and the sum of circulating n-6 PUFA (linoleic plus arachidonic acids).
Fig. 2 Associations of circulating long-chain n-3 PUFA levels with all-cause mortality: nonlinear dose-response meta-analysis in the Fatty Acids and Outcomes Research Consortium. Hazard ratios and cohort-specific quantiles are presented in the vertical and horizontal axis, respectively. The best estimates and their confidence intervals are presented as black lines and gray-shaded areas, respectively. The 10th percentile was selected as a reference level and the x-axis depicts 5th to 95th percentiles. Potential nonlinearity was identified for EPA (p = 0.0004) but not for the others (p > 0.05). All HRs are adjusted for age, sex, race, field center, body-mass index, education, occupation, marital status, smoking, physical activity, alcohol intake, prevalent diabetes, hypertension, and dyslipidemia, self-reported general health, and the sum of circulating n-6 PUFA (linoleic plus arachidonic acids).CC BY · PubMed Central

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Authors
Harris, W. S., Tintle, N. L., Imamura, F., Qian, F., Korat, A. V. A., Marklund, M., Djoussé, L., Bassett, J. K., Carmichael, P.-H., Chen, Y.-Y., Hirakawa, Y., Küpers, L. K., Laguzzi, F., Lankinen, M., Murphy, R. A., Samieri, C., Senn, M. K., Shi, P., Virtanen, J. K., Brouwer, I. A., Chien, K.-L., Eiriksdottir, G., Forouhi, N. G., Geleijnse, J. M., Giles, G. G., Gudnason, V., Helmer, C., Hodge, A., Jackson, R., Khaw, K.-T., Laakso, M., Lai, H., Laurin, D., Leander, K., Lindsay, J., Micha, R., Mursu, J., Ninomiya, T., Post, W., Psaty, B. M., Risérus, U., Robinson, J. G., Shadyab, A. H., Snetselaar, L., Sala-Vila, A., Sun, Y., Steffen, L. M., Tsai, M. Y., Wareham, N. J., Wood, A. C., Wu, J. H. Y., Hu, F., Sun, Q., Siscovick, D. S., Lemaitre, R. N., Mozaffarian, D., & The Fatty Acids and Outcomes Research Consortium (FORCE)
Affiliations
  • University of South Dakota (US)
  • Dordt University (US)
  • University of Cambridge (GB)
  • Brigham and Women's Hospital (US)
  • Johns Hopkins University (US)
  • Cancer Council Victoria (AU)
  • National Taiwan University (TW)
  • Kyushu University (JP)
  • Wageningen University & Research (NL)
  • Karolinska Institutet (SE)
  • University of Eastern Finland (FI)
  • BC Cancer Agency (CA)
  • Université de Bordeaux (FR)
  • Baylor College of Medicine (US)
  • Tufts University (US)
  • Amsterdam Public Health (NL)
  • The University of Melbourne (AU)
  • University of Iceland (IS)
  • The Ohio State University (US)
  • Université Laval (CA)
  • University of Ottawa (CA)
  • University of Washington (US)
  • Uppsala University (SE)
  • University of Iowa (US)
  • University of California San Diego (US)
  • University of Minnesota (US)
  • UNSW Sydney (AU)
  • New York Academy of Medicine (US)
Corresponding author
Harris, William S.
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2021-04-22
Volume
12
Issue
1
Pages
2329-2329
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-021-22370-2
PMC
PMC8062567
OpenAlex
W3155934512
Cited by
244
References
67
Citations by year
2026: 33 · 2025: 45 · 2024: 45 · 2023: 46 · 2022: 53 · 2021: 21
FWCI
26.29
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • VU Research Portal (publishedVersion, other-oa)
  • HAL (submittedVersion, cc-by)
  • Socio-Environmental Systems Modeling (submittedVersion, cc-by)
  • Opin vísindi (Opin vísindi) (submittedVersion, cc-by-nc-sa)
  • Apollo (University of Cambridge) (submittedVersion, cc-by)
  • Digital Commons-TMC (Texas Medical Center) (submittedVersion)
  • Uppsala University Publications (Uppsala University) (submittedVersion, other-oa)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Minerva Access (University of Melbourne) (submittedVersion, cc-by)
  • Opin vísindi (Opin vísindi) (submittedVersion, other-oa)
  • Oskar-Bordeaux (Universite de Bordeaux) (submittedVersion, cc-by)
  • Repositori digital de la UPF (Universitat Pompeu Fabra) (submittedVersion, cc-by)
  • Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
  • Data Archiving and Networked Services (DANS) (submittedVersion, cc-by)
  • Apollo
  • Apollo (cc-by)
Funders
  • Bill and Melinda Gates Foundation
  • Rockefeller Foundation
  • Amgen
  • Eli Lilly and Company
  • Sanofi
  • Yale University
  • Pharmavite
  • Cleveland Clinic
  • Cleveland Clinic Foundation
  • Danone
  • Regeneron Pharmaceuticals
  • Amarin Corporation
  • California Walnut Commission
  • National Institute for Health and Care Research (NIHR202397)
  • Cambridge University Hospitals (146281)
  • Esperion Therapeutics
  • National Institutes of Health
  • Medical Research Council (MC_UU_12015/5, MC_UU_12015/1)
  • National Cancer Institute (T32CA009001)
Topics
  • Health Sciences › Nursing › Nutrition and Dietetics › Fatty Acid Research and Health
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Nutritional Studies and Diet
  • Life Sciences › Agricultural and Biological Sciences › Aquatic Science › Aquaculture Nutrition and Growth
Keywords
omega-3 fatty acids, blood fatty acid levels, all-cause mortality, cardiovascular mortality, cancer mortality, eicosapentaenoic acid, docosahexaenoic acid, docosapentaenoic acid, alpha-linolenic acid, marine omega-3 fatty acids, cause-specific mortality
MeSH terms
Aged, Aged, 80 and over, Cause of Death, Female, Follow-Up Studies, Humans, Male, Middle Aged, Prospective Studies, Risk Factors, Fatty Acids, Omega-3, Mortality, Premature, Protective Factors

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