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

William S Harris^{1

2}, Nathan L Tintle^{3

4}, Fumiaki Imamura⁵, Frank Qian^{6

7}, Andres V Ardisson Korat⁷, Matti Marklund^{8

9}, Luc Djoussé⁷, Julie K Bassett¹⁰, Pierre-Hugues Carmichael¹¹, Yun-Yu Chen¹², Yoichiro Hirakawa¹³, Leanne K Küpers¹⁴, Federica Laguzzi¹⁵, Maria Lankinen¹⁶, Rachel A Murphy¹⁷, Cécilia Samieri¹⁸, Mackenzie K Senn¹⁹, Peilin Shi²⁰, Jyrki K Virtanen¹⁶, Ingeborg A Brouwer²¹, Kuo-Liong Chien^{22

23}, Gudny Eiriksdottir²⁴, Nita G Forouhi⁵, Johanna M Geleijnse¹⁴, Graham G Giles²⁵, Vilmundur Gudnason^{24

26}, Catherine Helmer¹⁸, Allison Hodge²⁵, Rebecca Jackson²⁷, Kay-Tee Khaw⁵, Markku Laakso²⁸, Heidi Lai^{20

29}, Danielle Laurin^{11

30}, Karin Leander¹⁵, Joan Lindsay³¹, Renata Micha²⁰, Jaako Mursu¹⁶, Toshiharu Ninomiya³², Wendy Post¹⁰, Bruce M Psaty³³, Ulf Risérus³⁴, Jennifer G Robinson^{35

36}, Aladdin H Shadyab³⁷, Linda Snetselaar³⁶, Aleix Sala-Vila^{3

38}, Yangbo Sun^{36

39}, Lyn M Steffen⁴⁰, Michael Y Tsai⁴¹, Nicholas J Wareham⁵, Alexis C Wood¹⁹, Jason H Y Wu⁸, Frank Hu^{6

7}, Qi Sun^{6

7}, David S Siscovick⁴², Rozenn N Lemaitre³³, Dariush Mozaffarian²⁰; Fatty Acids and Outcomes Research Consortium (FORCE)

Affiliations

¹ Department of Internal Medicine, Sanford School of Medicine, University of South Dakota, Sioux Falls, SD, USA. wsh@faresinst.com.
² The Fatty Acid Research Institute, Sioux Falls, SD, USA. wsh@faresinst.com.
³ The Fatty Acid Research Institute, Sioux Falls, SD, USA.
⁴ Department of Mathematics and Statistics, Dordt University, Sioux Center, IA, USA.
⁵ MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Cambridge, UK.
⁶ Department of Nutrition, Harvard T.H. Chan School of Public Health and Harvard Medical School, Boston, MA, USA.
⁷ Department of Medicine, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA, USA.
⁸ The George Institute for Global Health and the Faculty of Medicine, University New South Wales, Sydney, Australia.
⁹ Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
¹⁰ Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, VIC, Australia.
¹¹ Centre D'excellence Sur le Vieillissement de Québec, CIUSSS-CN, Quebec, QC, Canada.
¹² Department of Medicine, Taipei Veterans General Hospital; and Institute of Epidemiology and Preventive Medicine, National Taiwan University, Taipei, Taiwan.
¹³ Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
¹⁴ Division of Human Nutrition and Health, Wageningen University, Wageningen, The Netherlands.
¹⁵ Institute of Environmental Medicine, Karolinska Institute, Stockholm, Sweden.
¹⁶ Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland.
¹⁷ Cancer Control Research, BC Cancer Agency; and School of Population and Public Health, University of British Columbia, Vancouver, BC, Canada.
¹⁸ Bordeaux Population Health Research Centre, INSERM, University of Bordeaux, Bordeaux, France.
¹⁹ USDA/ARS Children's Nutrition Research Center, Baylor College of Medicine, Houston, TX, USA.
²⁰ Freidman School of Nutrition Science and Policy, Tufts University, Boston, MA, USA.
²¹ Department of Health Sciences, Faculty of Science, Vrije Universiteit Amsterdam, Amsterdam and Amsterdam Public Health Research Institute, Amsterdam, The Netherlands.
²² Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan.
²³ Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.
²⁴ Icelandic Heart Association, Kopavogur, Iceland.
²⁵ Centre for Epidemiology and Biostatistics, The University of Melbourne, Melbourne, Australia.
²⁶ School of Health Sciences, University of Iceland, Reykjavík, Iceland.
²⁷ Department of Internal Medicine, Division of Endocrinology, The Ohio State University, Columbus, OH, USA.
²⁸ Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland.
²⁹ Department of Primary Care and Public Health, Imperial College, London, UK.
³⁰ VITAM Research Centers, Laval University, Quebec, QC, Canada.
³¹ School of Epidemiology and Public Health, University of Ottawa, Ottawa, Canada.
³² Department of Epidemiology and Public Health, Kyushu University, Fukuoka, Japan.
³³ Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA.
³⁴ Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism, Uppsala University, Uppsala, Sweden.
³⁵ Department of Medicine, University of Iowa, Iowa City, IA, USA.
³⁶ Department of Epidemiology, University of Iowa, Iowa City, IA, USA.
³⁷ Department of Family Medicine and Public Health, University of California San Diego School of Medicine, La Jolla, CA, USA.
³⁸ Hospital del Mar Medical Research Institute & Barcelona βeta Brain Research Center, Pasqual Maragall Foundation, Barcelona, Spain.
³⁹ Department of Preventive Medicine, University of Tennessee Health Science Center, Memphis, TN, USA.
⁴⁰ School of Public Health, Division of Epidemiology and Community Health, University of Minnesota, Minneapolis, MN, USA.
⁴¹ Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, USA.
⁴² The New York Academy of Medicine, New York, NY, USA.

PMID: 33888689
PMCID: PMC8062567
DOI: 10.1038/s41467-021-22370-2

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

William S Harris et al. Nat Commun. 2021.

. 2021 Apr 22;12(1):2329.

doi: 10.1038/s41467-021-22370-2.

Authors

Affiliations

¹ Department of Internal Medicine, Sanford School of Medicine, University of South Dakota, Sioux Falls, SD, USA. wsh@faresinst.com.
² The Fatty Acid Research Institute, Sioux Falls, SD, USA. wsh@faresinst.com.
³ The Fatty Acid Research Institute, Sioux Falls, SD, USA.
⁴ Department of Mathematics and Statistics, Dordt University, Sioux Center, IA, USA.
⁵ MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Cambridge, UK.
⁶ Department of Nutrition, Harvard T.H. Chan School of Public Health and Harvard Medical School, Boston, MA, USA.
⁷ Department of Medicine, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA, USA.
⁸ The George Institute for Global Health and the Faculty of Medicine, University New South Wales, Sydney, Australia.
⁹ Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
¹⁰ Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, VIC, Australia.
¹¹ Centre D'excellence Sur le Vieillissement de Québec, CIUSSS-CN, Quebec, QC, Canada.
¹² Department of Medicine, Taipei Veterans General Hospital; and Institute of Epidemiology and Preventive Medicine, National Taiwan University, Taipei, Taiwan.
¹³ Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
¹⁴ Division of Human Nutrition and Health, Wageningen University, Wageningen, The Netherlands.
¹⁵ Institute of Environmental Medicine, Karolinska Institute, Stockholm, Sweden.
¹⁶ Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland.
¹⁷ Cancer Control Research, BC Cancer Agency; and School of Population and Public Health, University of British Columbia, Vancouver, BC, Canada.
¹⁸ Bordeaux Population Health Research Centre, INSERM, University of Bordeaux, Bordeaux, France.
¹⁹ USDA/ARS Children's Nutrition Research Center, Baylor College of Medicine, Houston, TX, USA.
²⁰ Freidman School of Nutrition Science and Policy, Tufts University, Boston, MA, USA.
²¹ Department of Health Sciences, Faculty of Science, Vrije Universiteit Amsterdam, Amsterdam and Amsterdam Public Health Research Institute, Amsterdam, The Netherlands.
²² Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan.
²³ Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.
²⁴ Icelandic Heart Association, Kopavogur, Iceland.
²⁵ Centre for Epidemiology and Biostatistics, The University of Melbourne, Melbourne, Australia.
²⁶ School of Health Sciences, University of Iceland, Reykjavík, Iceland.
²⁷ Department of Internal Medicine, Division of Endocrinology, The Ohio State University, Columbus, OH, USA.
²⁸ Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland.
²⁹ Department of Primary Care and Public Health, Imperial College, London, UK.
³⁰ VITAM Research Centers, Laval University, Quebec, QC, Canada.
³¹ School of Epidemiology and Public Health, University of Ottawa, Ottawa, Canada.
³² Department of Epidemiology and Public Health, Kyushu University, Fukuoka, Japan.
³³ Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA.
³⁴ Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism, Uppsala University, Uppsala, Sweden.
³⁵ Department of Medicine, University of Iowa, Iowa City, IA, USA.
³⁶ Department of Epidemiology, University of Iowa, Iowa City, IA, USA.
³⁷ Department of Family Medicine and Public Health, University of California San Diego School of Medicine, La Jolla, CA, USA.
³⁸ Hospital del Mar Medical Research Institute & Barcelona βeta Brain Research Center, Pasqual Maragall Foundation, Barcelona, Spain.
³⁹ Department of Preventive Medicine, University of Tennessee Health Science Center, Memphis, TN, USA.
⁴⁰ School of Public Health, Division of Epidemiology and Community Health, University of Minnesota, Minneapolis, MN, USA.
⁴¹ Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, USA.
⁴² The New York Academy of Medicine, New York, NY, USA.

PMID: 33888689
PMCID: PMC8062567
DOI: 10.1038/s41467-021-22370-2

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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Conflict of interest statement

The authors below declare the following competing interests outside of the submitted work. A.I.B., Involvement in a research project partly funded by Unilever. A.S.V., Grants and support to attend professional meetings from the California Walnut Commission. B.M.P., Data and Safety Monitoring Board of a clinical trial funded by Zoll LifeCor; Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. D.M., Research grants to Institution: the National Institutes of Health, the Gates Foundation, and the Rockefeller Foundation; Personal Fees: the Global Organization for EPA and DHA Omega-3, Bunge, Indigo Agriculture, Motif FoodWorks, Amarin, Acasti Pharma, Cleveland Clinic Foundation, Danone, and America’s Test Kitchen; Scientific Advisory Boards: Brightseed, Calibrate, DayTwo, Elysium Health, Filtricine, Foodome, Human Co., and Tiny Organics; and Chapter Royalties: UpToDate. J.G.R., Research grants to Institution: Acasti, Amarin, Amgen, Astra-Zeneca, Eli Lilly, Esperion, Medicines Company, Merck, Novartis, Novo-Nordisk, Regeneron, and Sanofi. Consultant: Getz Pharma, Medicines Company, and Sanofi. R.A.M., Research grants to Institution: I.L.S.I. North America; Personal Fees from PharmaVite. The author below declares the following competing interests related to the submitted work. W.S.H., Stock in OmegaQuant Analytics, LLC (a laboratory that offers blood fatty acid testing); Schiff Institute Science and Innovation Advisory Board. The remaining authors declare no competing interests.

Figures

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. 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).

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References

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

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

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Conflict of interest statement

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