Meta-Analysis

. 2017 Dec;5(12):965-974.

doi: 10.1016/S2213-8587(17)30307-8. Epub 2017 Oct 12.

Omega-6 fatty acid biomarkers and incident type 2 diabetes: pooled analysis of individual-level data for 39 740 adults from 20 prospective cohort studies

Jason H Y Wu¹, Matti Marklund², Fumiaki Imamura³, Nathan Tintle⁴, Andres V Ardisson Korat⁵, Janette de Goede⁶, Xia Zhou⁷, Wei-Sin Yang⁸, Marcia C de Oliveira Otto⁹, Janine Kröger¹⁰, Waqas Qureshi¹¹, Jyrki K Virtanen¹², Julie K Bassett¹³, Alexis C Frazier-Wood¹⁴, Maria Lankinen¹², Rachel A Murphy¹⁵, Kalina Rajaobelina¹⁶, Liana C Del Gobbo¹⁷, Nita G Forouhi³, Robert Luben¹⁸, Kay-Tee Khaw¹⁹, Nick Wareham³, Anya Kalsbeek²⁰, Jenna Veenstra²⁰, Juhua Luo²¹, Frank B Hu⁵, Hung-Ju Lin²², David S Siscovick²³, Heiner Boeing¹⁰, Tzu-An Chen¹⁴, Brian Steffen²⁴, Lyn M Steffen⁷, Allison Hodge¹³, Gudny Eriksdottir²⁵, Albert V Smith²⁵, Vilmunder Gudnason²⁵, Tamara B Harris²⁶, Ingeborg A Brouwer²⁷, Claudine Berr²⁸, Catherine Helmer¹⁶, Cecilia Samieri¹⁶, Markku Laakso²⁹, Michael Y Tsai²⁴, Graham G Giles¹³, Tarja Nurmi¹², Lynne Wagenknecht¹¹, Matthias B Schulze¹⁰, Rozenn N Lemaitre³⁰, Kuo-Liong Chien³¹, Sabita S Soedamah-Muthu⁶, Johanna M Geleijnse⁶, Qi Sun⁵, William S Harris³², Lars Lind³³, Johan Ärnlöv³⁴, Ulf Riserus², Renata Micha³⁵, Dariush Mozaffarian³⁵; Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Fatty Acids and Outcomes Research Consortium (FORCE)

Affiliations

¹ The George Institute for Global Health, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia. Electronic address: jwu1@georgeinstitute.org.au.
² Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism, Uppsala University, Uppsala, Sweden.
³ Medical Research Council Epidemiology Unit, University of Cambridge, Cambridge, UK.
⁴ Department of Mathematics and Statistics, Dordt College, Sioux Center, IA, USA.
⁵ Department of Nutrition and Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
⁶ Division of Human Nutrition, Wageningen University, Wageningen, Netherlands.
⁷ School of Public Health, Division of Epidemiology and Community Health, University of Minnesota, Minneapolis, MN, USA.
⁸ Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan.
⁹ Division of Epidemiology, Human Genetics and Environmental Sciences, The University of Texas Health Science Center, School of Public Health, Houston, TX, USA.
¹⁰ German Institute of Human Nutrition, Potsdam, Germany.
¹¹ Wake Forest University, Winston-Salem, NC, USA.
¹² Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland.
¹³ Cancer Council Victoria, Melbourne, VIC, Australia.
¹⁴ US Department of Agriculture/Agricultural Research Service, Children's Nutrition Research Center, Houston, TX, USA.
¹⁵ University of British Columbia, Vancouver, BC, Canada.
¹⁶ University of Bordeaux, INSERM, Bordeaux Population Health Research Centre, UMR 1219, Bordeaux, France.
¹⁷ Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA, USA.
¹⁸ Department of Public Health and Primary Care, School of Clinical Medicine, University of Cambridge, Cambridge, UK.
¹⁹ Department of Public Health and Primary Care, School of Clinical Medicine, University of Cambridge, Cambridge, UK; Department of Mathematics and Statistics, Dordt College, Sioux Center, IA, USA.
²⁰ Department of Mathematics and Statistics, Dordt College, Sioux Center, IA, USA; Department of Biology, Dordt College, Sioux Center, IA, USA.
²¹ Department of Epidemiology and Biostatistics, Indiana University, Bloomington, IN, USA.
²² Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.
²³ The New York Academy of Medicine, New York, NY, USA.
²⁴ Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, USA.
²⁵ Icelandic Heart Institute, Kópavogur, Iceland.
²⁶ National Institute on Aging, Bethesda, MD, USA.
²⁷ Health Sciences, Vrije Universiteit Amsterdam, Amsterdam, Netherlands.
²⁸ INSERM U1061, Neuropsychiatry: Epidemiological and Clinical Research, and Montpellier University Hospital, Montpellier University, Montpellier, France.
²⁹ Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland.
³⁰ Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA.
³¹ Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan; Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.
³² Department of Internal Medicine, Sanford School of Medicine, University of South Dakota, Sioux Falls, SD, USA; OmegaQuant Analytics, Sioux Falls, SD, USA.
³³ Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
³⁴ Department of Neurobiology, Care Sciences and Society, Division of Family Medicine, Karolinska Institute, Stockholm, Sweden; School of Health and Social Studies, Dalarna University, Falun, Sweden.
³⁵ Friedman School of Nutrition Science and Policy, Tufts University, Boston, MA, USA.

PMID: 29032079
PMCID: PMC6029721
DOI: 10.1016/S2213-8587(17)30307-8

Meta-Analysis

Omega-6 fatty acid biomarkers and incident type 2 diabetes: pooled analysis of individual-level data for 39 740 adults from 20 prospective cohort studies

Jason H Y Wu et al. Lancet Diabetes Endocrinol. 2017 Dec.

. 2017 Dec;5(12):965-974.

doi: 10.1016/S2213-8587(17)30307-8. Epub 2017 Oct 12.

Authors

Affiliations

¹ The George Institute for Global Health, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia. Electronic address: jwu1@georgeinstitute.org.au.
² Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism, Uppsala University, Uppsala, Sweden.
³ Medical Research Council Epidemiology Unit, University of Cambridge, Cambridge, UK.
⁴ Department of Mathematics and Statistics, Dordt College, Sioux Center, IA, USA.
⁵ Department of Nutrition and Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
⁶ Division of Human Nutrition, Wageningen University, Wageningen, Netherlands.
⁷ School of Public Health, Division of Epidemiology and Community Health, University of Minnesota, Minneapolis, MN, USA.
⁸ Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan.
⁹ Division of Epidemiology, Human Genetics and Environmental Sciences, The University of Texas Health Science Center, School of Public Health, Houston, TX, USA.
¹⁰ German Institute of Human Nutrition, Potsdam, Germany.
¹¹ Wake Forest University, Winston-Salem, NC, USA.
¹² Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland.
¹³ Cancer Council Victoria, Melbourne, VIC, Australia.
¹⁴ US Department of Agriculture/Agricultural Research Service, Children's Nutrition Research Center, Houston, TX, USA.
¹⁵ University of British Columbia, Vancouver, BC, Canada.
¹⁶ University of Bordeaux, INSERM, Bordeaux Population Health Research Centre, UMR 1219, Bordeaux, France.
¹⁷ Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA, USA.
¹⁸ Department of Public Health and Primary Care, School of Clinical Medicine, University of Cambridge, Cambridge, UK.
¹⁹ Department of Public Health and Primary Care, School of Clinical Medicine, University of Cambridge, Cambridge, UK; Department of Mathematics and Statistics, Dordt College, Sioux Center, IA, USA.
²⁰ Department of Mathematics and Statistics, Dordt College, Sioux Center, IA, USA; Department of Biology, Dordt College, Sioux Center, IA, USA.
²¹ Department of Epidemiology and Biostatistics, Indiana University, Bloomington, IN, USA.
²² Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.
²³ The New York Academy of Medicine, New York, NY, USA.
²⁴ Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, USA.
²⁵ Icelandic Heart Institute, Kópavogur, Iceland.
²⁶ National Institute on Aging, Bethesda, MD, USA.
²⁷ Health Sciences, Vrije Universiteit Amsterdam, Amsterdam, Netherlands.
²⁸ INSERM U1061, Neuropsychiatry: Epidemiological and Clinical Research, and Montpellier University Hospital, Montpellier University, Montpellier, France.
²⁹ Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland.
³⁰ Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA.
³¹ Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan; Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.
³² Department of Internal Medicine, Sanford School of Medicine, University of South Dakota, Sioux Falls, SD, USA; OmegaQuant Analytics, Sioux Falls, SD, USA.
³³ Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
³⁴ Department of Neurobiology, Care Sciences and Society, Division of Family Medicine, Karolinska Institute, Stockholm, Sweden; School of Health and Social Studies, Dalarna University, Falun, Sweden.
³⁵ Friedman School of Nutrition Science and Policy, Tufts University, Boston, MA, USA.

PMID: 29032079
PMCID: PMC6029721
DOI: 10.1016/S2213-8587(17)30307-8

Abstract

Background: The metabolic effects of omega-6 polyunsaturated fatty acids (PUFAs) remain contentious, and little evidence is available regarding their potential role in primary prevention of type 2 diabetes. We aimed to assess the associations of linoleic acid and arachidonic acid biomarkers with incident type 2 diabetes.

Methods: We did a pooled analysis of new, harmonised, individual-level analyses for the biomarkers linoleic acid and its metabolite arachidonic acid and incident type 2 diabetes. We analysed data from 20 prospective cohort studies from ten countries (Iceland, the Netherlands, the USA, Taiwan, the UK, Germany, Finland, Australia, Sweden, and France), with biomarkers sampled between 1970 and 2010. Participants included in the analyses were aged 18 years or older and had data available for linoleic acid and arachidonic acid biomarkers at baseline. We excluded participants with type 2 diabetes at baseline. The main outcome was the association between omega-6 PUFA biomarkers and incident type 2 diabetes. We assessed the relative risk of type 2 diabetes prospectively for each cohort and lipid compartment separately using a prespecified analytic plan for exposures, covariates, effect modifiers, and analysis, and the findings were then pooled using inverse-variance weighted meta-analysis.

Findings: Participants were 39 740 adults, aged (range of cohort means) 49-76 years with a BMI (range of cohort means) of 23·3-28·4 kg/m², who did not have type 2 diabetes at baseline. During a follow-up of 366 073 person-years, we identified 4347 cases of incident type 2 diabetes. In multivariable-adjusted pooled analyses, higher proportions of linoleic acid biomarkers as percentages of total fatty acid were associated with a lower risk of type 2 diabetes overall (risk ratio [RR] per interquintile range 0·65, 95% CI 0·60-0·72, p<0·0001; I²=53·9%, p_{heterogeneity}=0·002). The associations between linoleic acid biomarkers and type 2 diabetes were generally similar in different lipid compartments, including phospholipids, plasma, cholesterol esters, and adipose tissue. Levels of arachidonic acid biomarker were not significantly associated with type 2 diabetes risk overall (RR per interquintile range 0·96, 95% CI 0·88-1·05; p=0·38; I²=63·0%, p_{heterogeneity}<0·0001). The associations between linoleic acid and arachidonic acid biomarkers and the risk of type 2 diabetes were not significantly modified by any prespecified potential sources of heterogeneity (ie, age, BMI, sex, race, aspirin use, omega-3 PUFA levels, or variants of the FADS gene; all p_{heterogeneity}≥0·13).

Interpretation: Findings suggest that linoleic acid has long-term benefits for the prevention of type 2 diabetes and that arachidonic acid is not harmful.

Funding: Funders are shown in the appendix.

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Conflict of interest statement

Declaration of interests

JHYW received research grants from Unilever for this study.

LCDG received ad-hoc consulting fees from the Life Sciences Research Organization. CH received fees for a conference from Novartis.

JMG received funding from Unilever for epidemiological studies of dietary and circulating fatty acids and cardiometabolic disease.

RM received research grants from Unilever for this study. DM received ad-hoc honoraria and consulting fees from the Life Sciences Research Organization, AstraZeneca, Boston Heart Diagnostics, Global Organization for EPA and DHA Omega-3, DSM, Nutrition Impact, the Haas Avocado Board, and Pollock Communications; and chapter royalties from UpToDate. All other authors declare no competing interests.

Figures

**Figure 1. Pooled relative risks of type 2 diabetes according to interquintile range* of linoleic acid biomarker, per lipid compartment**
The association between linoleic acid and type 2 diabetes was assessed in multivariable models for each cohort, and the results were pooled using inverse-variance weighted fixed effects meta-analysis. If multiple biomarkers were available within a study, one was chosen for the overall analysis on the basis of its ability to reflect long-term dietary intake (in the following order of preference): adipose tissue, phospholipids, total plasma, and cholesterol esters. Similarly, data for erythrocyte phospholipids were preferred over plasma phospholipids if both were available from a cohort. References for all studies are shown in the appendix. RR=relative risk. AGES-Reykjavik=Age, Gene/Environment Susceptibility Study (Reykjavik). METSIM=Metabolic Syndrome in Men Study. MCCS=Melbourne Collaborative Cohort Study. FHS=Framingham Heart Study. 3C=Three City Study. EPIC-Norfolk=European Prospective Investigation into Cancer (Norfolk). EPIC-Potsdam=European Prospective Investigation into Cancer (Potsdam). ARIC=Atherosclerosis Risk in Communities. CHS=Cardiovascular Health Study. PIVUS=Prospective Investigation of the Vasculature in Uppsala Seniors. MESA=Multi-Ethnic Study of Atherosclerosis. HPFS=Health Professionals Follow-up Study. WHIMS=Women’s Health Initiative Memory Study. NHS=Nurses’ Health Study. KIHD=Kuopio Ischaemic Heart Disease Risk Factor Study. IRAS=Insulin Resistance Atherosclerosis Study. CCCC=Chin-Shan Community Cardiovascular Cohort Study. ULSAM-50=Uppsala Longitudinal Study of Adult Men-50. AOC=Alpha Omega Cohort. ULSAM-70=Uppsala Longitudinal Study of Adult Men-70. *Difference between the midpoints of the first and fifth quintiles.

**Figure 2. Pooled relative risks of type 2 diabetes according to interquintile range* of arachidonic acid biomarker, per lipid compartment**
Association between arachidonic acid and type 2 diabetes was assessed in multivariable models for each cohort, and the results were pooled using inverse-variance weighted fixed effects meta-analysis. If multiple biomarkers were available within a study, one was chosen for the overall analysis on the basis of its ability to reflect long-term dietary intake (in the following order of preference): adipose tissue, phospholipids, total plasma, and cholesterol esters. Similarly, data for erythrocyte phospholipids was preferred over plasma phospholipids if both were available from a cohort. References for all studies are shown in the appendix. RR=relative risk. HPFS=Health Professionals Follow-up Study. EPIC-Potsdam=European Prospective Investigation into Cancer (Potsdam). NHS=Nurses’ Health Study. WHIMS=Women’s Health Initiative Memory Study. FHS=Framingham Heart Study. EPIC-Norfolk=European Prospective Investigation into Cancer (Norfolk). MCCS=Melbourne Collaborative Cohort Study. 3C=Three City Study. PIVUS=Prospective Investigation of the Vasculature in Uppsala Seniors. MESA=Multi-Ethnic Study of Atherosclerosis. ARIC=Atherosclerosis Risk in Communities. CHS=Cardiovascular Health Study. AGES-Reykjavik=Age, Gene/Environment Susceptibility Study (Reykjavik). METSIM=Metabolic Syndrome in Men Study. IRAS=Insulin Resistance Atherosclerosis Study. KIHD=Kuopio Ischaemic Heart Disease Risk Factor Study. CCCC=Chin-Shan Community Cardiovascular Cohort Study. ULSAM-50=Uppsala Longitudinal Study of Adult Men-50. AOC=Alpha Omega Cohort. ULSAM-70=Uppsala Longitudinal Study of Adult Men-70. *Difference between the midpoints of the first and fifth quintiles.

**Figure 3. Pooled relative risks of type 2 diabetes per quintile of linoleic acid and arachidonic acid biomarker**
Association of linoleic acid and arachidonic acid levels with type 2 diabetes was assessed in multivariable models for each cohort, and results were pooled using inverse-variance weighted meta-analysis. The lowest quintile was used as the reference group. For studies in which multiple biomarkers were available, one was chosen for the overall analysis on the basis of its ability to reflect long-term dietary intake (in the following order of preference): adipose tissue, phospholipids, total plasma, and cholesterol esters. Similarly, data for erythrocyte phospholipids was preferable to plasma phospholipids if data on both biomarkers were available. The Age, Gene/Environment Susceptibility Study (Reykjavik) was excluded from these analyses due to the small number of patients who developed incident type 2 diabetes, so the effect estimates were pooled from the other 19 cohorts. RR=relative risk. Q=quintile.

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Comment in

Linoleic acid and risk of type 2 diabetes.
Riccardi G. Riccardi G. Lancet Diabetes Endocrinol. 2017 Dec;5(12):929-930. doi: 10.1016/S2213-8587(17)30322-4. Epub 2017 Oct 12. Lancet Diabetes Endocrinol. 2017. PMID: 29032077 No abstract available.
Diabetes: Omega-6 PUFAs and T2DM.
Bradley CA. Bradley CA. Nat Rev Endocrinol. 2017 Dec;13(12):689. doi: 10.1038/nrendo.2017.143. Epub 2017 Oct 27. Nat Rev Endocrinol. 2017. PMID: 29076507 No abstract available.
Linoleic acid and diabetes prevention.
Henderson G, Crofts C, Schofield G. Henderson G, et al. Lancet Diabetes Endocrinol. 2018 Jan;6(1):12-13. doi: 10.1016/S2213-8587(17)30404-7. Lancet Diabetes Endocrinol. 2018. PMID: 29273163 No abstract available.
Linoleic acid and diabetes prevention - Authors' reply.
Wu JHY, Mozaffarian D. Wu JHY, et al. Lancet Diabetes Endocrinol. 2018 Jan;6(1):13. doi: 10.1016/S2213-8587(17)30406-0. Lancet Diabetes Endocrinol. 2018. PMID: 29273164 No abstract available.

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Omega-6 fatty acid biomarkers and incident type 2 diabetes: pooled analysis of individual-level data for 39 740 adults from 20 prospective cohort studies

Affiliations

Omega-6 fatty acid biomarkers and incident type 2 diabetes: pooled analysis of individual-level data for 39 740 adults from 20 prospective cohort studies

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