Associations of circulating very-long-chain saturated fatty acids and incident type 2 diabetes: A pooled analysis of prospective cohort studies

Amanda M. Fretts, Fumiaki Imamura, Matti Marklund, Renata Micha, Jason H.Y. Wu, Rachel A. Murphy, Kuo Liong Chien, Barbara McKnight, Nathan Tintle, Nita G. Forouhi, Waqas T. Qureshi, Jyrki K. Virtanen, Kerry Wong, Alexis C. Wood, Maria Lankinen, Kalina Rajaobelina, Tamara B. Harris, Luc Djoussé, Bill Harris, Nick J. WarehamMarkku Laakso, Lyn M Steffen, Cécilia Samieri, Ingeborg A. Brouwer, Chaoyu Ian Yu, Albert Koulman, Catherine Helmer, Brian Steffen, David Siscovick, Vilmundur Gudnason, Inter Act Consortium, Lynne Wagenknecht, Sari Voutilainen, Michael Y. Tsai, Matti Uusitupa, Michael Y Tsai, Claudine Berr, Dariush Mozaffarian, Rozenn N. Lemaitre

Research output: Contribution to journalArticlepeer-review

42 Scopus citations


Background: Saturated fatty acids (SFAs) of different chain lengths have unique metabolic and biological effects, and a small number of recent studies suggest that higher circulating concentrations of the very-long-chain SFAs (VLSFAs) arachidic acid (20:0), behenic acid (22:0), and lignoceric acid (24:0) are associated with a lower risk of diabetes. Confirmation of these findings in a large and diverse population is needed. Objective: We investigated the associations of circulating VLSFAs 20:0, 22:0, and 24:0 with incident type 2 diabetes in prospective studies. Methods: Twelve studies that are part of the Fatty Acids and Outcomes Research Consortium participated in the analysis. Using Cox or logistic regression within studies and an inverse-varianceweighted meta-analysis across studies, we examined the associations of VLSFAs 20:0, 22:0, and 24:0 with incident diabetes among 51,431 participants. Results: There were 14,276 cases of incident diabetes across participating studies. Higher circulating concentrations of 20:0, 22:0, and 24:0 were each associated with a lower risk of incident diabetes. Pooling across cohorts, the RR (95% CI) for incident diabetes comparing the 90th percentile to the 10th percentile was 0.78 (0.70, 0.87) for 20:0, 0.84 (0.77, 0.91) for 22:0, and 0.75 (0.69, 0.83) for 24:0 after adjustment for demographic, lifestyle, adiposity, and other health factors. Results were fully attenuated in exploratory models that adjusted for circulating 16:0 and triglycerides. Conclusions: Results from this pooled analysis indicate that higher concentrations of circulating VLSFAs 20:0, 22:0, and 24:0 are each associated with a lower risk of diabetes.

Original languageEnglish (US)
Pages (from-to)1216-1223
Number of pages8
JournalAmerican Journal of Clinical Nutrition
Issue number4
StatePublished - Apr 1 2019

Bibliographical note

Funding Information:
The authors’ contributions were as follows—AMF, FI, BM, DM, and RNL: designed the research (project conception, development of the overall research plan, and study oversight); NGF, KR, TBH, LD, NJW, LMS, A. Koulman, DS, IAB, VG, SV, BH, M Lankinen, JV, CS, BTS, CH, NS, AK, MU, MYT, LW, CB, and K-LC: conducted the research (hands-on conduct of the experiments and data collection); NGF, AK, DS, IAB, VG, SV, BH, ML, MU, MYT, LW, CB, and K-LC: provided essential materials; AMF, FI, CIY, RAM, NT, JKV, ML, KW, ACW, and WTQ: analyzed the data or performed statistical analysis; AMF, FI, MM, RM, JHYW, DM, and RNL: wrote the paper; AMF: had primary responsibility for final content.All authors read and approved the final manuscript. JHYW and RM report research support from Unilever for other projects on fatty acid biomarkers. CH reports receiving fees for a conference from Novartis. IAB reports involvement in a research project partly funded by Unilever. DM reports receiving ad hoc honoraria from Bunge, Pollock Institute, and Quaker Oats; ad hoc consulting for Foodminds, Life Sciences Research Organization, Nutrition Impact, Amarin, AstraZeneca, Winston, and Strawn LLP; membership in Unilever North America Scientific Advisory Board; and chapter royalties from UpToDate. FI, NGF, and NJW report research support from the United Kingdom Medical Research Council Epidemiology Unit core grants MC_UU_12015/1 and MC_UU_12015/5. None of the other authors reported a conflict of interest related to the study.

Funding Information:
Supported by NIH grant 5KL2TR000421 (to AMF), a University of New South Wales Scientia Fellowship (to JHYW), MRC Epidemiology Unit grants MC_UU_12015/1 and MC_UU_12015/5 (to NJW, NGF, and FI), National Institute for Health Research Biomedical Research Centre Cambridge grant IS-BRC-1215-20014 (to NGF, AK, and NJW), MRC Elsie Widdowson Laboratory grant MC_UD99999906 (to A Koulman), and Cambridge Lipidomics Biomarker Research Initiative grant G0800783 (to A Koulman). Age, Gene/Environment Susceptibility Study Reykjavik was funded by Office of Dietary Supplements, NIH contract N01-AG012100, the National Institute of Aging (NIA) Intramural Research Program, Hjartavernd (the Icelandic Heart Association), and the Althingi (the Icelandic Parliament), with additional contribution from Canadian Cancer Society grant #704735. Chin-Shan Community Cardiovascular Study was funded by Ministry of Science and Technology and National Taiwan University, Taiwan grants MOST 103-2314-B-002-135–MY3 (to K-LC), NSC 100-2314-B-002-113–MY3, NTUH 105-S3120, and NTUH 106-S3453. The Cardiovascular Health Study (CHS) was supported by contracts HHSN268201200036C, HHSN268200800007C, HHSN268201800001C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, and grants U01HL080295 and U01HL130114 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 National Institute on Aging (NIA) grant R01AG023629. The Framingham Heart Study was supported by the NHLBI in collaboration with Boston University (contract no. N01-HC-25195). The Insulin Resistance Atherosclerosis Study was funded by NHLBI grants U01-HL-47892, U01-HL-47902, DK-29867, R01-58329, and DK-079888 and NIH grant M01-RR-43. The EPIC-Interact project was funded by the EU FP6 programme, grant no. LSHM_CT_2006_037197. The Kuopio Ischaemic Heart Disease Risk Factor Study (KIHD) was supported mainly by funding from the Academy of Finland to Jukka T Salonen. The Melbourne Collaborative Cohort Study was funded by VicHealth, The Cancer Council Victoria, and the National Health and Medical Research Council, grants 124317, 126402, 126403, 180705, 180706, 194327, 209057, 251533. The Multi-Ethnic Study of Atherosclerosis (MESA) was funded by NHLBI contracts HHSN268201500003I, 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, and N01-HC-95169, and by National Center for Advancing Translational Sciences grants UL1-TR-000040, UL1-TR-001079, and UL1-TR-001420. The Metabolic Syndrome in Men Study was funded by grants from the European Union, the Academy of Finland, and the Juselius Foundation. The Three City Study was conducted under a partnership agreement between the Institut National de la Santé et de la Recherche Médicale, the University Bordeaux 2 Victor Segalen, and Sanofi. 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 Salaries, Direction Générale de la Santé, MGEN, Institut de la Longévité, Conseils Régionaux d’Aquitaine et Bourgogne, Fondation de France, Ministry of Research—Institut National de la Santé and de la Recherche Médicale Programme Cohortes, Agence Nationale de la Recherche grant COGINUT ANR-06-PNRA-005, Fondation Plan Alzheimer grant FCS 2009–2012, and the Caisse Nationale de Solidarité pour l’Autonomie. The Women’s Health Initiative (WHI) program was funded by the NHLBI, NIH, US Department of Health and Human Services through contracts HHSN268201600018C, HHSN268201600001C, HHSN268201600002C, HHSN268201600003C, and HHSN268201600004C. A full listing of the CHS, MESA, and

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© 2019 American Society for Nutrition. All rights reserved.


  • Cohorts for Heart and Aging Research in Genomic Epidemiology
  • Diabetes
  • Fatty Acids and Outcomes Research Consortium
  • Meta-analysis
  • Saturated fatty acids
  • Very-long-chain saturated fatty acids


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