Association of Plasma Phospholipid n-3 and n-6 Polyunsaturated Fatty Acids with Type 2 Diabetes: The EPIC-InterAct Case-Cohort Study

N. G. Forouhi; F. Imamura; S. J. Sharp; A. Koulman; M. B. Schulze; I. Sluijs; M. Guevara; J. M. Huerta; J. Kroger; K. Summerhill; E. J. Feskens; A. Affret; P. Amiano; H. Boeing; C. Dow; G. Fagherazzi; P. W. Franks; C. Gonzalez; R. Kaaks; T. J. Key; K. T. Khaw; T. Kuhn; L. M. Mortensen; P. M. Nilsson; K. Overvad; V. Pala; D. Palli; S. Panico; J. R. Quiros; M. Rodriguez-Barranco; O. Rolandsson; C. Sacerdote; A. Scalbert; N. Slimani; A. M. Spijkerman; A. Tjonneland; M. J. Tormo; R. Tumino; A. Dl van der; Y. T. van der Schouw; C. Langenberg; E. Riboli; N. J. Wareham

doi:10.1371/journal.pmed.1002094

Association of Plasma Phospholipid n-3 and n-6 Polyunsaturated Fatty Acids with Type 2 Diabetes: The EPIC-InterAct Case-Cohort Study

N. G. Forouhi, F. Imamura, S. J. Sharp, A. Koulman, M. B. Schulze, I. Sluijs, M. Guevara, J. M. Huerta, J. Kroger, K. Summerhill, E. J. Feskens, A. Affret, P. Amiano, H. Boeing, C. Dow, G. Fagherazzi, P. W. Franks, C. Gonzalez, R. Kaaks, T. J. KeyK. T. Khaw, T. Kuhn, L. M. Mortensen, P. M. Nilsson, K. Overvad, V. Pala, D. Palli, S. Panico, J. R. Quiros, M. Rodriguez-Barranco, O. Rolandsson, C. Sacerdote, A. Scalbert, N. Slimani, A. M. Spijkerman, A. Tjonneland, M. J. Tormo, R. Tumino, A. Dl van der, Y. T. van der Schouw, C. Langenberg, E. Riboli, N. J. Wareham

School of Biological Sciences

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Abstract

Background:
Whether and how n-3 and n-6 polyunsaturated fatty acids (PUFAs) are related to type 2 diabetes (T2D) is debated. Objectively measured plasma PUFAs can help to clarify these
associations.
Methods and Findings:
Plasma phospholipid PUFAs were measured by gas chromatography among 12,132 incident T2D cases and 15,919 subcohort participants in the European Prospective Investigation into Cancer and Nutrition (EPIC)-InterAct study across eight European countries.
Country-specific hazard ratios (HRs) were estimated using Prentice-weighted Cox regression and pooled by random-effects meta-analysis. We also systematically reviewed published prospective studies on circulating PUFAs and T2D risk and pooled the quantitative
evidence for comparison with results from EPIC-InterAct. In EPIC-InterAct, among longchain n-3 PUFAs, α-linolenic acid (ALA) was inversely associated with T2D (HR per standard deviation [SD] 0.93; 95% CI 0.88–0.98), but eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) were not significantly associated. Among n-6 PUFAs, linoleic acid
(LA) (0.80; 95% CI 0.77–0.83) and eicosadienoic acid (EDA) (0.89; 95% CI 0.85–0.94)
were inversely related, and arachidonic acid (AA) was not significantly associated, while
significant positive associations were observed with γ-linolenic acid (GLA), dihomo-GLA,
docosatetraenoic acid (DTA), and docosapentaenoic acid (n6-DPA), with HRs between
1.13 to 1.46 per SD. These findings from EPIC-InterAct were broadly similar to comparative
findings from summary estimates from up to nine studies including between 71 to 2,499
T2D cases. Limitations included potential residual confounding and the inability to distinguish between dietary and metabolic influences on plasma phospholipid PUFAs.
Conclusions:
These large-scale findings suggest an important inverse association of circulating plant-origin n-3 PUFA (ALA) but no convincing association of marine-derived n3 PUFAs (EPA and
DHA) with T2D. Moreover, they highlight that the most abundant n6-PUFA (LA) is inversely
associated with T2D. The detection of associations with previously less well-investigated
PUFAs points to the importance of considering individual fatty acids rather than focusing on
fatty acid class.

Original language	Undefined/Unknown
Article number	e1002094
Number of pages	17
Journal	PLoS Medicine
Volume	13
Issue number	7
DOIs	https://doi.org/10.1371/journal.pmed.1002094
Publication status	Published - 19 Jul 2016

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Association of Plasma Phospholipid n-3 and n-6 Polyunsaturated Fatty Acids with Type 2 Diabetes: The EPIC-InterAct Case-Cohort Study
© 2016 The Authors. This is an open access article published under a Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution and reproduction in any medium, provided the author and source are cited.
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Cite this

Forouhi, N. G., Imamura, F., Sharp, S. J., Koulman, A., Schulze, M. B., Sluijs, I., Guevara, M., Huerta, J. M., Kroger, J., Summerhill, K., Feskens, E. J., Affret, A., Amiano, P., Boeing, H., Dow, C., Fagherazzi, G., Franks, P. W., Gonzalez, C., Kaaks, R., ... Wareham, N. J. (2016). Association of Plasma Phospholipid n-3 and n-6 Polyunsaturated Fatty Acids with Type 2 Diabetes: The EPIC-InterAct Case-Cohort Study. PLoS Medicine, 13(7), Article e1002094. https://doi.org/10.1371/journal.pmed.1002094

@article{3b8563cfacd648e0a5190e050a5fa8bc,

title = "Association of Plasma Phospholipid n-3 and n-6 Polyunsaturated Fatty Acids with Type 2 Diabetes: The EPIC-InterAct Case-Cohort Study",

abstract = "Background:Whether and how n-3 and n-6 polyunsaturated fatty acids (PUFAs) are related to type 2 diabetes (T2D) is debated. Objectively measured plasma PUFAs can help to clarify theseassociations.Methods and Findings:Plasma phospholipid PUFAs were measured by gas chromatography among 12,132 incident T2D cases and 15,919 subcohort participants in the European Prospective Investigation into Cancer and Nutrition (EPIC)-InterAct study across eight European countries.Country-specific hazard ratios (HRs) were estimated using Prentice-weighted Cox regression and pooled by random-effects meta-analysis. We also systematically reviewed published prospective studies on circulating PUFAs and T2D risk and pooled the quantitativeevidence for comparison with results from EPIC-InterAct. In EPIC-InterAct, among longchain n-3 PUFAs, α-linolenic acid (ALA) was inversely associated with T2D (HR per standard deviation [SD] 0.93; 95% CI 0.88–0.98), but eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) were not significantly associated. Among n-6 PUFAs, linoleic acid(LA) (0.80; 95% CI 0.77–0.83) and eicosadienoic acid (EDA) (0.89; 95% CI 0.85–0.94)were inversely related, and arachidonic acid (AA) was not significantly associated, whilesignificant positive associations were observed with γ-linolenic acid (GLA), dihomo-GLA,docosatetraenoic acid (DTA), and docosapentaenoic acid (n6-DPA), with HRs between1.13 to 1.46 per SD. These findings from EPIC-InterAct were broadly similar to comparativefindings from summary estimates from up to nine studies including between 71 to 2,499T2D cases. Limitations included potential residual confounding and the inability to distinguish between dietary and metabolic influences on plasma phospholipid PUFAs.Conclusions:These large-scale findings suggest an important inverse association of circulating plant-origin n-3 PUFA (ALA) but no convincing association of marine-derived n3 PUFAs (EPA andDHA) with T2D. Moreover, they highlight that the most abundant n6-PUFA (LA) is inverselyassociated with T2D. The detection of associations with previously less well-investigatedPUFAs points to the importance of considering individual fatty acids rather than focusing onfatty acid class.",

author = "Forouhi, {N. G.} and F. Imamura and Sharp, {S. J.} and A. Koulman and Schulze, {M. B.} and I. Sluijs and M. Guevara and Huerta, {J. M.} and J. Kroger and K. Summerhill and Feskens, {E. J.} and A. Affret and P. Amiano and H. Boeing and C. Dow and G. Fagherazzi and Franks, {P. W.} and C. Gonzalez and R. Kaaks and Key, {T. J.} and Khaw, {K. T.} and T. Kuhn and Mortensen, {L. M.} and Nilsson, {P. M.} and K. Overvad and V. Pala and D. Palli and S. Panico and Quiros, {J. R.} and M. Rodriguez-Barranco and O. Rolandsson and C. Sacerdote and A. Scalbert and N. Slimani and Spijkerman, {A. M.} and A. Tjonneland and Tormo, {M. J.} and R. Tumino and {van der}, {A. Dl} and {van der Schouw}, {Y. T.} and C. Langenberg and E. Riboli and Wareham, {N. J.}",

year = "2016",

month = jul,

day = "19",

doi = "10.1371/journal.pmed.1002094",

language = "Undefined/Unknown",

volume = "13",

journal = "PLoS Medicine",

issn = "1549-1277",

publisher = "Public Library of Science",

number = "7",

}

Forouhi, NG, Imamura, F, Sharp, SJ, Koulman, A, Schulze, MB, Sluijs, I, Guevara, M, Huerta, JM, Kroger, J, Summerhill, K, Feskens, EJ, Affret, A, Amiano, P, Boeing, H, Dow, C, Fagherazzi, G, Franks, PW, Gonzalez, C, Kaaks, R, Key, TJ, Khaw, KT, Kuhn, T, Mortensen, LM, Nilsson, PM, Overvad, K, Pala, V, Palli, D, Panico, S, Quiros, JR, Rodriguez-Barranco, M, Rolandsson, O, Sacerdote, C, Scalbert, A, Slimani, N, Spijkerman, AM, Tjonneland, A, Tormo, MJ, Tumino, R, van der, AD, van der Schouw, YT, Langenberg, C, Riboli, E & Wareham, NJ 2016, 'Association of Plasma Phospholipid n-3 and n-6 Polyunsaturated Fatty Acids with Type 2 Diabetes: The EPIC-InterAct Case-Cohort Study', PLoS Medicine, vol. 13, no. 7, e1002094. https://doi.org/10.1371/journal.pmed.1002094

TY - JOUR

T1 - Association of Plasma Phospholipid n-3 and n-6 Polyunsaturated Fatty Acids with Type 2 Diabetes: The EPIC-InterAct Case-Cohort Study

AU - Forouhi, N. G.

AU - Imamura, F.

AU - Sharp, S. J.

AU - Koulman, A.

AU - Schulze, M. B.

AU - Sluijs, I.

AU - Guevara, M.

AU - Huerta, J. M.

AU - Kroger, J.

AU - Summerhill, K.

AU - Feskens, E. J.

AU - Affret, A.

AU - Amiano, P.

AU - Boeing, H.

AU - Dow, C.

AU - Fagherazzi, G.

AU - Franks, P. W.

AU - Gonzalez, C.

AU - Kaaks, R.

AU - Key, T. J.

AU - Khaw, K. T.

AU - Kuhn, T.

AU - Mortensen, L. M.

AU - Nilsson, P. M.

AU - Overvad, K.

AU - Pala, V.

AU - Palli, D.

AU - Panico, S.

AU - Quiros, J. R.

AU - Rodriguez-Barranco, M.

AU - Rolandsson, O.

AU - Sacerdote, C.

AU - Scalbert, A.

AU - Slimani, N.

AU - Spijkerman, A. M.

AU - Tjonneland, A.

AU - Tormo, M. J.

AU - Tumino, R.

AU - van der, A. Dl

AU - van der Schouw, Y. T.

AU - Langenberg, C.

AU - Riboli, E.

AU - Wareham, N. J.

PY - 2016/7/19

Y1 - 2016/7/19

N2 - Background:Whether and how n-3 and n-6 polyunsaturated fatty acids (PUFAs) are related to type 2 diabetes (T2D) is debated. Objectively measured plasma PUFAs can help to clarify theseassociations.Methods and Findings:Plasma phospholipid PUFAs were measured by gas chromatography among 12,132 incident T2D cases and 15,919 subcohort participants in the European Prospective Investigation into Cancer and Nutrition (EPIC)-InterAct study across eight European countries.Country-specific hazard ratios (HRs) were estimated using Prentice-weighted Cox regression and pooled by random-effects meta-analysis. We also systematically reviewed published prospective studies on circulating PUFAs and T2D risk and pooled the quantitativeevidence for comparison with results from EPIC-InterAct. In EPIC-InterAct, among longchain n-3 PUFAs, α-linolenic acid (ALA) was inversely associated with T2D (HR per standard deviation [SD] 0.93; 95% CI 0.88–0.98), but eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) were not significantly associated. Among n-6 PUFAs, linoleic acid(LA) (0.80; 95% CI 0.77–0.83) and eicosadienoic acid (EDA) (0.89; 95% CI 0.85–0.94)were inversely related, and arachidonic acid (AA) was not significantly associated, whilesignificant positive associations were observed with γ-linolenic acid (GLA), dihomo-GLA,docosatetraenoic acid (DTA), and docosapentaenoic acid (n6-DPA), with HRs between1.13 to 1.46 per SD. These findings from EPIC-InterAct were broadly similar to comparativefindings from summary estimates from up to nine studies including between 71 to 2,499T2D cases. Limitations included potential residual confounding and the inability to distinguish between dietary and metabolic influences on plasma phospholipid PUFAs.Conclusions:These large-scale findings suggest an important inverse association of circulating plant-origin n-3 PUFA (ALA) but no convincing association of marine-derived n3 PUFAs (EPA andDHA) with T2D. Moreover, they highlight that the most abundant n6-PUFA (LA) is inverselyassociated with T2D. The detection of associations with previously less well-investigatedPUFAs points to the importance of considering individual fatty acids rather than focusing onfatty acid class.

AB - Background:Whether and how n-3 and n-6 polyunsaturated fatty acids (PUFAs) are related to type 2 diabetes (T2D) is debated. Objectively measured plasma PUFAs can help to clarify theseassociations.Methods and Findings:Plasma phospholipid PUFAs were measured by gas chromatography among 12,132 incident T2D cases and 15,919 subcohort participants in the European Prospective Investigation into Cancer and Nutrition (EPIC)-InterAct study across eight European countries.Country-specific hazard ratios (HRs) were estimated using Prentice-weighted Cox regression and pooled by random-effects meta-analysis. We also systematically reviewed published prospective studies on circulating PUFAs and T2D risk and pooled the quantitativeevidence for comparison with results from EPIC-InterAct. In EPIC-InterAct, among longchain n-3 PUFAs, α-linolenic acid (ALA) was inversely associated with T2D (HR per standard deviation [SD] 0.93; 95% CI 0.88–0.98), but eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) were not significantly associated. Among n-6 PUFAs, linoleic acid(LA) (0.80; 95% CI 0.77–0.83) and eicosadienoic acid (EDA) (0.89; 95% CI 0.85–0.94)were inversely related, and arachidonic acid (AA) was not significantly associated, whilesignificant positive associations were observed with γ-linolenic acid (GLA), dihomo-GLA,docosatetraenoic acid (DTA), and docosapentaenoic acid (n6-DPA), with HRs between1.13 to 1.46 per SD. These findings from EPIC-InterAct were broadly similar to comparativefindings from summary estimates from up to nine studies including between 71 to 2,499T2D cases. Limitations included potential residual confounding and the inability to distinguish between dietary and metabolic influences on plasma phospholipid PUFAs.Conclusions:These large-scale findings suggest an important inverse association of circulating plant-origin n-3 PUFA (ALA) but no convincing association of marine-derived n3 PUFAs (EPA andDHA) with T2D. Moreover, they highlight that the most abundant n6-PUFA (LA) is inverselyassociated with T2D. The detection of associations with previously less well-investigatedPUFAs points to the importance of considering individual fatty acids rather than focusing onfatty acid class.

U2 - 10.1371/journal.pmed.1002094

DO - 10.1371/journal.pmed.1002094

M3 - Article

SN - 1549-1277

VL - 13

JO - PLoS Medicine

JF - PLoS Medicine

IS - 7

M1 - e1002094

ER -