Research Article: A combination of plasma phospholipid fatty acids and its association with incidence of type 2 diabetes: The EPIC-InterAct case-cohort study

Date Published: October 11, 2017

Publisher: Public Library of Science

Author(s): Fumiaki Imamura, Stephen J. Sharp, Albert Koulman, Matthias B. Schulze, Janine Kröger, Julian L. Griffin, José M. Huerta, Marcela Guevara, Ivonne Sluijs, Antonio Agudo, Eva Ardanaz, Beverley Balkau, Heiner Boeing, Veronique Chajes, Christina C. Dahm, Courtney Dow, Guy Fagherazzi, Edith J. M. Feskens, Paul W. Franks, Diana Gavrila, Marc Gunter, Rudolf Kaaks, Timothy J. Key, Kay-Tee Khaw, Tilman Kühn, Olle Melander, Elena Molina-Portillo, Peter M. Nilsson, Anja Olsen, Kim Overvad, Domenico Palli, Salvatore Panico, Olov Rolandsson, Sabina Sieri, Carlotta Sacerdote, Nadia Slimani, Annemieke M. W. Spijkerman, Anne Tjønneland, Rosario Tumino, Yvonne T. van der Schouw, Claudia Langenberg, Elio Riboli, Nita G. Forouhi, Nick J. Wareham, Ronald C. W. Ma

Abstract: BackgroundCombinations of multiple fatty acids may influence cardiometabolic risk more than single fatty acids. The association of a combination of fatty acids with incident type 2 diabetes (T2D) has not been evaluated.Methods and findingsWe measured plasma phospholipid fatty acids by gas chromatography in 27,296 adults, including 12,132 incident cases of T2D, over the follow-up period between baseline (1991–1998) and 31 December 2007 in 8 European countries in EPIC-InterAct, a nested case-cohort study. The first principal component derived by principal component analysis of 27 individual fatty acids (mole percentage) was the main exposure (subsequently called the fatty acid pattern score [FA-pattern score]). The FA-pattern score was partly characterised by high concentrations of linoleic acid, stearic acid, odd-chain fatty acids, and very-long-chain saturated fatty acids and low concentrations of γ-linolenic acid, palmitic acid, and long-chain monounsaturated fatty acids, and it explained 16.1% of the overall variability of the 27 fatty acids. Based on country-specific Prentice-weighted Cox regression and random-effects meta-analysis, the FA-pattern score was associated with lower incident T2D. Comparing the top to the bottom fifth of the score, the hazard ratio of incident T2D was 0.23 (95% CI 0.19–0.29) adjusted for potential confounders and 0.37 (95% CI 0.27–0.50) further adjusted for metabolic risk factors. The association changed little after adjustment for individual fatty acids or fatty acid subclasses. In cross-sectional analyses relating the FA-pattern score to metabolic, genetic, and dietary factors, the FA-pattern score was inversely associated with adiposity, triglycerides, liver enzymes, C-reactive protein, a genetic score representing insulin resistance, and dietary intakes of soft drinks and alcohol and was positively associated with high-density-lipoprotein cholesterol and intakes of polyunsaturated fat, dietary fibre, and coffee (p < 0.05 each). Limitations include potential measurement error in the fatty acids and other model covariates and possible residual confounding.ConclusionsA combination of individual fatty acids, characterised by high concentrations of linoleic acid, odd-chain fatty acids, and very long-chain fatty acids, was associated with lower incidence of T2D. The specific fatty acid pattern may be influenced by metabolic, genetic, and dietary factors.

Partial Text: Fatty acids play vital roles in metabolic homeostasis, serving as precursors of signalling molecules, energy sources, and constituents of membranes and functional lipids [1,2]. Reflecting their diverse roles, fatty acids have been evaluated as markers of physiological homeostasis, metabolic disorders, and dietary exposure in biological, clinical, and population-based research [3–5]. For example, blood or tissue levels of omega-3 polyunsaturated fatty acids (PUFAs) have been studied as a cardio-protective factor in biochemical and clinical research and as a biomarker of dietary consumption of omega-3 PUFAs in epidemiological research [1,2,4–6]. However, research to date has largely evaluated individual fatty acids or single subgroups of fatty acids, rather than combinations of fatty acids, in terms of mechanism or as potential biomarkers.

The first component derived by PCA explained 16.1% of the variation of 27 fatty acids, and 6 to 10 components explained more variation than 1 fatty acid could explain (>3.7% of total; ‘eigenvalue’ > 1.0) (Fig 1). The first 4 components had loading values (e.g., >0.6 or <−0.6) in multiple fatty acid classes. Selected to gain insight into the biological importance of a combination of fatty acids, the first component reflected relationships between fatty acids varying in chain length and degree of unsaturation, including fatty acids that can be synthesised endogenously and those derived from dietary consumption (Table 1; Fig 1). A similar pattern was identified in cluster analysis, as fatty acids adjacent in the tree had similar loading values (Fig 1). Major contributors (correlation coefficients r > 0.5 or r < −0.5) were palmitic acid (16:0, r = −0.51), palmitoleic acid (16:1, r = −0.75), and γ-linolenic acid (18:3n-6, r = −0.51). Heptadecanoic acid (17:0) and very-long-chain SFAs (VLSFAs) with 20 or more carbons had positive contributions (r = 0.5–0.7), but their relative concentrations were low (<1% of total). While linoleic acid (18:2n-6) had a positive contribution (r = 0.45), the other PUFAs, and trans unsaturated fatty acids had lower contributions (−0.25 < r < 0.25) (Fig 1). The coefficient of variation of the FA-pattern score was 6.0% based on the quality control samples. We evaluated fatty acid profiles among adults in 8 European countries and derived a FA-pattern score that represents a combination of both essential and non-essential fatty acids and that is characterised by high relative concentrations of linoleic acid (18:2n-6), stearic acid (18:0), odd-chain SFAs, and VLSFAs (≥20 carbons), and by low relative concentrations of γ-linolenic acid (18:3n-6), monounsaturated fatty acids (MUFAs), and long-chain SFAs (14:0 and 16:0). The unique combination was associated with dietary, metabolic, and genetic factors, and prospectively associated with a lower incidence of T2D. Comparing the top fifth to the bottom fifth of the FA-pattern score, T2D incidence was lower by approximately 60%. This robust association with incident T2D was independent of established risk factors and also any single fatty acids or fatty acid subclasses. These findings support the hypothesis that a combination of multiple fatty acids is an important marker for the development of T2D above and beyond the roles of single types of fatty acids. The combination of essential and non-essential fatty acids is of strong interest for further clinical or population-based investigations to predict T2D risk, identify interventional agents for T2D prevention, and better understand the aetiology of T2D. Source:


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