Variation of serum metabolites related to habitual diet: a targeted metabolomic approach in EPIC-Potsdam

European Journal of Clinical Nutrition (2013) 67, 1100–1108 & 2013 Macmillan Publishers Limited All rights reserved 0954-3007/13 www.nature.com/ejcn ORIGINAL ARTICLE Variation of serum metabolites related to habitual diet: a targeted metabolomic approach in EPIC-Potsdam A Floegel1, A von Ruesten1,2, D Drogan1, MB Schulze3, C Prehn4, J Adamski4, T Pischon5 and H Boeing1 BACKGROUND/OBJECTIVE: Serum metabolites have been linked to higher risk of chronic diseases but determinants of serum metabolites are not clear. We aimed to investigate the association between habitual diet as a modifiable risk factor and relevant serum metabolites. SUBJECTS/METHODS: This cross-sectional study comprised 2380 EPIC-Potsdam participants. Intake of 45 food groups was assessed by food frequency questionnaire and concentrations of 127 serum metabolites were measured by targeted metabolomics. Reduced rank regression was used to find dietary patterns that explain the maximum variation of metabolites. RESULTS: In the multivariable-adjusted model, the proportion of explained variation by habitual diet was ranked as follows: acyl-alkyl-phosphatidylcholines (5.7%), sphingomyelins (5.1%), diacyl-phosphatidylcholines (4.4%), lyso-phosphatidylcholines (4.1%), acylcarnitines (3.5%), amino acids (2.2%) and hexose (1.6%). A pattern with high intake of butter and low intake of margarine was related to acylcarnitines, acyl-alkyl-phosphatidylcholines, lyso-phosphatidylcholines and hydroxy-sphingomyelins, particularly with saturated and monounsaturated fatty acid side chains. A pattern with high intake of red meat and fish and low intake of whole-grain bread and tea was related to hexose and phosphatidylcholines. A pattern consisting of high intake of potatoes, dairy products and cornflakes particularly explained methionine and branched chain amino acids. Dietary patterns related to type 2 diabetes-relevant metabolites included high intake of red meat and low intake of whole-grain bread, tea, coffee, cake and cookies, canned fruits and fish. CONCLUSIONS: Dietary patterns characterized by intakes of red meat, whole-grain bread, tea and coffee were linked to relevant metabolites and could be potential targets for chronic disease prevention. European Journal of Clinical Nutrition (2013) 67, 1100–1108; doi:10.1038/ejcn.2013.147; published online 14 August 2013 Keywords: metabolomics; metabolites; diet; food intake; reduced rank regression; systems epidemiology INTRODUCTION Advancement of technologies from analytical chemistry, particularly nuclear magnetic resonance spectroscopy and mass spectrometry (MS), made high-throughput metabolomic analysis of biological specimen possible. To date, an increasing number of metabolomic platforms enable robust and quick measurements of metabolites not only for single patients but also for large-scale metabolic profiling in epidemiologic studies. Thereby, metabolomics offers great potential to study metabolic alterations that are linked to higher risk of chronic diseases. Alterations in blood concentrations of metabolites were for example observed among obese individuals, people with impaired glucose tolerance and type 2 diabetes patients.1–5 These changes included acylcarnitines,1,3 amino acids,3,4 sugars2,5 and different lipid species.2,3 Recently, the use of tandem MS techniques in the frame of different prospective cohort studies has enabled the identification of metabolites that predict chronic diseases. Particularly, higher concentrations of branched chain and aromatic amino acids were identified to be linked to higher risk of type 2 diabetes in the Framingham Offspring study and the Malmö Diet and Cancer study.6 Recent work from our group confirmed this finding; additionally, we identified increased hexose and diacyl-phosphatidylcholines, and reduced acylalkyl- and lyso-phosphatidylcholines, and sphingomyelins to be associated with development of type 2 diabetes in the European Prospective Investigation into Cancer and Nutrition (EPIC)Potsdam study.7 From a public health perspective it is of interest to investigate modifiable risk factors that contribute to changes in metabolite concentrations related to disease risk. In this context, it has been suggested that metabolites may be very responsive to exposure of dietary, environmental and lifestyle factors.8 Particularly, one would expect that habitual dietary patterns are linked to blood concentrations of metabolites, as diet could be a primary source of metabolites, and secondarily, induce metabolic responses.9,10 In fact, a previous study suggested that self-reported nutrition 1 Department of Epidemiology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany; 2Department of Public Health and Community Medicine, University of Gothenburg, Gothenburg, Sweden; 3Department of Molecular Epidemiology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany; 4 Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany and 5Molecular Epidemiology Group, Max Delbrück Center for Molecular Medicine (MDC) Berlin-Buch, Berlin-Buch, Germany. Correspondence: Dr A Floegel, Department of Epidemiology, German Institute of Human Nutrition Potsdam-Rehbruecke, Arthur-Scheunert-Allee 114-116, 14558 Nuthetal, Germany. E-mail: anna.fl Contributors: AF designed the research, conducted the data analysis, interpreted the data, wrote the manuscript and had primary responsibility for data integrity and the final content; AvR, DD, MBS contributed to the conception of this study, helped with the interpretation of the results and provided critical comments on the manuscript; CP and JA conducted metabolomics measurements and provided critical comments on the manuscript; TP and HB obtained funding, designed the research, helped with the interpretation of the results and provided critical comments on the manuscript. Received 5 April 2013; revised 11 July 2013; accepted 12 July 2013; published online 14 August 2013 Serum metabolites related to habitual diet A Floegel et al 1101 habits may be reflected in metabolic profiles.11 However, the association between habitual diet and blood concentrations of different classes of metabolites related to disease risk has not been well examined at the population level. It would be of particular interest to identify those foods in the usual diet that explain most of the variation of metabolites. Thereby, the understanding of the biological mechanisms could be improved, and consequently, adequate dietary recommendations and prevention strategies for chronic disease risk could be developed. Thus, to investigate the association between habitual diet and serum metabolites, we applied a common method from dietary pattern analysis, that is, reduced rank regression (RRR),12 and used data on self-reported diet and measurement of serum metabolite concentrations from the EPIC-Potsdam study. In a first step, we investigated (...truncated)