Supplementary Information for. The effect of standardized food intake on the association between BMI and 1 H-NMR metabolites

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1 Supplementary Information for The effect of standardized food intake on the association between BMI and 1 H-NMR metabolites Bianca A.M. Schutte 1*, Erik B. van den Akker 1,2, Joris Deelen 1, Ondine van de Rest 3, Diana van Heemst 4, Edith J.M. Feskens 3 Marian Beekman 1# and P. Eline Slagboom 1#* 1 Department of Molecular Epidemiology, Leiden University Medical Center, 2300 RC Leiden, The Netherlands 2 The Delft Bioinformatics Lab, Delft University of Technology, 2628 CD Delft, The Netherlands 3 Division of Human Nutrition, Wageningen University, 6700 EV Wageningen, The Netherlands 4 Department of Gerontology and Geriatrics, Leiden University Medical Center, 2300 RC Leiden, The Netherlands # shared last author * corresponding author Supplementary Figure S1 Effect size of the association between BMI and metabolites in fasting status in this study and Würtz et al. (2014) 1 Supplementary Figure S2 Effect size of the association between BMI and metabolites before and after the standardized liquid meal Supplementary Figure S3 Effect size of the association between insulin and metabolites before and after the standardized liquid meal. Supplementary Figure S4 Histogram of the time between consumption of the SLM and the collection of the non-fasted blood sample, in minutes. Supplementary Table S1 Changes in metabolite levels after the standardized liquid meal Supplementary Table S2 Effect size of the association between BMI and metabolites before and after the standardized liquid meal Supplementary Table S3 Effect size of the association between BMI and metabolites in this study and study done by Würtz et al. (2014) 1 Supplementary Table S4 Interaction between SLM and BMI Supplementary Table S5 Effect size of the association between diastolic blood pressure and metabolites before and after the standardized liquid meal Supplementary Table S6 Effect size of the association between insulin and metabolites before and after the standardized liquid meal Supplementary Table S7 Nutritional content Nutridrink Supplementary Table S8 Nutritional content amino acids Nutridrink

2 Supplementary Figure S1 Effect size of the association between BMI and metabolites in fasting status in this study and Würtz et al. (2014) 1 Effect sizes indicate the association magnitudes in units of 1-SD metabolite concentration per 1- kg/m 2 increment in BMI. Each dot represents a metabolite. Purple diamonds indicate the metabolite was significantly associated with BMI in this study and Würtz et al.; green triangle: only significant in this study; orange circles: only significant in the study of Würtz et al; blue crosses: not significant in one of the studies

3 Supplementary Figure S2 Effect size of the association between BMI and metabolites before and after the standardized liquid meal Effect sizes indicate the association magnitudes in units of 1-SD metabolite concentration per 1-kg/m 2 increment in BMI. Error bars indicate 95% confidence interval. Red circles indicate the effect size in fasting samples; blue squares indicate the effect size in postprandial samples. Double bonds/fatty acids: the number of double bonds in fatty acids. VLDL, very low density lipoprotein; IDL, intermediate density lipoprotein; LDL, low density lipoprotein; HDL, high density lipoprotein. 3

4 Supplementary Figure S3 Effect size of the association between insulin and metabolites before and after the standardized liquid meal. Effect sizes indicate the association magnitudes in units of 1-SD metabolite concentration per 1-SD metabolite concentration per 1-MU/L increment in insulin. Each dot represents a metabolite. Purple squares indicate the metabolite was significantly associated with BMI before and after the standardized liquid meal; red circles: only significant in fasting samples; blue circles: only significant in postprandial samples; black circles: not significant in fasting and postprandial samples 4

5 Supplementary Figure S4 Histogram of the time between consumption of the SLM and the collection of the non-fasted blood sample, in minutes. 5

6 Supplementary Table S1 Changes in metabolite levels after the standardized liquid meal N Change P-value* 95% CI Fatty acids Total fatty acids E Fatty acid chain length E Double bonds / fatty acids Docosahexaenoic acid Linoleic acid Omega-3 fatty acids E Omega-6 fatty acids Polyunsaturated fatty acids Monounsaturated fatty acids Saturated fatty acids E Fatty acids, relative to total fatty acids Omega-3 fatty acids (%) Omega-6 fatty acids (%) Polyunsaturated fatty acids (%) Monounsaturated fatty acids (%) Saturated fatty acids (%) Cholesterol Total cholesterol E Non-HDL cholesterol E VLDL cholesterol E IDL cholesterol E LDL cholesterol HDL cholesterol E Cholesterol esterification E Lipoprotein lipid concentration Extremely large VLDL E Very large VLDL E Large VLDL E Medium VLDL E Small VLDL E Very small VLDL E IDL E Large LDL Medium LDL E Small LDL E Very large HDL E Large HDL E Medium HDL E Small HDL E

7 Supplementary Table S1 (continued) Changes in metabolite levels after the standardized liquid meal N Change P-value* 95% CI Lipoprotein particle size VLDL diameter E LDL diameter E HDL diameter E Apolipoproteins and lipids Triglycerides Total phosphoglyceride E Phosphatidylcholines Sphingomyelins E Apolipoprotein A-I E Apolipoprotein B E Glycolysis related metabolites Glucose E Lactate E Pyruvate Citrate Glycerol E Amino acids Alanine E Glutamine E Glycine E Histidine Isoleucine E Leucine E Valine E Phenylalanine E Tyrosine Ketone bodies Acetate E Acetoacetate E hydroxybutyrate E Fluid balance Creatinine E Albumin Inflammation markers Glycoprotein acetyls E Changes are in units of 1-SD metabolite concentration * Bold p-values indicate significant associations after FDR correction % of total fatty acids Double bonds/fatty acids: the number of double bonds in fatty acids. VLDL, very low density lipoprotein; IDL, intermediate density lipoprotein; LDL, low density lipoprotein; HDL, high density lipoprotein. 7

8 Supplementary Table S2 Effect size of the association between BMI and metabolites before and after the standardized liquid meal fasting postprandial N B p-value* 95% CI B p-value* 95% CI Fatty acids Total fatty acids Fatty acid chain length Double bonds / fatty acids Docosahexaenoic acid Linoleic acid Omega-3 fatty acids Omega-6 fatty acids Polyunsaturated fatty acids Monounsaturated fatty acids Saturated fatty acids Fatty acids, relative to total fatty acids Omega-3 fatty acids (%) Omega-6 fatty acids (%) Polyunsaturated fatty acids (%) Monounsaturated fatty acids (%) Saturated fatty acids (%) Cholesterol Total cholesterol Non-HDL cholesterol VLDL cholesterol IDL cholesterol LDL cholesterol HDL cholesterol Cholesterol esterification

9 Supplementary Table S2 (continued) Effect size of the association between BMI and metabolites before and after the standardized liquid meal fasting postprandial N B p-value* 95% CI B p-value* 95% CI Lipoprotein lipid concentration Extremely large VLDL Very large VLDL Large VLDL Medium VLDL E E Small VLDL E E Very small VLDL IDL Large LDL Medium LDL Small LDL Very large HDL Large HDL E Medium HDL Small HDL Lipoprotein particle size VLDL diameter E E LDL diameter HDL diameter E E Apolipoproteins and lipids Triglycerides E E Total phosphoglyceride Phosphatidylcholines Sphingomyelins Apolipoprotein A-I Apolipoprotein B

10 Supplementary Table S2 (continued) Effect size of the association between BMI and metabolites before and after the standardized liquid meal fasting postprandial N B p-value* 95% CI B p-value* 95% CI Glycolysis related metabolites Glucose Lactate Pyruvate Citrate Glycerol Amino acids Alanine Glutamine Glycine Histidine Isoleucine Leucine Valine Phenylalanine Tyrosine Ketone bodies Acetate Acetoacetate hydroxybutyrate Fluid balance Creatinine Albumin Inflammation markers Glycoprotein acetyls

11 Effect sizes indicate the association magnitudes in units of 1-SD metabolite concentration per 1-kg/m 2 increment in BMI * Bold p-values indicate significant associations after FDR correction. % of total fatty acids Double bonds/fatty acids: the number of double bonds in fatty acids. VLDL, very low density lipoprotein; IDL, intermediate density lipoprotein; LDL, low density lipoprotein; HDL, high density lipoprotein. 11

12 Supplementary Table S3 Effect size of the association between BMI and metabolites in this study and study done by Würtz et al. (2014) 1 GOTO Würtz B SE p-value B SE p-value Fatty acids Total fatty acids E-71 Fatty acid chain length E-03 Double bonds / fatty acids E-17 Docosahexaenoic acid E-07 Linoleic acid E-10 Omega-3 fatty acids E-13 Omega-6 fatty acids E-14 Polyunsaturated fatty acids E-15 Monounsaturated fatty acids E-145 Saturated fatty acids E-102 Fatty acids, relative to total fatty acids Omega-3 fatty acids (%) Omega-6 fatty acids (%) E-117 Polyunsaturated fatty acids (%) E-71 Monounsaturated fatty acids (%) E-159 Saturated fatty acids (%) E-04 Cholesterol Total cholesterol E-30 non HDL cholesterol E-107 VLDL cholesterol E-110 IDL cholesterol E-49 LDL cholesterol E-116 HDL cholesterol E-133 Cholesterol esterification E-05 Lipoprotein lipid concentration Extremely large VLDL E-287 Very large VLDL E-231 Large VLDL E-294 Medium VLDL E E-163 Small VLDL E E-114 Very small VLDL E-188 IDL E-90 Large LDL E-120 Medium LDL E-149 Small LDL E-202 Very large HDL E-03 Large HDL E-185 Medium HDL Small HDL

13 Supplementary Table S3 (continued) Effect size of the association between BMI and metabolites in this study and study done by Würtz et al. (2014) 1 GOTO Würtz B SE p-value B SE p-value Lipoprotein particle size VLDL diameter E E-206 LDL diameter E-21 HDL diameter E E-11 Apolipoproteins and lipids Triglycerides E Total phosphoglyceride E-12 Phosphatidylcholines E-06 Sphingomyelins E-30 Apolipoprotein A-I E-14 Apolipoprotein B E-100 Glycolysis related metabolites Glucose E-05 Lactate E-10 Pyruvate E-08 Citrate E-05 Glycerol E-11 Amino acids Alanine E-24 Glutamine E-07 Glycine E-04 Histidine Isoleucine E-105 Leucine E-249 Valine E-164 Phenylalanine E-292 Tyrosine E-60 Ketone bodies Acetate E-14 Acetoacetate E-08 3-hydroxybutyrate E-15 Fluid balance Creatinine Albumin Inflammation markers Glycoprotein acetyls E-53 Effect sizes indicate the association magnitudes in units of 1-SD metabolite concentration per 1-kg/m 2 increment in BMI * Bold p-values indicate significant associations after FDR correction. # Bold p-values indicate significant associations after Bonferroni correction. % of total fatty acids Double bonds/fatty acids: the number of double bonds in fatty acids. VLDL. very low density lipoprotein; IDL. intermediate density lipoprotein; LDL. low density lipoprotein; HDL. high density lipoprotein. 13

14 Supplementary Table S4 Interaction between SLM and BMI BMI SLM x BMI SLM N B p-value* 95% CI B p-value* 95% CI B p-value* 95% CI Fatty acids Total fatty acids Fatty acid chain length Double bonds / fatty acids Docosahexaenoic acid Linoleic acid Omega-3 fatty acids Omega-6 fatty acids Polyunsaturated fatty acids Monounsaturated fatty acids Saturated fatty acids Fatty acids, relative to total fatty acids Omega-3 fatty acids (%) Omega-6 fatty acids (%) Polyunsaturated fatty acids (%) Monounsaturated fatty acids (%) Saturated fatty acids (%) Cholesterol Total cholesterol non-hdl cholesterol VLDL cholesterol IDL cholesterol LDL cholesterol HDL cholesterol Cholesterol esterification

15 Supplementary Table S4 (continued) Interaction between SLM and BMI BMI BMI x SLM SLM N B p-value* 95% CI B p-value* 95% CI B p-value* 95% CI Lipoprotein lipid concentration Extremely large VLDL Very large VLDL Large VLDL Medium VLDL E Small VLDL E Very small VLDL IDL Large LDL Medium LDL Small LDL Very large HDL Large HDL Medium HDL Small HDL Lipoprotein particle size VLDL diameter E LDL diameter HDL diameter E Apolipoproteins and lipids Triglycerides Total phosphoglyceride Phosphatidylcholines Sphingomyelins Apolipoprotein A-I Apolipoprotein B

16 Supplementary Table S4 (continued) Interaction between SLM and BMI BMI SLM x BMI SLM N B p-value* 95% CI B p-value* 95% CI B p-value* 95% CI Glycolysis related metabolites Glucose Lactate Pyruvate Citrate Glycerol E Amino acids Alanine Glutamine Glycine Histidine Isoleucine Leucine Valine Phenylalanine Tyrosine Ketone bodies Acetate Acetoacetate hydroxybutyrate Fluid balance Creatinine Albumin Inflammation markers Glycoprotein acetyls

17 Used model: Metabolite = β0 + β1 * BMI + β2 * (SLMxBMI)+ β3 * SLM + β4 * Age + β5 * Gender + β6 * Status + β7 * Lipid lowering medication + β8 * Antihypertensive medication + u1 * Household + ε BMI reports β1, SLM x BMI reports β2; SLM reports β3 * Bold p-values indicate significant associations after FDR correction. % of total fatty acids SLM, standardized liquid meal; Double bonds/fatty acids, the number of double bonds in fatty acids. VLDL, very low density lipoprotein; IDL, intermediate density lipoprotein; LDL, low density lipoprotein; HDL, high density lipoprotein. 17

18 Supplementary Table S5 Effect size of the association between diastolic blood pressure and metabolites before and after the standardized liquid meal fasting postprandial N B p-value* 95% CI B p-value* 95% CI Fatty acids Total fatty acids Fatty acid chain length Double bonds / fatty acids Docosahexaenoic acid Linoleic acid Omega-3 fatty acids Omega-6 fatty acids Polyunsaturated fatty acids Monounsaturated fatty acids Saturated fatty acids Fatty acids, relative to total fatty acids Omega-3 fatty acids (%) Omega-6 fatty acids (%) Polyunsaturated fatty acids (%) Monounsaturated fatty acids (%) Saturated fatty acids (%) Cholesterol Total cholesterol non HDL cholesterol VLDL cholesterol IDL cholesterol LDL cholesterol HDL cholesterol Cholesterol esterification

19 Supplementary Table S5 (continued) Effect size of the association between diastolic blood pressure and metabolites before and after the standardized liquid meal fasting postprandial N B p-value* 95% CI B p-value* 95% CI Lipoprotein lipid concentration Extremely large VLDL Very large VLDL Large VLDL Medium VLDL Small VLDL Very small VLDL IDL Large LDL Medium LDL Small LDL Very large HDL Large HDL Medium HDL Small HDL Lipoprotein particle size VLDL diameter LDL diameter HDL diameter Apolipoproteins and lipids Triglycerides Total phosphoglyceride Phosphatidylcholines Sphingomyelins Apolipoprotein A-I Apolipoprotein B

20 Supplementary Table S5 (continued) Effect size of the association between diastolic blood pressure and metabolites before and after the standardized liquid meal fasting postprandial N B p-value* 95% CI B p-value* 95% CI Glycolysis related metabolites Glucose Lactate Pyruvate Citrate Glycerol Amino acids Alanine Glutamine Glycine Histidine Isoleucine Leucine Valine Phenylalanine Tyrosine Ketone bodies Acetate Acetoacetate hydroxybutyrate Fluid balance Creatinine Albumin Inflammation markers Glycoprotein acetyls Effect sizes indicate the association magnitudes in units of 1-SD metabolite concentration per 1-mmHg increment in diastolic blood pressure. 20

21 * Bold p-values indicate significant associations after FDR correction. % of total fatty acids Double bonds/fatty acids: the number of double bonds in fatty acids. VLDL, very low density lipoprotein; IDL, intermediate density lipoprotein; LDL, low density lipoprotein; HDL, high density lipoprotein. 21

22 Supplementary Table S6 Effect size of the association between insulin and metabolites before and after the standardized liquid meal fasting postprandial N B p-value* 95% CI B p-value* 95% CI Fatty acids Total fatty acids Fatty acid chain length Double bonds / fatty acids Docosahexaenoic acid Linoleic acid Omega-3 fatty acids Omega-6 fatty acids Polyunsaturated fatty acids Monounsaturated fatty acids Saturated fatty acids Fatty acids, relative to total fatty acids Omega-3 fatty acids (%) Omega-6 fatty acids (%) Polyunsaturated fatty acids (%) Monounsaturated fatty acids (%) Saturated fatty acids (%) Cholesterol Total cholesterol non HDL cholesterol VLDL cholesterol IDL cholesterol LDL cholesterol HDL cholesterol Cholesterol esterification

23 Supplementary Table S6 (continued) Effect size of the association between insulin and metabolites before and after the standardized liquid meal fasting postprandial N B p-value* 95% CI B p-value* 95% CI Lipoprotein lipid concentration Extremely large VLDL Very large VLDL Large VLDL Medium VLDL E Small VLDL Very small VLDL IDL Large LDL Medium LDL Small LDL Very large HDL E Large HDL Medium HDL Small HDL Lipoprotein particle size VLDL diameter E E LDL diameter HDL diameter E E Apolipoproteins and lipids Triglycerides Total phosphoglyceride Phosphatidylcholines Sphingomyelins Apolipoprotein A-I Apolipoprotein B

24 Supplementary Table S6 (continued) Effect size of the association between insulin and metabolites before and after the standardized liquid meal fasting postprandial N B p-value* 95% CI B p-value* 95% CI Glycolysis related metabolites Glucose Lactate E Pyruvate Citrate Glycerol Amino acids Alanine Glutamine Glycine Histidine Isoleucine E E Leucine E E Valine E Phenylalanine E Tyrosine E E Ketone bodies Acetate Acetoacetate hydroxybutyrate Fluid balance Creatinine Albumin Inflammation markers Glycoprotein acetyls E Effect sizes indicate the association magnitudes in units of 1-SD metabolite concentration per 1-MU/L increment in insulin. * Bold p-values indicate significant associations after FDR correction. % of total fatty acids 24

25 Double bonds/fatty acids: the number of double bonds in fatty acids. VLDL, very low density lipoprotein; IDL, intermediate density lipoprotein; LDL, low density lipoprotein; HDL, high density lipoprotein. 25

26 Supplementary Table S7 Nutritional content Nutridrink per 100 ml: Energy 150/625 kcal/kj Trace elements Iron 2.4 mg Fat (35 En%) 5.8 g Zinc 1.8 mg Saturated fat 0.6 g Copper 0.27 mg Monounsaturated fat 3.5 g Manganese 0.5 mg Polyunsaturated fat 1.7 g Fluorine 0.15 mg Linoleic acid 1.4 g Molybdenum 15 μg α-linolenic acid 0.27 g Selenium 8.6 μg Arachidonic acid - mg Chromium 10 μg Docosahexaenoic acid - mg Iodine 20 μg Eicosapentaenoic acid - mg Vitamins Carbohydrates (49 En%) 18.4 g A 123 μg-re Glucose 0.1 g Carotenoids 0.3 mg Fructose - g D 1.1 μg Lactose <0.025 g E 1.9 mg α-te Maltose 0.6 g K 8 μg Sacharose 6 g Thiamine 0.23 mg Polysacharose 11.3 g Riboflavin 0.24 mg Others 0.4 g Niacin 2.7 mg NE Pantothenic acid 0.8 mg Fibers - g Others Protein (16 En%) 5.9 g Carnitine - mg Casein 5.9 g Choline 55 mg Whey protein - g Taurine - mg Salt 0.23 g Osmolarity 455 mosmol/l Liquids 78 ml Minerals Sodium 90 mg Potassium 159 mg Chlorine 87 mg Calcium 91 mg Phosphorus 78 mg Magnesium 23 mg 26

27 Supplementary Table S8 Nutritional content amino acids Nutridrink per 100 ml: L-Alanine L-Arginine L-Asparagine zuur / L-Asparagine L-Cystine L-Glutaminezuur / L-Glutamine Glycine L-Histidine L-Isoleucine L-Leucine L-Lysine L-Methionine L-Fenylalanine L-Proline L-Serine L-Threonine L-Tryptofaan L-Tyrosine L-Valine L-Methione + L-Cystine L-Phenylalanine + L-Tyrosine 193 mg 227 mg 446 mg 20.8 mg 1,394 mg 115 mg 186 mg 338 mg 606 mg 545 mg 183 mg 323 mg 600 mg 381 mg 279 mg 82.2 mg 349 mg 432 mg 204 mg 673 mg 27

28 References 1 Würtz. P. et al. Metabolic signatures of adiposity in young adults: Mendelian randomization analysis and effects of weight change. PLoS. Med. 11. e (2014). 28