Fatty acids, cardiovascular disease and diabetes
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1 Fatty acids, cardiovascular disease and diabetes Rajiv Chowdhury, Nita Forouhi 28 th October 2015 Workshop on nutritional biomarkers A joint PHRI/MRC Epidemiology Unit Initiative
2 Population nutrient goal WHO, 2003 UK, COMA, 1991 US, USDA, 2010 AHA Goal (% of total energy) Total fat Saturated fat <10 <10 <10 <7
3
4 SFA and T2D Micha & Mozaffarian. Lipids 2010
5 Meta-analyses: SFA & CHD Meta-analysis N Studies Relative Risk (95% CI) Observational studies Jacobsen, (0.77, 0.97) Mente, (0.96, 1.15) Siri-Tarino, (0.96, 1.19) Chowdhury, (0.98, 1.07) Farvid, (0.85, 0.94) desouza, (0.95, 1.17) Trials Skeaff, (0.69, 1.00) Mozaffarian, (0.83, 0.97) Hooper, (0.84, 1.02) Ramsden, (0.82, 1.19) Schwingshackl, (0.54, 1.09) Harcombe, (0.78, 1.25) Hooper, (0.80, 1.01)
6 Meta-analyses: SFA & CHD Meta-analysis N Studies Relative Risk (95% CI) Observational studies Jacobsen, (0.77, 0.97) Mente, (0.96, 1.15) Siri-Tarino, (0.96, 1.19) Chowdhury, (0.98, 1.07) Farvid, (0.85, 0.94) desouza, (0.95, 1.17) Trials Skeaff, (0.69, 1.00) Mozaffarian, (0.83, 0.97) Hooper, (0.84, 1.02) Ramsden, (0.82, 1.19) Schwingshackl, (0.54, 1.09) Harcombe, (0.78, 1.25) Hooper, (0.80, 1.01)
7 Limitations Need to consider replacement nutrient Limitations of observational studies Limitations of clinical trials Measurement error in dietary assessment Can objective measurement help to advance our understanding?
8 Fatty acids and cardiovascular disease
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10 What is the current evidence on fatty acids and cardiovascular disease? Fatty Acids Cardiovascular disease Our systematic review and meta-analysis of the published literature aimed to quantify 3 aspects of the evidence: self-reported dietary fatty acid intake individual fatty acid biomarkers randomized controlled trials
11 Self-reported dietary fatty acid intake and coronary outcomes Studies, n Participants, n Events, n Risk Ratio (95% CI) Dietary fatty acids intake Total saturated fatty acids ( ) Total monounsaturated fatty acids ( ) ω-3 fatty. acids α-linolenic ( ) Total long-chain ω ( ) Total ω-6 fatty acids ( ) Total trans fatty acids ( ) RR (95% CI) Comparing Top vs. Bottom Thirds of Baseline Dietary Fatty Acid Intake Chowdhury R et al, Ann Intern Med 2014
12 Self-reported dietary fatty acid intake and stroke Siri-Tarino et al, Am J Clin Nutr 2010
13 Fatty acid biomarkers and coronary outcomes Circulating fatty acids composition Studies, n Participants, n Events, n Risk Ratio (95% CI) Total saturated fatty acids 14:0, Myristic 15:0, Pentadecanoic ( ) 0.96 ( ) 0.94 ( ) 16:0, Palmitic 17:0, Heptadecanoic or margaric 15:0, Pentadecanoic + 17:0, Margaric ( ) 0.77 ( ) 0.81 ( ) 18:0, Stearic ( ) Total trans fatty acids ( ) 18:1, trans-oleic ( ) 18:2, trans-linoleic ( ) RR (95% CI) Comparing Top vs. Bottom Thirds Chowdhury R et al, Ann Intern Med 2014
14 Fatty acid biomarkers and coronary outcomes Circulating fatty acids composition Studies, n Participants, n Events, n RR (95% CI) Total monounsaturated fatty acids ( ) 16:1n-7, Palmitoleic ( ) 18:1cis-9, Oleic ( ) ω-3 polyunsaturated fatty acids 18:3n-3, α-linolenic ( ) Total long-chain ω ( ) 20:5n-3, Eicosapentaenoic ( ) 22:6n-3, Docosahexaenoic ( ) 20:5n-3, Eicosapentaenoic + 22:6n-3, Docosahexaenoic ( ) 22:5n-3, Docosapentaenoic ( ) Total ω-6 polyunsaturated fatty acids 18:2n-6, Linoleic 18:3n-6, γ-linolenic ( ) 0.99 ( ) 1.03 ( ) 20:2n-6, Eicosadienoic ( ) 20:3n-6, Dihomo- γ -linolenic 20:4n-6, Arachidonic ( ) 0.83 ( ) 22:4n-6, Docosatetraenoic 22:5n-6, Docosapentaenoic ( ) 0.97 ( ) RR (95% CI) Comparing Top vs. Bottom Thirds Chowdhury R et al, Ann Intern Med 2014
15 How can we better understand the association between fatty acids and cardiovascular disease? Fatty Acids Cardiovascular disease Powerful prospective studies measuring comprehensive panel of individual fatty acids biomarkers, intermediate phenotypes and diet
16 Fatty acids and type 2 diabetes
17 EPIC-InterAct Nested case-cohort study within EPIC Europe Large 455,680 individuals at baseline Long follow-up 3.99 million person years 12,403 incident cases of T2D Stored blood Data on diet/physical activity Exposure heterogeneity Research groups in 8 countries Langenberg C et al, Diabetologia 2011
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19 Blood fatty acids method for high throughput 2013 GC & robotics - 37 fatty acids
20 Circulating SFA & T2D Lancet Diabetes Endocrinol, 2014 (14:0, 16:0, 18:0) 12,132 T2D cases
21 Circulating SFA & T2D Lancet Diabetes Endocrinol, 2014 (14:0, 16:0, 18:0) 12,132 T2D cases (15:0, 17:0)
22 Individual saturated fatty acids and T2D Per 1SD: c16:0 Hazard Country Ratio (95% CI) France Italy Spain UK Netherlands Germany Sweden Denmark Overall (I-squared = 77.3%, p = 0.000) 1.45 (1.13, 1.86) 1.70 (1.41, 2.05) 1.31 (1.15, 1.50) 1.58 (1.22, 2.04) 1.30 (1.09, 1.55) 1.11 (0.99, 1.26) 0.98 (0.83, 1.14) 1.13 (0.99, 1.29) 1.28 (1.13, 1.45) Adjusted for age, centre, sex, physical activity, smoking, education level, energy intake, alcohol, BMI
23 Individual saturated fatty acids and T2D Per 1SD: c15:0 Hazard Country Ratio (95% CI) France 0.81 (0.65, 1.00) Italy 0.85 (0.75, 0.97) Spain 0.85 (0.78, 0.93) UK 0.91 (0.80, 1.03) Netherlands 0.70 (0.60, 0.82) Germany 0.87 (0.79, 0.97) Sweden 0.70 (0.59, 0.84) Denmark 0.70 (0.62, 0.79) Overall (I-squared = 63.7%, p = 0.007) 0.80 (0.74, 0.87) Adjusted for age, centre, sex, physical activity, smoking, education level, energy intake, alcohol, BMI
24 Individual saturated fatty acids and T2D Per 1SD: c17:0 Hazard Country Ratio (95% CI) France 0.63 (0.51, 0.78) Italy 0.72 (0.64, 0.81) Spain 0.76 (0.72, 0.81) UK 0.68 (0.60, 0.77) Netherlands 0.56 (0.46, 0.70) Germany 0.75 (0.67, 0.84) Sweden 0.59 (0.49, 0.73) Denmark 0.71 (0.65, 0.78) Overall (I-squared = 53.2%, p = 0.037) 0.70 (0.66, 0.74) Adjusted for age, centre, sex, physical activity, smoking, education level, energy intake, alcohol, BMI
25 Correlation between foods and even-numbered SFA group (sum of 14:0, 16:0 and 18:0) Fruit/vegetables Fruit/vegetables Potatoes Bread Potatoes Pasta/rice Bread Cereal/cereal products Pasta/rice Cereal/cereal Alcohol products Soft drinks Alcohol Nuts/seeds Soft drinks Cakes/cookies Nuts/seeds Cakes/cookies Margarine Olive Margarine oil Vegetable Olive oils oil Fatty/very Vegetable fatty fishoils Fatty/very Lean fatty fish fish Fish/shellfish Lean fish Fish/shellfish Butter Cheese Butter Yoghurt/thick Cheese milk Yoghurt/thick Milkmilk Dairy productsmilk Dairy Poultry products Red/processed meat Poultry Red/processed Processed meat meat Processed Red meat meat Red meat Spearman -.2 correlation 0 (95% CI).2.4 Spearman correlation (95% CI)
26 Correlation between foods and odd-numbered SFA group (sum of 15:0 and 17:0) Fruit/vegetables Potatoes Bread Pasta/rice Cereal/cereal products Alcohol Soft drinks Nuts/seeds Cakes/cookies Margarine Olive oil Vegetable oils Fatty/very fatty fish Lean fish Fish/shellfish Butter Cheese Yoghurt/thick milk Milk Dairy products Poultry Red/processed meat Processed meat Red meat Spearman correlation (95% CI)
27 Issues in interpretation Within SFA group, individual SFAs exert different effects Consider Dietary fat intake vs. metabolism De novo lipogenesis Are there Direct effects of fatty acids or are the fatty acids markers of other constituents in foods?
28 Source of SFA matters Differential health effects depending on food source SFA-rich foods Other nutrients Other compounds Other diet factors Displacement effects Other lifestyles
29 Fatty acids and T2D: work in progress PUFA n-3 18:3n3 (Alpha-linolenic), 20:5n3 (Eicosapentaenoic), 22:5n3 (Docosapentaenoic), 22:6n3 (Docosahexaenoic) n-6 18:2n6c (Linoleic), 18:3n6 (Gamma linolenic), 20:2n6 (Eicosadienoic), 20:3n6 (Dihomo-gamma-linolenic), 20:4n6 +20:3n3 (Arachidonic acid(20_4n6) + Eicosatrienoic Acid(20_3n3)), 22:2n6 (Docosadienoic), 22:4n6 (Docosatetraenoic), 22:5n6 (Docosapentenoic) MUFA 14:1 (Myristoleic), 15:1 (no name) 16:1 (Palmitoleic), 17:1 18:1n9c (Oleic), 20:1n9 (Gondoic), 22:1n9 (Erucic), 24:1 (Nervonic) Trans-FA 18:1n9t (Elaidic acid), 18:2n6t (Conjugated linoleic), trans-palmitoleic acid (16:1n7t)
30 EPIC-Heart & EPIC-CVD Nested case-cohort study within EPIC Europe 510,000 individuals at baseline ~16,500 incident cases of CHD ~10,500 incident cases of stroke Stored blood Data on diet Exposure heterogeneity Research groups in 10 countries; 28 centres
31 EPIC-CVD- work in progress Dietary saturated fat and incidence of CHD & stroke Substitution effects of replacing saturated fat with Polyunsaturated fatty acids Monounsaturated fatty acids Carbohydrates Protein Measurement of 38 blood fatty acids is now complete Embarking on analyses of association between circulating fatty acids and incidence of CHD & stroke
32 Future directions Saturated fatty acids & T2DM Is the association causal? Work in progress Genome wide Association study (GWAS) Causal inference using Mendelian Randomisation (MR) approach Lancet Diabetes Endocrinol, 2014
33 Conclusions Recommendations on fat intake have been the cornerstone of dietary guidance for decades It has emerged that quality/type of fat matters replacement nutrient matters Controversies remain New technologies are opening up possibilities for greater understanding EPIC-InterAct and EPIC-CVD projects are advancing this area of science on large scale Future direction: how best to combine information from self report and objective measurement Interdisciplinary research for better interpretation
34 Thank you Acknowledgements Contact at:
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