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
Population nutrient goal WHO, 2003 UK, COMA, 1991 US, USDA, 2010 AHA Goal (% of total energy) Total fat 15-30 33 20-35 25-35 Saturated fat <10 <10 <10 <7
SFA and T2D Micha & Mozaffarian. Lipids 2010
Meta-analyses: SFA & CHD Meta-analysis N Studies Relative Risk (95% CI) Observational studies Jacobsen, 2009 11 0.87 (0.77, 0.97) Mente, 2009 11 1.06 (0.96, 1.15) Siri-Tarino, 2010 16 1.07 (0.96, 1.19) Chowdhury, 2014 20 1.03 (0.98, 1.07) Farvid, 2014 10 0.90 (0.85, 0.94) desouza, 2015 12 1.06 (0.95, 1.17) Trials Skeaff, 2009 8 0.83 (0.69, 1.00) Mozaffarian, 2010 8 0.90 (0.83, 0.97) Hooper, 2012 23 0.93 (0.84, 1.02) Ramsden, 2013 7 0.98 (0.82, 1.19) Schwingshackl, 2014 12 0.76 (0.54, 1.09) Harcombe, 2015 7 0.99 (0.78, 1.25) Hooper, 2015 11 0.90 (0.80, 1.01)
Meta-analyses: SFA & CHD Meta-analysis N Studies Relative Risk (95% CI) Observational studies Jacobsen, 2009 11 0.87 (0.77, 0.97) Mente, 2009 11 1.06 (0.96, 1.15) Siri-Tarino, 2010 16 1.07 (0.96, 1.19) Chowdhury, 2014 20 1.03 (0.98, 1.07) Farvid, 2014 10 0.90 (0.85, 0.94) desouza, 2015 12 1.06 (0.95, 1.17) Trials Skeaff, 2009 8 0.83 (0.69, 1.00) Mozaffarian, 2010 8 0.90 (0.83, 0.97) Hooper, 2012 23 0.93 (0.84, 1.02) Ramsden, 2013 7 0.98 (0.82, 1.19) Schwingshackl, 2014 12 0.76 (0.54, 1.09) Harcombe, 2015 7 0.99 (0.78, 1.25) Hooper, 2015 11 0.90 (0.80, 1.01)
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?
Fatty acids and cardiovascular disease
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
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 20 276 763 10 155 1.03 (0.98-1.07) Total monounsaturated fatty acids 9 144 219 6031 1.00 (0.91-1.10) ω-3 fatty. acids α-linolenic 7 157 258 7431 0.99 (0.86-1.14) Total long-chain ω-3 16 422 786 9089 0.87 (0.78-0.97) Total ω-6 fatty acids 8 206 376 8155 0.98 (0.90-1.06) Total trans fatty acids 5 155 270 4662 1.16 (1.06-1.27) 0.75 1 1.25 1.50 RR (95% CI) Comparing Top vs. Bottom Thirds of Baseline Dietary Fatty Acid Intake Chowdhury R et al, Ann Intern Med 2014
Self-reported dietary fatty acid intake and stroke Siri-Tarino et al, Am J Clin Nutr 2010
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 8 5 4 15 590 10 598 5490 3758 2932 2283 1.06 (0.86-1.30) 0.96 (0.83-1.12) 0.94 (0.67-1.32) 16:0, Palmitic 17:0, Heptadecanoic or margaric 15:0, Pentadecanoic + 17:0, Margaric 10 4 4 25 554 5490 5490 4318 2283 2283 1.15 (0.96-1.37) 0.77 (0.63-0.93) 0.81 (0.62-1.06) 18:0, Stearic 8 22 266 3654 1.23 (0.93-1.61) Total trans fatty acids 4 7661 2389 1.05 (0.76-1.44) 18:1, trans-oleic 2 921 380 1.20 (0.39-3.73) 18:2, trans-linoleic 2 921 380 1.36 (0.83-2.22) 0.50 0.75 1 1.25 1.50 2.00 RR (95% CI) Comparing Top vs. Bottom Thirds Chowdhury R et al, Ann Intern Med 2014
Fatty acid biomarkers and coronary outcomes Circulating fatty acids composition Studies, n Participants, n Events, n RR (95% CI) Total monounsaturated fatty acids 6 14 356 3236 1.06 (0.97-1.17) 16:1n-7, Palmitoleic 9 17 927 4127 0.96 (0.86-1.08) 18:1cis-9, Oleic 9 22 664 3687 1.09 (0.97-1.23) ω-3 polyunsaturated fatty acids 18:3n-3, α-linolenic 8 14 945 3426 0.93 (0.83-1.03) Total long-chain ω-3 4 10 558 2753 0.84 (0.63-1.11) 20:5n-3, Eicosapentaenoic 13 23 065 4624 0.78 (0.65-0.94) 22:6n-3, Docosahexaenoic 13 23 065 4624 0.79 (0.67-0.93) 20:5n-3, Eicosapentaenoic + 22:6n-3, Docosahexaenoic 13 20 809 4073 0.75 (0.62-0.89) 22:5n-3, Docosapentaenoic 4 7155 2565 0.64 (0.47-0.89) Total ω-6 polyunsaturated fatty acids 18:2n-6, Linoleic 18:3n-6, γ-linolenic 2 10 4 7432 23 022 8285 1877 3866 2259 0.94 (0.84-1.06) 0.99 (0.77-1.28) 1.03 (0.90-1.17) 20:2n-6, Eicosadienoic 2 4029 1689 1.18 (0.93-1.50) 20:3n-6, Dihomo- γ -linolenic 20:4n-6, Arachidonic 6 10 14 189 22 948 3214 3739 1.11 (0.93-1.33) 0.83 (0.74-0.92) 22:4n-6, Docosatetraenoic 22:5n-6, Docosapentaenoic 2 2 4029 4029 1689 1689 1.20 (0.99-1.45) 0.97 (0.50-1.88) 0.50 0.75 1 1.25 1.50 2.00 RR (95% CI) Comparing Top vs. Bottom Thirds Chowdhury R et al, Ann Intern Med 2014
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
Fatty acids and type 2 diabetes
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
Blood fatty acids method for high throughput 2013 GC & robotics - 37 fatty acids
Circulating SFA & T2D Lancet Diabetes Endocrinol, 2014 (14:0, 16:0, 18:0) 12,132 T2D cases
Circulating SFA & T2D Lancet Diabetes Endocrinol, 2014 (14:0, 16:0, 18:0) 12,132 T2D cases (15:0, 17:0)
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).5 1 2 Adjusted for age, centre, sex, physical activity, smoking, education level, energy intake, alcohol, BMI
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).5 1 2 Adjusted for age, centre, sex, physical activity, smoking, education level, energy intake, alcohol, BMI
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).5 1 2 Adjusted for age, centre, sex, physical activity, smoking, education level, energy intake, alcohol, BMI
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 -.4 -.2 0.2.4 -.4 Spearman -.2 correlation 0 (95% CI).2.4 Spearman correlation (95% CI)
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 -.4 -.2 0.2.4 Spearman correlation (95% CI)
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?
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
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)
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
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
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
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
Thank you Acknowledgements Contact at: nita.forouhi@mrc-epid.cam.ac.uk rc436@medschl.cam.ac.uk