Coffee, Caffeine and Cardiovascular Disease Ahmed El-Sohemy Canada Research Chair in Nutrigenomics Department of Nutritional Sciences University of Toronto

Diet Genes Nutrigenomics: Using genomic information and techniques in molecular genetics & genomics to address issues important to nutrition and health. Diet Genes Food preferences

Why bother with genetics/genomics?  Challenges for Nutritional Epidemiology Measurement error Confounding (residual) Recall Bias (case-control)

Is Coffee associated with CVD?  Risk No Effect  Risk

Is Coffee associated with CVD? Coffee or associated lifestyle? Are coffee abstainers at  risk? Does risk depend on age? Which component of coffee? There are a number of important issues that often need to be addressed regarding the epidemiology of coffee and heart disease, which might explain some of the inconsistencies in studies In some populations, coffee is assoicated with unhealthy lifstyle factors such as smoking and inactivity, factors of which may be associated with the disease. Therefor its possible that previous associations might have been due to residual confounding It has been proposed that the higher risk of heart disease among the group with the lowest intake might be due to individuals with underlying diseases who are limiting their coffee intake 12,14. Some studies report that young individuals may be more sensitive to the effects of coffeeor alteratively, cofee becomes a less significant health factor. Therefor studies made up of predominately younger subjects would more likely report an associatiion compared to studies consisting of older subjects.

Bioactives in coffee aliphatic acids magnesium potassium caffeine melanoidins This is especially difficult given the numerous compounds found in a single cup of coffee, which may have benefical or adverse effects on the heart. Of all these compounds however, caffeine has been one which has been strongly implicated in the development of hdx . diterpenoids polyphenols

Caffeine (1,3,7-trimethylxanthine) Caffeine has been consumed in some form for thousands of years and is currenlty the most widely consumed stimulant in the world with an estimated 80 to 90% of adults reporting regular consumption of caffeine-containing beverages and foods. Sources of caffeine. Intakes vary by courntry and individual

Caffeine Metabolism SNPs Caffeine Target SNPs Coffee CVD

Caffeine Metabolism SNPs Caffeine Target SNPs Coffee CVD

Caffeine Paraxanthine 1,7-dimethyluric acid CYP1A2 Paraxanthine 1-methylxanthine 1-methyluric acid 5-acetylamino-6-formylamino-3-methyluracil 1,7-dimethyluric acid Para- 1,7 dimethylxanthine

Genetic Variation in CYP1A2 -163 AC fast slow

Costa Rica Study 2013 cases (myocardial infarction) 2013 population-based controls - matched (age, sex, area of residence) Data collection: - food frequency questionnaire - health and lifestyle questionnaire - fasting blood sample (DNA)

CYP1A2 Genotype Distribution Controls % Cases A/A A/C C/C 46 43 10 45 44 11 rapid slow

Coffee Intake and Risk of Myocardial Infarction * * P<0.05 Cornelis et al., JAMA 295: 1135-41, 2006

Coffee Intake and Risk of Myocardial Infarction * * A/A A/C + C/C * P<0.05 Cornelis et al., JAMA 295: 1135-41, 2006

Coffee Intake and Risk of Myocardial Infarction Subjects <50 Years of Age * * * * A/A A/C + C/C * P<0.05 Cornelis et al., JAMA 295: 1135-41, 2006

Personalized Dietary Advice vs Public Health Recommendations

Recommended Maximum Caffeine Intake (Health Canada)

Genetic modifiers of exposure Genetic modifiers of biological effect CYP1A2 FMO CYP2A6 NAT2 CYP2E1 UGT SULT CYP1A2 CYP3A4 CYP2D6 CYP1A1 UGT SULT CYP2C9 CYP2E1 GST ADR ADORA HTT GRK HTR COMT CETP PLTP LDLR ACAT SREBP GST ACE TNF NFkB VCAM1 PKC PPARG PDE CREB GLUT PKA GLP1R GLUT FAS1 ACE NOX G6PT1 Caffeine Diterpenes CHD Risk Flavonoids Figure 2 Potential genetic modifiers of exposure and biological effect Polyphenols Curr. Opin. Lipidol, 18: 13-19, 2007

Health Outcome Coffee Genes Genotype A Increase Genotype B No effect Genotype C Genotype B Increase Decrease No effect

Caffeine Consumption Habits Study Healthy Men and Women aged 20-29 years (n=940) Food Frequency Questionnaire Caffeine consumption Caffeine Consumption Habits Questionnaire - Acute effects of caffeine - Caffeine withdrawal symptoms - Limiting or avoiding caffeine

DRD2 C957T Genotype and “Elevated Mood” Among Men and Women ** * * P<0.05 ** P<0.005

DRD2 C957T Genotype and Caffeine Intake Among Men and Women * This is the old one when there were a total of ~640 subjects HOWEVER, this analysis excluded mood disorder * P<0.05

ACKNOWLEDGMENTS Hannia Campos Edmond Kabagambe Tom Wolever CCD Investigators Paul Corey David Jenkins Hyeon-Joo Lee Lindsay Stewart Daiva Nielsen Alejandra Navarro-Allende Susana Huang Sarah Herd Darren Brenner Bibiana Garcia-Bailo Marilyn Cornelis Leah Cahill Karen Eny Bénédicte Fontaine-Bisson Ilana Platt Stephen Ozsungur Clare Toguri Advanced Foods and Materials Network Centres of Excellence Natural Sciences and Engineering Research Council Canadian Institutes of Health Research Canada Research Chairs