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Biological Markers: New Horizons from -omics Jose M. Ordovas JM-USDA-HNRCA at Tufts Univ. Boston, MA

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Current and Future Practice of Disease Prevention/Therapy 2004 circa2010 Predisposition Focused Screening Early detection Personalized Prevention/Therapy Therapeutic Monitoring DiagnosisGlobal Advice/Therapy Based on Classical and New Biomarkers Based on Genetics Public Health Policy/

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Hypertension Blood lipids Obesity / Overweight Diabetes Glucose Intolerance Non-modifiable Risk Factors Age Sex Genes Behavioural Risk Factors Tobacco Diet Physical Activity Alcohol Socio-economic, Cultural & Environmental Conditions Modernization, Mechanization, Urbanization, Globalization Coronary heart disease Stroke Peripheral vascular disease Health, wellbeing End Points Intermediate Risk Factors CVD RISK FACTORS and Prevention Priorities

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Hypertension Blood lipids Obesity / Overweight Diabetes Glucose Intolerance Non-modifiable Risk Factors Age Sex Genes Behavioural Risk Factors Tobacco Diet Physical Activity Alcohol Socio-economic, Cultural & Environmental Conditions Modernization, Mechanization, Urbanization, Globalization Coronary heart disease Stroke Peripheral vascular disease Health, wellbeing End Points Intermediate Risk Factors CVD RISK FACTORS and Prevention Priorities

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Hypertension Blood lipids Obesity / Overweight Diabetes Glucose Intolerance Non-modifiable Risk Factors Age Sex Genes Behavioural Risk Factors Tobacco Diet Physical Activity Alcohol Socio-economic, Cultural & Environmental Conditions Modernization, Mechanization, Urbanization, Globalization Coronary heart disease Stroke Peripheral vascular disease Health, wellbeing End Points Intermediate Risk Factors CVD RISK FACTORS and Prevention Priorities

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Hypertension Blood lipids Obesity / Overweight Diabetes Glucose Intolerance Non-modifiable Risk Factors Age Sex Genes Behavioural Risk Factors Tobacco Diet Physical Activity Alcohol Socio-economic, Cultural & Environmental Conditions Modernization, Mechanization, Urbanization, Globalization Coronary heart disease Stroke Peripheral vascular disease Health, wellbeing End Points Intermediate Risk Factors CVD RISK FACTORS and Prevention Priorities

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Hypertension Blood lipids Obesity / Overweight Diabetes Glucose Intolerance Non-modifiable Risk Factors Age Sex Genes Behavioural Risk Factors Tobacco Diet Physical Activity Alcohol Socio-economic, Cultural & Environmental Conditions Modernization, Mechanization, Urbanization, Globalization Coronary heart disease Stroke Peripheral vascular disease Health, wellbeing End Points Intermediate Risk Factors CVD RISK FACTORS and Prevention Priorities

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Hypertension Blood lipids Obesity / Overweight Diabetes Glucose Intolerance Non-modifiable Risk Factors Age Sex Genes Behavioural Risk Factors Tobacco Diet Physical Activity Alcohol Socio-economic, Cultural & Environmental Conditions Modernization, Mechanization, Urbanization, Globalization Coronary heart disease Stroke Peripheral vascular disease Health, wellbeing End Points Intermediate Risk Factors CVD RISK FACTORS and Prevention Priorities

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Hypertension Blood lipids Obesity / Overweight Diabetes Glucose Intolerance Non-modifiable Risk Factors Age Sex Genes Behavioural Risk Factors Tobacco Diet Physical Activity Alcohol Socio-economic, Cultural & Environmental Conditions Modernization, Mechanization, Urbanization, Globalization Coronary heart disease Stroke Peripheral vascular disease Health, wellbeing End Points Intermediate Risk Factors CVD RISK FACTORS and Prevention Priorities

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Hypertension Blood lipids Obesity / Overweight Diabetes Glucose Intolerance Non-modifiable Risk Factors Age Sex Genes Behavioural Risk Factors Tobacco Diet Physical Activity Alcohol Socio-economic, Cultural & Environmental Conditions Modernization, Mechanization, Urbanization, Globalization Coronary heart disease Stroke Peripheral vascular disease Health, wellbeing End Points Intermediate Risk Factors CVD RISK FACTORS and Prevention Priorities

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Lipoprotein Metabolism Exogenous - Pathway - Endogenous Intestine Dietary Fat & Cholesterol LPL Chylomicron Remnant FFA Liver LPL VLDL IDL FFA Bile Acids + Cholesterol LDL Peripheral Tissues HDL APOE

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APOE Gene and Plasma Cholesterol

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APOE Genotype, Glucose and BMI in the Framingham Offspring Study P interaction = 0.031 Elosua et al. Obes Res. 2003 Dec;11:1502-8.

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Intestine Dietary Fat & Cholesterol CHM LPL Chylomicron Remnant FFA Liver LPL VLDL IDL FFA Bile Acids + Cholesterol LDL Peripheral Tissues HDL Lipoprotein Metabolism Exogenous - Pathway -Endogenous LPL

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Genotype/Phenotype Associations: Lack of Consistency Meta-analyses of population-based studies of effect of Gly188Glu, Asp9Asn, Asn291Ser, and Ser447Ter substitutions at the LPL locus on plasma triglycerides. Wittrup: Circulation, Volume 99(22).June 8, 1999.2901-2907

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LPL, influence of obesity over the phenotypic expression of the genotype Corella and Ordovas. The metabolic syndrome: a crossroad for genotype-phenotype associations in atherosclerosis. Current Atherosclerosis Reports, 2004.

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Hypertension Blood lipids Obesity / Overweight Diabetes Glucose Intolerance Non-modifiable Risk Factors Age Sex Genes Behavioural Risk Factors Tobacco Diet Physical Activity Alcohol Socio-economic, Cultural & Environmental Conditions Modernization, Mechanization, Urbanization, Globalization Coronary heart disease Stroke Peripheral vascular disease Health, wellbeing End Points Intermediate Risk Factors CVD RISK FACTORS and Prevention Priorities

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Perilipin function and Gene Structure Triacylglycerols Perilipin Hormone sensitive lipase 6209 10171 11482 13041 14995 (T>C) (A>T) (G>A) (A>G) (A>T) Exon1 Exon2 Exon3 Exon4 Exon5 Exon6 Exon7 Exon8 Exon9 Perilipin

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Knock-out mice: the effects on body fat accumulation Martinez-Botas J, Nat Genet. 2000 Dec;26(4):474-9

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Valencia

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Odds Ratio for obesity according to PLIN genotypes MENWOMEN Lu et al. Clin Genet 2004: 66: 299310

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Combined effect of the PLIN polymorphisms on weight and BMI (Valencia) Obese phenotype Lean phenotype PLIN1 PLIN4 PLIN5 PLIN6

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Replication of PLIN Associations Lu et al. Obesity Research, 2004 Lu et al. J Mol Med, 2005

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Weight reduction in response to a low caloric diet depending on the PLIN (11482G>A ) polymorphism in obese subjects P=0.015 for interaction detween diet and PLIN

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Current and Future Practice of Disease Prevention/Therapy 2004 circa2010 Predisposition Focused Screening Early detection Personalized Prevention/Therapy Therapeutic Monitoring DiagnosisGlobal Advice/Therapy Based on Classical and New Biomarkers Based on Genetics Public Health Policy/

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Genome Gene Regulation/Expression Metabolism Metabonomics Chemometrics and Bioinformatics CONTROL LEVELS Organelle Cell Tissue Organ Biofluid Organism Proteomics Measurement of Biological Interactions at Different Levels of Biomolecular Organisation: Systems Biology Transcriptomics Proteins PHENOTYPE AND DISEASE? ENVIRONMENT

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NMR Farm

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SAMPLE Lipid Extract Phosphatidylinositol Lyso-PLCholine Triglycerides Diglycerides Phosphatidylcholine Phosphatidylserine Phosphatidylethanolamine Cardiolipin Sphingomyelin Free Fatty Acids Cholesterol Esters Sterols PATIENT CLINICAL / HEALTH INFORMATION DATABASE TrueMass Analysis (Lipomics)

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Surveyor Data Visualization

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Metabonomics Tools 800 MHz Ultrashielded NMR spectrometer AVANCE 800 spectrometer with the UltraShield- UltraStabilized 800 magnet at Bruker Application Lab

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900 MHz 1 H 1D NMR Spectrum of Human Urine Nmr radiofrequency scale in arbitary units Intensity (proportional to micromolar proton concentration)

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125 128 129 101 102103 104 105 106 107 108 111 112 113114 117 119 120 121 122 123 124 125 128 129 Human Population Response Vector Analysis: Multivariate Effect of Statin Treatment PHARMACO-METABONOMICS: EACH LINE REPRESENTS AN INDIVIDUALS RESPONSE VECTOR CONNECTING PRE-AND POST-TREATMENT Strong % decrease in TRG Strong % increase in TRG % increase in TRG, LDL, CHOL and HDL (bis sample trajectory) PC1 Good Responders Poor Responders subjects

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Pattern Recognition Analysis: Control and Soya Dosed Humans Systematic metabolic effect of diet

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The New Horizon Remains Obscured by Fog and Obstacles

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Population Studies of appropriate experimental design Clinical trials of adequate size and quality Genetic associations Product-specific clinical trials in subjects selected for specific genetic variants Proper evaluation of benefit (FDA?) Address DTC genetic testing issues Educate service providers (physicians, nutritionists) Publish high quality research!! Meeting the Challenges

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