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Biological Markers: New Horizons from -omics. Jose M. Ordovas JM-USDA-HNRCA at Tufts Univ. Boston, MA. Current and Future Practice of Disease Prevention/Therapy. 2004. Public Health Policy/ . Diagnosis. Global Advice/Therapy. Focused Screening. Early detection. Personalized

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biological markers new horizons from omics

Biological Markers: New Horizons from -omics

Jose M. Ordovas

JM-USDA-HNRCA at Tufts Univ.

Boston, MA

current and future practice of disease prevention therapy
Current and Future Practice of Disease Prevention/Therapy

2004

Public Health Policy/

Diagnosis

Global Advice/Therapy

Focused

Screening

Early

detection

Personalized

Prevention/Therapy

Therapeutic

Monitoring

Predisposition

circa2010

Based on Classical and New Biomarkers

Based on Genetics

cvd risk factors and prevention priorities
Hypertension
  • Blood lipids
  • Obesity / Overweight
  • Diabetes
  • Glucose Intolerance
CVD RISK FACTORS and Prevention Priorities
  • Non-modifiable
  • Risk Factors
  • Age
  • Sex
  • Genes
  • Coronary heart
  • disease
  • Stroke
  • Peripheral vascular
  • disease
  • Health, wellbeing

End Points

Intermediate

Risk Factors

  • Behavioural
  • Risk Factors
  • Tobacco
  • Diet
  • Physical Activity
  • Alcohol

Socio-economic, Cultural

& Environmental Conditions

Modernization, Mechanization,

Urbanization, Globalization

cvd risk factors and prevention priorities1
Hypertension
  • Blood lipids
  • Obesity / Overweight
  • Diabetes
  • Glucose Intolerance
CVD RISK FACTORS and Prevention Priorities
  • Non-modifiable
  • Risk Factors
  • Age
  • Sex
  • Genes
  • Coronary heart
  • disease
  • Stroke
  • Peripheral vascular
  • disease
  • Health, wellbeing

End Points

Intermediate

Risk Factors

  • Behavioural
  • Risk Factors
  • Tobacco
  • Diet
  • Physical Activity
  • Alcohol

Socio-economic, Cultural

& Environmental Conditions

Modernization, Mechanization,

Urbanization, Globalization

cvd risk factors and prevention priorities2
Hypertension
  • Blood lipids
  • Obesity / Overweight
  • Diabetes
  • Glucose Intolerance
CVD RISK FACTORS and Prevention Priorities
  • Non-modifiable
  • Risk Factors
  • Age
  • Sex
  • Genes
  • Coronary heart
  • disease
  • Stroke
  • Peripheral vascular
  • disease
  • Health, wellbeing

End Points

Intermediate

Risk Factors

  • Behavioural
  • Risk Factors
  • Tobacco
  • Diet
  • Physical Activity
  • Alcohol

Socio-economic, Cultural

& Environmental Conditions

Modernization, Mechanization,

Urbanization, Globalization

cvd risk factors and prevention priorities3
Hypertension
  • Blood lipids
  • Obesity / Overweight
  • Diabetes
  • Glucose Intolerance
CVD RISK FACTORS and Prevention Priorities
  • Non-modifiable
  • Risk Factors
  • Age
  • Sex
  • Genes
  • Coronary heart
  • disease
  • Stroke
  • Peripheral vascular
  • disease
  • Health, wellbeing

End Points

Intermediate

Risk Factors

  • Behavioural
  • Risk Factors
  • Tobacco
  • Diet
  • Physical Activity
  • Alcohol

Socio-economic, Cultural

& Environmental Conditions

Modernization, Mechanization,

Urbanization, Globalization

cvd risk factors and prevention priorities4
Hypertension
  • Blood lipids
  • Obesity / Overweight
  • Diabetes
  • Glucose Intolerance
CVD RISK FACTORS and Prevention Priorities
  • Non-modifiable
  • Risk Factors
  • Age
  • Sex
  • Genes
  • Coronary heart
  • disease
  • Stroke
  • Peripheral vascular
  • disease
  • Health, wellbeing

End Points

Intermediate

Risk Factors

  • Behavioural
  • Risk Factors
  • Tobacco
  • Diet
  • Physical Activity
  • Alcohol

Socio-economic, Cultural

& Environmental Conditions

Modernization, Mechanization,

Urbanization, Globalization

cvd risk factors and prevention priorities5
Hypertension
  • Blood lipids
  • Obesity / Overweight
  • Diabetes
  • Glucose Intolerance
CVD RISK FACTORS and Prevention Priorities
  • Non-modifiable
  • Risk Factors
  • Age
  • Sex
  • Genes
  • Coronary heart
  • disease
  • Stroke
  • Peripheral vascular
  • disease
  • Health, wellbeing

End Points

Intermediate

Risk Factors

  • Behavioural
  • Risk Factors
  • Tobacco
  • Diet
  • Physical Activity
  • Alcohol

Socio-economic, Cultural

& Environmental Conditions

Modernization, Mechanization,

Urbanization, Globalization

cvd risk factors and prevention priorities6
Hypertension
  • Blood lipids
  • Obesity / Overweight
  • Diabetes
  • Glucose Intolerance
CVD RISK FACTORS and Prevention Priorities
  • Non-modifiable
  • Risk Factors
  • Age
  • Sex
  • Genes
  • Coronary heart
  • disease
  • Stroke
  • Peripheral vascular
  • disease
  • Health, wellbeing

End Points

Intermediate

Risk Factors

  • Behavioural
  • Risk Factors
  • Tobacco
  • Diet
  • Physical Activity
  • Alcohol

Socio-economic, Cultural

& Environmental Conditions

Modernization, Mechanization,

Urbanization, Globalization

cvd risk factors and prevention priorities7
Hypertension
  • Blood lipids
  • Obesity / Overweight
  • Diabetes
  • Glucose Intolerance
CVD RISK FACTORS and Prevention Priorities
  • Non-modifiable
  • Risk Factors
  • Age
  • Sex
  • Genes
  • Coronary heart
  • disease
  • Stroke
  • Peripheral vascular
  • disease
  • Health, wellbeing

End Points

Intermediate

Risk Factors

  • Behavioural
  • Risk Factors
  • Tobacco
  • Diet
  • Physical Activity
  • Alcohol

Socio-economic, Cultural

& Environmental Conditions

Modernization, Mechanization,

Urbanization, Globalization

lipoprotein metabolism exogenous pathway endogenous
Dietary Fat

& Cholesterol

Peripheral

Tissues

Bile Acids

+

Cholesterol

LDL

Liver

Intestine

HDL

IDL

Chylomicron

Remnant

VLDL

Chylomicron

LPL

LPL

FFA

FFA

Lipoprotein MetabolismExogenous - Pathway - Endogenous

APOE

slide16
APOE Genotype, Glucose and BMI in the Framingham Offspring Study

P interaction = 0.031

Elosua et al. Obes Res. 2003 Dec;11:1502-8.

slide17
Lipoprotein Metabolism

Exogenous - Pathway -Endogenous

LPL

Dietary Fat

& Cholesterol

Peripheral

Tissues

Bile Acids

+

Cholesterol

LDL

Liver

Intestine

CHM

HDL

IDL

Chylomicron

Remnant

VLDL

LPL

LPL

FFA

FFA

genotype phenotype associations lack of consistency
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

lpl influence of obesity over the phenotypic expression of the genotype
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.

cvd risk factors and prevention priorities8
Hypertension
  • Blood lipids
  • Obesity / Overweight
  • Diabetes
  • Glucose Intolerance
CVD RISK FACTORS and Prevention Priorities
  • Non-modifiable
  • Risk Factors
  • Age
  • Sex
  • Genes
  • Coronary heart
  • disease
  • Stroke
  • Peripheral vascular
  • disease
  • Health, wellbeing

End Points

Intermediate

Risk Factors

  • Behavioural
  • Risk Factors
  • Tobacco
  • Diet
  • Physical Activity
  • Alcohol

Socio-economic, Cultural

& Environmental Conditions

Modernization, Mechanization,

Urbanization, Globalization

slide21
Perilipin function and Gene Structure

Hormone sensitive

lipase

Perilipin

Triacylglycerols

Exon1 Exon2 Exon3 Exon4 Exon5 Exon6 Exon7 Exon8 Exon9

Perilipin

6209 10171 11482 13041 14995

(T>C) (A>T) (G>A) (A>G) (A>T)

slide22
Knock-out mice: the effects on body fat accumulation

Martinez-Botas J , Nat Genet. 2000 Dec;26(4):474-9

odds ratio for obesity according to plin genotypes
Odds Ratio for obesity according to PLIN genotypes

MEN

WOMEN

Lu et al. Clin Genet 2004: 66: 299–310

slide25
Combined effect of the PLIN polymorphisms on weight and BMI

(Valencia)

PLIN1 PLIN4 PLIN5 PLIN6

Obese phenotype

Lean phenotype

replication of plin associations
Replication of PLIN Associations

Lu et al. Obesity Research, 2004

Lu et al. J Mol Med, 2005

slide28
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

current and future practice of disease prevention therapy1
Current and Future Practice of Disease Prevention/Therapy

2004

Public Health Policy/

Diagnosis

Global Advice/Therapy

Focused

Screening

Early

detection

Personalized

Prevention/Therapy

Therapeutic

Monitoring

Predisposition

circa2010

Based on Classical and New Biomarkers

Based on Genetics

slide30
Chemometrics and Bioinformatics

PHENOTYPE AND

DISEASE?

ENVIRONMENT

Measurement of Biological Interactions at Different Levels of Biomolecular Organisation: Systems Biology

CONTROL LEVELS

Organelle

Cell

Tissue

Organ

Biofluid

Organism

Transcriptomics

Genome

Gene Regulation/Expression

Metabolism

Proteins

Metabonomics

Proteomics

truemass analysis lipomics
TrueMass® Analysis (Lipomics)

CLINICAL / HEALTH INFORMATION

Phosphatidylcholine

PATIENT

Phosphatidylserine

Phosphatidylethanolamine

Cardiolipin

Sphingomyelin

Phosphatidylinositol

LipidExtract

Lyso-PLCholine

Triglycerides

SAMPLE

Diglycerides

DATABASE

Free Fatty Acids

Cholesterol Esters

Sterols

metabonomics tools 800 mhz ultrashielded nmr spectrometer
Metabonomics Tools800 MHz Ultrashielded NMR spectrometer

AVANCE 800 spectrometer with

the UltraShield-

UltraStabilized 800 magnet at Bruker Application Lab

slide37
900 MHz 1H 1D NMR Spectrum of Human Urine

Intensity (proportional to micromolar proton concentration)

Nmrradiofrequencyscale in arbitary units

slide38
Human Population Response Vector Analysis:

Multivariate Effect of Statin Treatment

4

101

3

102

103

104

105

2

106

107

108

1

111

112

113

0

114

PC2

117

119

-1

120

Good Responders

121

122

-2

123

124

-3

-4

-10

-8

-6

-4

-2

0

2

4

Poor Responders

subjects

124

Strong % increase

in TRG

Strong % decrease in TRG

111

122

108

121

113

129

123

114

104

107

103

102

105

112

106

128

125

119

101

117

% increase in TRG,

LDL, CHOL and HDL

(bis sample trajectory)

125

120

128

129

PC1

PHARMACO-METABONOMICS:EACH LINE REPRESENTS AN INDIVIDUALS’

RESPONSE VECTOR CONNECTING PRE-AND POST-TREATMENT

meeting the challenges
Meeting the Challenges
  • 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!!
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