Biological Markers: New Horizons from -omics

1
Biological Markers New Horizons from -omics

• Jose M. Ordovas
• JM-USDA-HNRCA at Tufts Univ.
• Boston, MA

2
Current and Future Practice of Disease
Prevention/Therapy
2004
Diagnosis
Global Advice/Therapy
Public Health Policy/
Focused Screening
Early detection
Personalized Prevention/Therapy
Therapeutic Monitoring
Predisposition
circa2010
Based on Classical and New Biomarkers
Based on Genetics
3
(No Transcript)
4
(No Transcript)
5
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, Urbanizat
ion, Globalization
6
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, Urbanizat
ion, Globalization
7
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, Urbanizat
ion, Globalization
8
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, Urbanizat
ion, Globalization
9
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, Urbanizat
ion, Globalization
10
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, Urbanizat
ion, Globalization
11
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, Urbanizat
ion, Globalization
12
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, Urbanizat
ion, Globalization
13
Lipoprotein Metabolism Exogenous - Pathway
- Endogenous
APOE
14
APOE Gene and Plasma Cholesterol
15
(No Transcript)
16
APOE Genotype, Glucose and BMI in the Framingham
Offspring Study
P interaction 0.031
Elosua et al. Obes Res. 2003 Dec111502-8.
17
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
18
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
19
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.
20
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, Urbanizat
ion, Globalization
21
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 (TgtC)
(AgtT) (GgtA)
(AgtG) (AgtT)
22
Knock-out mice the effects on body fat
accumulation
Martinez-Botas J , Nat Genet. 2000
Dec26(4)474-9
23
Valencia
24
Odds Ratio for obesity according to PLIN genotypes
MEN
WOMEN
Lu et al. Clin Genet 2004 66 299310
25
Combined effect of the PLIN polymorphisms on
weight and BMI (Valencia)
PLIN1 PLIN4 PLIN5 PLIN6
Obese phenotype
Lean phenotype
26
Replication of PLIN Associations
Lu et al. Obesity Research, 2004 Lu et al. J Mol
Med, 2005
27
(No Transcript)
28

Weight reduction in response to a low caloric
diet depending on the PLIN (11482GgtA )
polymorphism in obese subjects
P0.015 for interaction detween diet and PLIN

29
Current and Future Practice of Disease
Prevention/Therapy
2004
Diagnosis
Global Advice/Therapy
Public Health Policy/
Focused Screening
Early detection
Personalized Prevention/Therapy
Therapeutic Monitoring
Predisposition
circa2010
Based on Classical and New Biomarkers
Based on Genetics
30
Measurement of Biological Interactions at
Different Levels of Biomolecular Organisation
Systems Biology
CONTROL LEVELS Organelle Cell Tissue Organ Bioflui
d Organism
Transcriptomics
Genome
Gene Regulation/Expression
Metabolism
Proteins
Metabonomics
Proteomics
31
(No Transcript)
32
NMR Farm
33
(No Transcript)
34
TrueMass Analysis (Lipomics)
CLINICAL / HEALTH INFORMATION
Phosphatidylcholine
PATIENT
Phosphatidylserine
Phosphatidylethanolamine
Cardiolipin
Sphingomyelin
Phosphatidylinositol
Lipid Extract
Lyso-PLCholine
Triglycerides
SAMPLE
Diglycerides
DATABASE
Free Fatty Acids
Cholesterol Esters
Sterols
35
Surveyor Data Visualization
36
Metabonomics Tools800 MHz Ultrashielded NMR
spectrometer
AVANCE 800 spectrometer with the
UltraShield- UltraStabilized 800 magnet at Bruker
Application Lab
37
900 MHz 1H 1D NMR Spectrum of Human Urine
Intensity (proportional to micromolar proton
concentration)
Nmr radiofrequency scale in arbitary units
38
Human Population Response Vector
Analysis Multivariate Effect of Statin Treatment
Poor Responders
subjects
124
Strong increase in TRG
Strong decrease in TRG
111
122
108
121
113
114
123
129
104
107
102
103
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
39
Pattern Recognition AnalysisControl and Soya
Dosed Humans
Systematic metabolic effect of diet
40
The New Horizon Remains Obscured by Fog and
Obstacles
41
(No Transcript)
42
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!!

43
(No Transcript)