16 Genomics and Transcriptomics Finding genes for obesity

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Genomics and Transcriptomics: Finding genes for
obesity-related CVD risk factors
RAUL A. BASTARRACHEA, M.D.
Staff Scientist
Department of Genetics
TEXAS BIOMEDICAL RESEARCH INSTITUTE
San Antonio, Texas, USA
E-mail: [email protected]
ANUNCIO PRELIMINAR
V Curso Internacional sobre Obesidad en Español
SAN ANTONIO, TEXAS 2012
OBESIDAD Y METABOLISMO DEL TEJIDO ADIPOSO:
CONCEPTOS ACTUALES
(De sus bases biológicas a su tratamiento clínicofarmacológico integral)
Tema Central:
LA CIENCIA DE LA SACIEDAD Y EL APETITO II
Fecha:
Jueves 15, Viernes 16 y Sábado 17 de Noviembre de 2012
Informes: [email protected]
www.amcien.com
Current treatment programs
for obese individuals are not
very effective over the long
term, leading to the
common wisdom that
persons who successfully
lose weight will regain it all
within 5 years.
Brownell KD, Jeffrey RW. Improving
long-term weight loss: pushing the
limits of treatment. Behav Ther
1987;18:353–74.
Ghrelin-PYY-OXMGLP-1-IncretinsAmylin
Filtros Biológicos
•
FILTRO CORTICAL: Se integran las
señales en
la corteza cerebral
provenientes de estímulos asociados a
los alimentos y al hambre (olor, visión,
sabor, etc).
•
FILTRO EMOCIONAL Y DE PLACER:
Incluye los centros dopaminérgicos y
canabinoides
localizados
en
la
amígdala,
el
sistema
mesocorticolímbico
y
el
núcleo
acumbente cerebral donde se integran
las señales de ingesta por recompensa
y adicción.
•
FILTRO METABÓLICO: Incluye el
centro del hambre del hipotálamo y las
vías catabólicas y anabólicas y sus
conecciones
periféricas
con
los
factores de saciedad gastrointestinales
y
las
señales
de
adiposidad
representadas por la leptina y la
insulina en la grasa y la amilina en el
páncreas.
Zheng, H. et al.
Physiology 23:
75-83 2008
NON-HUMAN PRIMATE STUDIES
Metabolic profiling in baboons
Pharmacogenomics of hunger and satiety
Euglycemic-Hyperinsulinemic clamp in
baboons
Omentectomy project – Fatty acid kinetics
Type 2 diabetes through surgery –
hemipancreatectomy
Development of an obese baboon colony
Reversal of STZ-induced diabetes using ultrasound destruction of microbubbles for
the delivery of genes to the baboon pancreas.
1251PC Protocol/2011/Grayburn-Bastarrachea
PHENOTYPE MEASUREMENTS
Identificación de la secuencia de DNA
Búsqueda de polimorfismos asociados a fenotipos
Genome-Wide Scan
~9.5 cM
~ 363 markers
9.5 cM = 9.500
Kb
Quantitative Linkage Analysis
Phenotypes:
Circulating Proteins
Physiological
Parameters
Disease risk
QTL in Chr 16
Searching for Genes for Complex Genetic Disease:
The Standard Model
mutation
SNPs
1. pedigrees
2. Linkage
(allele
sharing)
3. Association
LD mapping
5. Function/activity
Microarrays
Expression
Homology
Tg/Ko/RNAi
4. positional
candidate gene
variants
PROGRAMA PARA LA INVESTIGACIÓN GENÉTICA DE LAS ENFERMEDADES METABÓLICAS
RELACIONADAS CON LA NUTRICIÓN A NIVEL POBLACIONAL
Bases Genómicas del Metabolismo Posprandial
San Antonio
CONSORCIO
Chihuahua
Monterrey*
Mérida*
San Luis Potosi
Ciudad Victoria
DF
Guadalajara
Veracruz
GEMM Family Study
Genética de las
Enfermedades Metabólicas
en México
Morelia
Cuernavaca
Oaxaca
GENOMICS
DNA (30,000)
Transcription – mRNA (100,000)
PROTEOMICS
Polypeptide chain – Modification – Functional
Protein
(1,000,000)
Illumina Beadscan GX
High throughput (whole genome) gene expression
•
•
•
•
•



Confocal laser scanning system
Resolution, 0.8 micron
Two lasers 532, 635 nm
– Supports Cy3 & Cy5
–
imaging
Fully automated operation
Supports genotyping, expression and
proteomics applications
Fibre optic bead (Illumina) technology facilitates rapid
measurement of genome-wide gene expression profiles
Software to visualize and summarize large data sets in
graphical format Increased sensitivity, high throughput
Illumina Beadscan GX technology detects expression of
48,000 transcripts simultaneously
Whole genome
48,000 probe
array
Gene Expression: Preliminary
Results
• Transcriptional profiles on 1013 Mexican Americans
from the San Antonio Family Heart Study
• RNA extracted from stored lymphocytes
• 22,120 detected quantitative transcripts
• Of these, 16,028 are heritable
• Developed new statistical methods for high
dimensional biomarker/endophenotype search
Interacción entre Genes y Nutrimentos
Gen
Transcripción
Traducción
Modificaciones
Post-traduccionales
Función
La utilización lenta de los metabolitos es la huella digital del proceso
patológico (disregulación molecular de nutrientes)
Date
Patient ID Age
10/25/2010
10/25/2010
10/25/2010
10/25/2010
1
2
3
4
Height
49
27
22
47
Weight BMI
156
153
156
160
71
57.3
40.4
83.3
Fat Mass Kg Fat (%) Lean Mass (Kg)
29.2
24.5
16.6
32.5
27.8
17.5
4.8
31.6
38.8
30.5
11.9
38
43.5
39.8
35.6
51.7
Mixed Meal
GEMM Study
160
150
Glucose-mg/dl
140
130
120
Patient 1
110
Patient 2
100
Patient 3
90
Patient 4
80
70
60
0
15
30
45
Time (minutes)
60
90
120
GEMM Study:
Monterrey
Even in this very small
sample we observed
substantial correlation of
expression across
tissues.
Ingenuity Pathway Analysis (IPA)
IPA functional class assignments for correlated transcripts: IPA is a powerful curated database and
analysis system for understanding how proteins work together to effect cellular changes. We use this
system to classify the correlated sets by gene function. This figure shows the top ten functional classes
for each focal transcript. There is considerable consistency in functional assignment across tissues.
FUTURE APPROACH:
Genetically-based programs
COMPLEMENTING
“Environmentally”-based
programs
of prevention and therapy for
Common Complex Diseases:
Obesity and T2DM
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