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Genomics and Transcriptomics: Finding genes for obesity-related CVD risk factors
RAUL A. BASTARRACHEA, M.D.Staff Scientist
Department of GeneticsTEXAS BIOMEDICAL RESEARCH INSTITUTE
San Antonio, Texas, USA
E-mail: [email protected]
ANUNCIO PRELIMINARV 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 clínico-farmacológico 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-OXM-GLP-1-Incretins-Amylin
Zheng, H. et al. Physiology 23: 75-83 2008
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.
NON-HUMAN PRIMATE STUDIESMetabolic 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 DNAIdentificación de la secuencia de DNA
Búsqueda de polimorfismos asociados a fenotiposBúsqueda de polimorfismos asociados a fenotipos
Genome-Wide Scan
~9.5 cM
Disease risk
Phenotypes:
Circulating Proteins
Physiological Parameters
Quantitative Linkage Analysis
~ 363 markers 9.5 cM = 9.500 Kb
QTL in Chr 16
Searching for Genes for Complex Genetic Disease: Searching for Genes for Complex Genetic Disease: The Standard ModelThe Standard Model
1. pedigrees1. pedigrees
2. Linkage2. Linkage(allele (allele sharing)sharing)
3. Association3. AssociationLD mappingLD mapping
4. positional 4. positional candidate genecandidate gene
variantsvariants
SNPsSNPs
mutationmutation
MicroarraysMicroarraysExpressionHomologyTg/Ko/RNAi
5. Function/activity
Mérida*
Monterrey*
San Luis Potosi
Guadalajara
Veracruz
Oaxaca
Ciudad Victoria
Chihuahua
San Antonio
GEMM Family StudyGenética de las
Enfermedades Metabólicasen México
Morelia
Cuernavaca
DF
PROGRAMA PARA LA INVESTIGACIÓN GENÉTICA DE LAS ENFERMEDADES METABÓLICAS RELACIONADAS CON LA NUTRICIÓN A NIVEL POBLACIONAL
Bases Genómicas del Metabolismo Posprandial
CONSORCIO
GENOMICS
DNA (30,000) Transcription – mRNA (100,000)
PROTEOMICS
Polypeptide chain – Modification – Functional
Protein
(1,000,000)
Illumina Beadscan GX
• 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
High throughput (whole genome) gene expression
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
GenGen TranscripciónTranscripción TraducciónTraducción ModificacionesModificacionesPost-traduccionalesPost-traduccionales FunciónFunción
Interacción entre Genes y NutrimentosInteracción entre Genes y Nutrimentos
La utilización lenta de los metabolitos es la huella digital del proceso patológico (disregulación molecular de nutrientes)
Date Patient ID Age Height Weight BMI Fat Mass Kg Fat (%) Lean Mass (Kg)
10/25/2010 1 49 156 71 29.2 27.8 38.8 43.510/25/2010 2 27 153 57.3 24.5 17.5 30.5 39.810/25/2010 3 22 156 40.4 16.6 4.8 11.9 35.610/25/2010 4 47 160 83.3 32.5 31.6 38 51.7
GEMM Study: Monterrey
Even in this very small sample we observed substantial correlation ofexpression across tissues.
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.
Ingenuity Pathway Analysis (IPA)
FUTURE APPROACH:
Genetically-based programs COMPLEMENTING
“Environmentally”-based programs
of prevention and therapy for Common Complex
Diseases:
Obesity and T2DM