Genomics and Transcriptomics: Finding genes for obesity-related CVD risk factors

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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
raulbs_at_TxBiomedGenetics.org
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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 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
office_at_amcien.com www.amcien.com
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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 19871835374.
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Ghrelin-PYY-OXM-GLP-1-Incretins-Amylin
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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
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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
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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
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Identificación de la secuencia de DNA
A U T C G
Búsqueda de polimorfismos asociados a
fenotipos
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Genome-Wide Scan
363 markers 9.5 cM 9.500 Kb
9.5 cM
Quantitative Linkage Analysis
Phenotypes Circulating Proteins Physiological
Parameters
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QTL in Chr 16
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Searching for Genes for Complex Genetic Disease
The Standard Model
2. Linkage (allele sharing)
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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
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GENOMICS DNA (30,000)
Transcription mRNA (100,000)
PROTEOMICS Polypeptide chain
Modification Functional
Protein

(1,000,000)
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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

Whole genome 48,000 probe array

• 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

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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
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Interacción entre Genes y Nutrimentos

• Gen
• Transcripción
• Traducción
• Modificaciones
• Post-traduccionales
• Función

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La utilización lenta de los metabolitos es la
huella digital del proceso patológico
(disregulación molecular de nutrientes)
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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 43.5
10/25/2010 2 27 153 57.3 24.5 17.5 30.5 39.8
10/25/2010 3 22 156 40.4 16.6 4.8 11.9 35.6
10/25/2010 4 47 160 83.3 32.5 31.6 38 51.7
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GEMM Study Monterrey Even in this very small
sample we observed substantial correlation
of expression across tissues.
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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.
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FUTURE APPROACH Genetically-based programs
COMPLEMENTING Environmentally-based
programs of prevention and therapy for Common
Complex Diseases Obesity and T2DM