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04 rencontres biomédicale LIR Philippe Froguel
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04 rencontres biomédicale LIR Philippe Froguel

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2ND INTERNATIONAL RESEARCH MEETING …

2ND INTERNATIONAL RESEARCH MEETING
4 JUNE 2010- HÔTEL DE MARIGNY PARIS

Published in Health & Medicine , Technology
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  • However, few genes were identified and consistently replicated, and their association with T2D was relatively modest. At this time, we did’nt know if one could find more interesting markers.

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  • 1. From Human Genomics to Personalized Metabolic Medicine [email_address] CNRS 8199-University Lille 2 Pasteur Institute, Lille, France
  • 2. 2005 2007 3) High density DNA variant arrays
    • Human genome
    • sequence
    2) Haplotypic maps Human Genomics brings breakthroughs in common diseases 2006 2001-04 4) Genome Wide Association Studies 12th of February 2007 ... > 800 loci found through GWAS of common diseases
  • 3. TCF7L2 Exploration of Linkage Peaks ENPP1* HNF4A* ADIPOQ* CAPN10* PPARG KCNJ11 HNF1B WFS1 Biological Candidates Gene Studies HNF1A* CDKN2A/2B IGF2BP2 CDKAL1 HHEX/IDE SLC30A8 KCNQ1 IRS1 TSPAN8/LGR5 ADAMTS9 NOTCH2 CDC123/CAMK1D THADA JAZF1 GWAS for T2D DGKB/TMEM195 MTNR1B GCKR GCK ADCY5 PROX1 GWAS for T2D-related traits Mean Increased Risk for T2D SNPs = 10 to 40% Genes/loci associated with T2D
  • 4. Most T2D genes found by GWAS are suggested to play a role in pancreatic  -cell function
  • 5. The BMI/Obesity Gene map BMI Childhood Obesity Waist MC4R FTO TMEM18 NEGR1 SEC16B ETV5 BDNF FAIM2 SH2B1 KCTD15 GNPDA2 MTCH2 NRXN3 TFAP2B MSRA LYPLAL1 NPC1 MAF PTER GPRC5B RBJ MAP2K5 FANCL QPCTL TNNI3K LRRN6C FLJ35779 SLC39A8 TMEM160 CADM2 PRKD1 LRP1B MTIF3 ZNF608 RPL27A NUDT3 PTBP2 RSPO3 VEGFA TBX15-WARS2 NFE2L3 GRB14 DNM3-PIGC ITPR2-SSPN LY86 HOXC13 ADAMTS9 ZNRF3-KREMEN1 NISCH-STAB1 CPEB4
  • 6. Central Nervous System Adipose Tissue FTO MC4R POMC PCSK1 LEPR ENPP1 NPC1 PRL BDNF TRKB SIM1 TMEM18 KCTD15 SH2B1 NEGR1 GNPDA2 NRXN3 LEP LEPR MAF PRL, ENPP1 NEGR1 Obesity is a neuro (endocrine) disorder
  • 7. From the frequent variants/frequent disease theory to the rare variants/frequent disease hypothesis Allele frequency Effect size ENPP1 PPARG KCNJ11 CAPN10 HNF4A HNF1A “ Rare but common” variants with strong effects on physiology Frequent DNA variants (SNP) only explain modest part of the heritability “ Rare” variants: Copy Number Variations (GSV) and point mutations
  • 8. Walters et al, nature, 4th of February, 2010 The screening of children with extreme obesity identify rare CNV
  • 9. Walters et al, nature, 2010 The effect of the chromosome 16p 11.2 microdeletion on obesity is age-dependent 25 kg/m 2 Morbid obesity Obesity The increased risk for Morbid Obesity is 4300%
  • 10. Rare but Common potent mutations
  • 11. Towards a rapid molecular diagnosis of familial T2D towards personalized medicine using the full exome new generation sequencing ‘ exons capture’-based technology + High-throughput sequencing
    • Agilent SureSelect > 20 000 genes
    • Sequencing Illumina-GAII (10-12 Gb/run)
  • 12.  
  • 13. Whole Genome Sequencing identifies mutations increasing disease risk and modulating response to various drugs
  • 14. The evaluation of the interaction of the environment with the clinical genome allows a comprehensive health assessment
  • 15. Genomics and System Medicine can bring an optimized Metabolic/CV disease care The Personalized Medicine shift challenge
  • 16. The advantages of integrated Human Genomics towards Personalized Medicine
    • Causative rare DNA variants with strong effects identify more potent potential drug targets
    • Individuals with natural lack of function mutations inform on side effects of new drugs (e.g. an enzyme inhibitor)
    • Genetic profiling should make easier clinical trials by selecting more homogenous cohorts
    • Personalized medicine should predict drug failure , help to combine better current drugs and will give arguments for the use of novel molecules ( vs generics)
  • 17. The advantages of integrated Human Genomics towards Personalized Medicine
    • Human genomics and system medicine will be a new tool to overcome some of the current limitations of the drug development process and will improve long term patient care