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Genomic Medicine and Prevention

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Genomic Medicine and Prevention Paul Kruszka, M.D., M.P.H. Commander, USPHS National Human Genome Research Institute (NHGRI) – PowerPoint PPT presentation

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Title: Genomic Medicine and Prevention


1
Genomic Medicine and Prevention
  • Paul Kruszka, M.D., M.P.H.
  • Commander, USPHS
  • National Human Genome Research Institute (NHGRI)

2
National Institutes of Health Bethesda, MD USA
3
NHGRI PHS PHYSICIANS CDR Paul Kruszka, Clinical
Fellow CDR Melissa Meredith, Staff Clinician CAPT
David Ng, Staff Clinician CAPT Ellen Sidransky,
Senior Investigator
4
Objectives
  • Case presentation and its application to Genomic
    Medicine and Prevention
  • A (very) basic understanding of
  • Single Nucleotide Polymorphisms
  • Microarray Technology
  • Single Gene (Mendelian) vs. Complex Disorders
  • Genome Wide Associate Studies (GWAS)
  • Next Generation Sequencing (NGS)
  • Our future with Genomics

5
What is Genomic Medicine?
  • Genetic Medicine
  • Genomic Medicine
  • Is based on understanding the impact of single
    genes on disease
  • Is based on understanding the impact of our
    entire genome and environmental factors on
    disease and health

6
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7
CASE
Italian
Italian
65y CAD 50y
45y
MI 42y
CAD 46y
21y
17y
8
Information about your risk score Information about your risk score
Age 45
Gender male
Total Cholesterol 180 mg/dL
HDL Cholesterol 50 mg/dL
Smoker No
Systolic Blood Pressure 112 mm/Hg
On medication for HBP      No
Risk Score 2Means 2 of 100 people with this level of risk will have a heart attack in the next 10 years.
  Your risk score was calculated using an equation. Other NCEP products, such as printed ATP III materials, use a point system to determine a risk score that is close to the equation score.
9
Classic Case Mentality
10
Old Ideas New Paradigm
  • The doctor does not treat man except
    accidentally he treats Callius or Socrates or
    someone else described in this way, who is
    accidentally manand thus knows the universal
    without knowing the individuals contained in it,
    he will often fail in his treatment for it is
    the individual who has to be treated. Aristotle

11
Individual/Genomic/Personalized Medicine
  • At its most basic, personalized medicine refers
    to using information about a persons genetic
    makeup to tailor strategies for the detection,
    treatment or prevention of disease
  • Francis Collins (Boston Globe 2005)

12
What has changed to help our patient?
  • 1990 Initiation of HGP
  • Completion of HGP Draft
  • International HapMap Project begins
  • Next generation sequencing (Illumina)
  • 2007 GWAS explosion (100 new studies)
  • Initiation of 1000 Genomes Project
  • 2010 More than 17 million SNPs in human genome
    catalogue SNP Database

13
The Human Genome Project
  • 3 billion base pairs (3,000 Mb)
  • Genes (protein coding) 22,000
  • Known Function 75
  • The exome 50 Mb (1.5)

14
The Genomic Era
  • Birth date 14 April 2003, completion of the
    Human Genome Project
  • 49 years and 354 days after Watson and Cricks
    description of the DNA double helix

15
Brief Review of Genetics
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17
What is a gene?
18
The Central Dogma
The Increasing Complexity of the Central Dogma of
Molecular Biology
Feero W et al. N Engl J Med 20103622001-2011
19
The Human Genome
  • Only ,1.5 of the human genome encodes protein
    sequence
  • Comparative analysis with the mouse, rat and dog
    genomes showed that at least 5 is under
    purifying selection and thus probably functional
  • 3.5 consists of non-coding elements with
    probable regulatory roles.

4 7 6 N AT U R E VO L 4 7 8 2 7 O C T O B E
R 2 0 1 1
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?
Genomic Medicine
22
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What has changed to help our patient?
  • 1990 Initiation of HGP
  • Completion of HGP Draft
  • International HapMap Project begins
  • Next generation sequencing (Illumina)
  • 2007 GWAS explosion (100 new studies)
  • Initiation of 1000 Genomes Project
  • 2010 More than 17 million SNPs in human genome
    catalogue SNP Database

24
HapMap
  • Validated millions of SNPs
  • Characterized linkage disequilibrium in
    populations of European, Asian, and African
    ancestry

25
SINGLE NUCLEOTIDE POLYMORPHISM (SNP)
http//learn.genetics.utah.edu/content/health/phar
ma/snips/
26
LINKAGE DISEQUILIBRIUM
http//learn.genetics.utah.edu/content/health/phar
ma/snips/
27
Microarray Technologies
Microarray Technology
Feero W et al. N Engl J Med 20103622001-2011
28
What has changed to help our patient?
  • 1990 Initiation of HGP
  • Completion of HGP Draft
  • International HapMap Project begins
  • Next generation sequencing (Illumina)
  • 2007 GWAS explosion (100 new studies)
  • Initiation of 1000 Genomes Project
  • 2010 More than 17 million SNPs in human genome
    catalogue SNP Database

29
Genome Wide Associated Study (GWAS)
30
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Genome.gov
32
Examples
  • Mendelian (monogenic)
  • Common/Complex (polygenic)
  • Familial Hypercholesterolemia
  • Cystic fibrosis
  • Sickle cell anemia
  • Huntington disease
  • Tay-Sachs disease
  • Duchene Muscular dystrophy
  • Hypertension
  • Coronary artery disease
  • Hyperlipidemia
  • Diabetes
  • Autism Spectrum Disorders

33
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35
Published Genome-Wide Associations through
06/2011, 1,449 published GWA at p5x10-8 for 237
traits
NHGRI GWA Catalog www.genome.gov/GWAStudies
36
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38
July 1, 2009, 510 pm Hoopla, and Disappointment,
in Schizophrenia Research By NICHOLAS WADE
more of a historic defeat, a Pearl Harbor of
schizophrenia research. The principal news from
the three studies is that schizophrenia is caused
by a very large number of errant genes, not a
manageable and meaningful handful.
http//tierneylab.blogs.nytimes.com/2009/07/01/hoo
pla-and-disappointment-in-schizophrenia-research/?
em
39
The Missing Heritability of Complex Diseases
  • Copy Number Variations (CNV)
  • Rare (lower frequency) SNPs
  • Insertion and deletions (indels)
  • Structural variations

40
What has changed to help our patient?
  • 1990 Initiation of HGP
  • Completion of HGP Draft
  • International HapMap Project begins
  • Next generation sequencing (Illumina)
  • 2007 GWAS explosion (100 new studies)
  • Initiation of 1000 Genomes Project
  • 2010 More than 17 million SNPs in human genome
    catalogue SNP Database

41
The Beginning of the Next Generation in
sequencing
Science 2005, 3091728-1732
Nature 2005, 437376-380
42
http//www.lcsciences.com
43
g Technologies
Next-Generation Sequencing
Feero W et al. N Engl J Med 20103622001-2011
44
genome.gov/sp2011
45
What has changed to help our patient?
  • 1990 Initiation of HGP
  • Completion of HGP Draft
  • International HapMap Project begins
  • Next generation sequencing (Illumina)
  • 2007 GWAS explosion (100 new studies)
  • Initiation of 1000 Genomes Project
  • 2010 More than 17 million SNPs in human genome
    catalogue SNP Database

46
1000 Genomes Project
  • Goal sequencing at least 1000 genomes around
    world
  • Provide a comprehensive map of genetic variation
    for future disease association studies

47
http//www.sciencemag.org/content/early/recent /
17 May 2012/ Page 1/ 10.1126/science.1219240
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PC2-Z will systematically review, evaluate, and
summarize medical evidence regarding genomic
associations that are clinically actionable for
application in clinic settings and develop and
enhance existing AFMS information technology
systems to capture and analyze genetic
information for enhanced clinical decisionmaking.
50
http//www.cpmc.coriell.org/Sections/Genes/?SId10
51
http//www.cpmc.coriell.org/Sections/Genes/CAD.asp
x?PgId104
52
To him who devotes his life to science, nothing
can give more happiness than increasing the
number of discoveries, but his cup of joy is full
when the results of his studies immediately find
practical applications. Louis Pasteur
53
Paul Kruszka, M.D., M.P.H. Commander,
U.S.P.H.S. Paul.Kruszka_at_nih.gov
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