Molecular Medicine - PowerPoint PPT Presentation

Loading...

PPT – Molecular Medicine PowerPoint presentation | free to download - id: 43883f-YTY4N



Loading


The Adobe Flash plugin is needed to view this content

Get the plugin now

View by Category
About This Presentation
Title:

Molecular Medicine

Description:

Molecular Medicine Mainstream or Marginal? Richard Cooper, MD Department of Preventive Medicine Loyola University Medical School Glucose Intolerance is the Norm ... – PowerPoint PPT presentation

Number of Views:774
Avg rating:3.0/5.0
Slides: 41
Provided by: richardc70
Category:

less

Write a Comment
User Comments (0)
Transcript and Presenter's Notes

Title: Molecular Medicine


1
Molecular Medicine Mainstream or
Marginal? Richard Cooper, MD Department of
Preventive Medicine Loyola University Medical
School
2
What is the universe made of? What is the
biological basis of consciousness? To what
extent are genetic variation and personal
health linked?
July 2005
3
Public Health and Molecular Genetics Nature
Nurture Redux Common disease common
environmental exposure. Disease patterns in
populations have been studied through the methods
of public health. Since the mid-19th century we
have known that large variation in disease
occurrence results from exposure to external
causes. Mass disease means society is out of
joint. Rudolf Virchow, 1855
4
Overweight is the norm in US Society Mean BMI by
Race and Sex, BRFSS, 1984-2002
Age adjusted
5
Glucose Intolerance is the Norm in the US
Population
Fasting Blood Sugar, NHANES, 1999-2004
Fasting Insulin in Nigerians and African
Americans
Diabetes Pre-Diabetes
110 105 100 95 90 85
20
FBS
Normoglycemia
20- 30- 40- 50- 60- 70 20
Age
6
Public Health and Molecular Genetics
Cases
Population
Common Exposures
Drugs and other therapies work for almost all
We are now describing the basis of inherent
susceptibility.
7
Public Health and Molecular Genetics Nature
Nurture Redux What are the practical
implications of knowing susceptibility variants?
What is the appropriate role for molecular
technology in control of common disease?
8
Potential Impact of Molecular Genetics for Common
Disease
NHGRI, 2002
  • Diagnostic testing / Risk stratification
  • Define susceptibility to common disease
  • Drug discovery / Predicting drug response
  • Explain health disparities

9
Vision for the Transformation of Medicine in the
21st Century
Predictive
Preemptive
Personalized
"I predict that comprehensive, genomics-based
health care will become the norm with
individualized preventive medicine and early
detection of illnesses (Zerhouni, 2006)
10
Additional Perspectives on the Uses of Molecular
Genetics
  • Inside James Watsons Genes
  • NY Times June 1, 2007
  • The full genome of James D. Watson . . . has
    been deciphered, making what some scientists
    believe is the gateway to an impending era of
    personalized genomic medicine.
  • Im thrilled to see my genome, Dr. Watson
    said.
  • He will make his entire genome available for
    researchers to study, with the single
    exception of his apolipoprotein E gene . . .

11
Additional Perspectives on the Uses of Molecular
Genetics
  • 6 Billion Bits of Data About Me, Me, Me!
  • NY Times June 3, 2007
  • Dr. Venter said he consulted his genome profile
    every time a new announcement of a gene discovery
    came out. Just last month . . he found out that
    he carries a gene that raises the risk of heart
    disease.
  • He might have guessed that from his family
    history, but knowing individual risk, rather than
    a statistical average, is a stronger motivator to
    change, Dr. Venter said.
  • Because of another risk gene he carries, he
    alerted his diet and has been taking a
    cholesterol-lowering drug for several years.

12
Additional Perspectives on the Uses of Molecular
Genetics
  • Anonymous molecular biologist at a meeting

  • This research will produce an avalanche of new
    information, orthogonal to what we already know.
  • Comments from a news article on a study of genes
    for diabetes
  • In general, XX believes the most likely result
    of findings (. . from large genetic studies . .)
    will be diagnostic tests that predict who is at
    high risk of disease.
  • Quoted in Nature Feb 15, 2007, pg 688
  • Conclusions to an article
  • Understanding how variation in the FTO gene
    region is associated with adiposity may provide
    insights into novel pathways involved in the
    control of adiposity.
  • Science, 2007316889

13
Molecular Genetics What Impact on Common
Disease?
The current advances in molecular genetics are
driven by technology, not conceptual
breakthroughs. While geneticists have advanced
the biology, population health scientists have
not done enough to assess its utility. What
is missing are criteria to evaluate the
contribution of molecular genetics to the
control of common disease.
14
  • Molecular Genetics What Impact on Common
    Disease?
  • Key elements of an evaluation framework
  • How does it fit with what we already know?
  • 2. Can it offer prediction / risk
    stratification?
  • 3. Will it yield insights into pathogenesis /
    pathways?

15
Causal Process in Atherosclerosis
Hypertension
Obesity / Diabetes
Diet High in Elevated
Atherosclerosis
Animal Fat Cholesterol
Physical Inactivity
Smoking
16
CHD and Saturated Fat Intake in 40 Countries
Serum Cholesterol and Risk of CHD, MRFIT
17
Death Rates from CHD and Stroke, US, 1950-2002
CHD
70
Rate Per 100,000
Stroke
70
18
Cancer Death Rates, Men, US, 1930-2003
Rate Per 100,000
Lung bronchus
Stomach
Prostate
Colon rectum
Pancreas
Liver
Leukemia
19
Stages of Molecular Research Discovery to
Application 1. Technology to sequence and
genotype 2. Localize susceptibility
variants in the genome 3. Define
molecular mechanisms ? 4. Clinical
application ??????
20
Association of GNB3 and Hypertension Bagos et al,
J Hypertens March 2007
34 Studies Cases 14,094 Controls
17,760 Total 31,654
21
Genome-Wide Association with Replication Have now
Started to Produce Reliable Results
  • Prostate cancer, diabetes, macular degeneration,
    obesity,
  • inflammatory bowel disease, CHD . . .
  • So What Does the Genetic Architecture of
    Quantitative Traits Look Like?
  • Most variants have low relative risk (ie, lt
    1.3).

22
Nature, June 7, 2007
Distribution of ORs for 70 Common Disease
Variants

Odds Ratio
23
What Will the Payoff be from Finding
Susceptibility Loci?
  • First Option Prediction / Risk
    stratification

24
All Studies Combined 14,585 cases 17,968
controls 1.17 1.12 1.13 1.20
1.12 1.14 1.12 1.37 1.14 1.14
TCF7L2
Science, June 1, 2007
25
Odds Ratios for Diabetes for Persons Carrying
more than one Risk Allele
? s for TCF7 1.03
? s for family Hx 3.0
Weedon et al. PLoS Med 200631877-1882
26
Prediction is an Unlikely Use of Knowledge of
Susceptibility Loci
  • Genetic testing for individual patients
  • To be useful for diagnosis or risk
    stratification, a test must substantially
    increase the post-test probability.
  • Eg. Probability before test 10 test
    performed, probability is now 80.
  • The test must also provide supplemental and
    independent information beyond available tests.
  • Assume for diabetes, cumulative incidence 20,
    and a locus increases the odds by 1.5
  • a positive test yields a post-test probability
    of 27.

27
Predicting Diabetes from Known Susceptibility
Genes vs. Clinical Measurements
ROC for Information Provided by TCF7L2, PPARG,
and CNJ11 Variants
ROC for Information Provided by BMI, FBG, Family
Hx, BP, HDL
AUC 0.58
AUC 0.88
Weedon et al. PLoS Med 200631877
Wilson et al. Arch Int Med 20071671068
28
What Will the Payoff be from Finding
Susceptibility Loci?
  • Risk stratification Revisiting the High Risk
    vs. Population Strategy
  • Assumption
  • Persons known to be at high risk will benefit
    from earlier, more intensive interventions,
    either through lifestyle or drugs.
  • Response
  • Risk stratification has important limitations as
    a public health strategy. When both exposure and
    susceptibility are widespread, population-wide
    measures are often the most effective (e.g.,
    smoking, cholesterol).
  • Likewise, the phenotype (eg, ? BP) is likely to
    be provide more information than the genotype.

29
What Will the Payoff be from Finding
Susceptibility Loci?
  • Second Option Susceptibility genes mimic
    pathogenesis, and leads to understanding of
    pathways.
  • Assumption
  • Knowledge of new physiologic pathways will
    create new opportunities for interventions,
    through prevention or drugs.
  • Concern
  • Without a thorough understanding of the biology,
    genetic markers cannot unravel pathways.
  • Knowledge of pathways / mechanisms is only
    useful if it leads to modifiable exposures or
    drugs.

30
(No Transcript)
31
Major Established Genetic Risks in Adults
New therapies have not generally developed
from knowledge of variants Gene Condition H
FE Hereditary hemochromatosis APOE
4 Alzheimers CYP2D6 Cytochrome P450
activity BRCA 1 Breast cancer BRCA 2 Breast
cancer Factor V Leiden Venous thrombosis CFH A
ge-related macular degeneration
32
Genotype has generally not been a useful guide to
therapy even for monogenic disorders
Examples Long QT Syndrome
Marfan Factor V Leiden - Venous
thrombosis Hereditary hemochromatosis
33
Challenges Narrowing the gap between vision
and reality
  • 1. Make realistic estimates of precision of
    individual prediction.
  • 2. Revisit the tradeoffs of the high risk vs.
    population strategy in the context of how
    genetic screening will be used for common
    disease.
  • 3. Describe and experimentally verify the
    procedures to move from anonymous markers to
    causal variants.
  • 4. Describe how knowledge of pathways will open
    new preventive and therapeutic options.

34
What Are the Potential Costs of Molecular
Medicine?
  • 1. Diversion of resources in the research
    community.
  • 2. Diversion of resources from preventive
    interventions that already work.
  • 3. Fostering the impression that technology will
    solve social problems.
  • 4. Rekindling the debate over biological
    determinism and racial/ethnic health disparities.

35
Nature, June 7, 2007
Indeed, given the likely distribution of effect
sizes . . . there are strong grounds for GWA
studies on an even larger scale.
We view the WTCCC study as an important first
step towards harnessing molecular tools . . to
dissect the biological basis of common disease
and translating those findings into improvements
in human health.
36
Per capita Daily Energy Intake in Cuba, 1980-2005
37
Prevalence of Obesity in Cienfuegos and Havana,
Cuba, 1990-2000
Havana
Cienfuegos
38
Trends in Mortality from Diabetes, CHD, Cancer
and All-Causes, Cuba, 1980 - 2005
Cancer
Diabetes
All Causes
All-Causes
Mortality Rate
CHD
Mortality Rate
Per 100,000
39
Some Conclusions . . Molecular medicine
will remain marginal in the control of common
diseases for the foreseeable future But - 1. We
will learn about a whole new dimension of
biology, and this will - in some instances -
illuminate causal processes. 2. In some cases,
prediction will be sufficiently precise, and
interventions will exist, so that genetic
testing will have clinical utility. 3. Some drug
discovery will be made possible. 4. There will
also be substantial costs (ie, negative
consequences)
40
Molecular medicine relies heavily on unproven
assumptions of the role of technology
Genomics may hold the potential to advance the
claims of a science belief system over the
pragmatic needs of the long-term movement toward
prevention through creation of a healthier
environment as the most effective means to
control common disease.
Cooper, Psaty, Genomics and Medicine, Ann Int
Med, 2003
About PowerShow.com