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Biochemistry

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Biochemistry & Genetics of Asthma: Attempts to Resolve an Epidemic ... Biochemistry & Immunology. Genetics. Medical / Public Health Implications. Asthma Stats ... – PowerPoint PPT presentation

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Title: Biochemistry


1
Biochemistry Genetics of Asthma Attempts to
Resolve an Epidemic
  • Natural History
  • Environmental/Infectious/Hereditary
  • Biochemistry Immunology
  • Genetics
  • Medical / Public Health Implications

2
Asthma Stats
  • 155 Million Individuals Affected
  • 6 billion / year in US
  • 5.5 billion worldwide for pharmaceuticals to
    treat disease

3
EPIDEMIOLOGY IS A BRANCH OF MEDICAL SCIENCE THAT
MOVES SLOWLY BUT WITH GREAT FORCE
  • 10-fold regional differences in prevalence of
    asthma
  • Allergic disease is more common in clean,
    westernized environments
  • Hygiene hypothesis
  • Asthma is less common in younger siblings
  • Asthma is less common in households with
    dogs Cookson, Nature, 4021999

4
BIOLOGIC BASIS OF ASTHMA
5
Symptoms of Asthma
  • Wheezing
  • Chest tightness
  • Shortness of Breath
  • Coughing

6
Asthma Pathophysiology
  • Muscles around bronchial tubes contract
  • Bronchial tubes become inflamed
  • Excess mucus plugs airways
  • INDUCED BY TRIGGERS(ENVT, ETC.)

7
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8
Asthma as an Atopic Disease?
  • Atopic (extrinsic)
  • high serum IgE
  • Non-atopic (intrinsic)
  • normal serum IgE
  • no positive skin test

9
Asthma as an Atopic Disease?
  • Only a subset of atopic individuals develop
    asthma
  • 25-30 of atopic children/adults develop asthma
  • gt90 of adult asthmatics are atopic
  • Allergy doesnt appear to be a primary cause of
    asthma it is a secondary inducer of attacks
  • AIRWAY HYPERSENSITIVITY IS CENTRAL TO DISEASE

10
Immunology of AsthmaInduction of type I
hypersensitivity
  • Sensitization Phase
  • Activation Phase
  • Late Phase
  • Acute/Chronic Phase
  • Airway Remodeling
  • Localization of reaction is an essential
    consideration

11
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12
Late Phase Reaction
13
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14
Th1 / Th2 transition
15
Conclusions
  • Selection of Th2 important step in determination
    of susceptibility to atopy
  • IL-4, IL-13, IL-9 central mediators
  • Immunologic/ Cellular mechanisms of airway
    hypersensitivity are complex and diverse
  • Molecular Therapeutics

16
Genetic Basis of Asthma TraitsPhenotypic Traits
  • Elevation of total serum IgE
  • Nonspecific airway responsiveness to inhaled
    spasmogens (eg histamine, methacholine)
  • Age of onset

17
Asthma is Genetically Complex
  • Multiple genes, multiple interactions
  • Environmental Modifiers
  • Maternal Effects

18
Gene Discovery
  • Candidate gene approaches
  • Genome scans/Positional Cloning
  • Animal Models

19
Candidate Genes
  • 5q31 (cytokine cluster) IL-4,IL-13,CD-14
  • b-adrenergic receptor
  • 6p MHC
  • 10 5-lipoxygenase
  • 9p22 IFN-a
  • 11q 13 Fce R1- b
  • 16p12 IL-4RA
  • CF genes, a-anti trypsin, T-cell receptor a/g
    complex, etc..

20
Whole-Genome Strategies-Microsatellite
Marker/SNP Genome Scans
  • Chromosome Candidate Genes
  • 2 IL-1, IL-1RA
  • 5 p/q IL-4, IL-13, IL-9
  • 6p MHC II (HLA)
  • 8p ?
  • 12q IFN-g
  • 13q ?
  • 14q ?
  • 16q ?

21
Conclusions
  • Good correlation between candidate gene and
    genome scan approaches
  • Targets for pharmacogenetics, asthmatic phenotype
    determination

22
The Role of Public Health
  • Community education, support and action
  • Environmental Measures
  • Public Policy

23
Integration of Medicine and Public Health in
Asthma Treatment
  • Cellular Immunology Treatment, Diagnosis
  • Genetics Diagnosis, Treatment, Prevention
  • Public Health Prevention, Treatment

24
ASTHMA Conclusions
  • Many environmental factors
  • Many biologic determinants/genes
  • Complex etiology must be determined but when it
    is there are many potential targets that may be
    exploited to alleviate disease
  • Prevention is still optimal goal
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