Biochemistry

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Biochemistry Genetics of Asthma Attempts to
Resolve an Epidemic

• Natural History
• Environmental/Infectious/Hereditary
• Biochemistry Immunology
• Genetics
• Medical / Public Health Implications

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Asthma Stats

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

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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

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BIOLOGIC BASIS OF ASTHMA
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Symptoms of Asthma

• Wheezing
• Chest tightness
• Shortness of Breath
• Coughing

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Asthma Pathophysiology

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

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Asthma as an Atopic Disease?

• Atopic (extrinsic)
• high serum IgE
• Non-atopic (intrinsic)
• normal serum IgE
• no positive skin test

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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

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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

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Late Phase Reaction
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Th1 / Th2 transition
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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

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Genetic Basis of Asthma TraitsPhenotypic Traits

• Elevation of total serum IgE
• Nonspecific airway responsiveness to inhaled
  spasmogens (eg histamine, methacholine)
• Age of onset

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Asthma is Genetically Complex

• Multiple genes, multiple interactions
• Environmental Modifiers
• Maternal Effects

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Gene Discovery

• Candidate gene approaches
• Genome scans/Positional Cloning
• Animal Models

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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..

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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 ?

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Conclusions

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

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The Role of Public Health

• Community education, support and action
• Environmental Measures
• Public Policy

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Integration of Medicine and Public Health in
Asthma Treatment

• Cellular Immunology Treatment, Diagnosis
• Genetics Diagnosis, Treatment, Prevention
• Public Health Prevention, Treatment

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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