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Asthma: Role of Interaction Between Genes and Environment

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If persons with certain genes are exposed to the right substances, they are protected against asthma BOTH the genes AND the exposure are needed BUT, ... – PowerPoint PPT presentation

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Title: Asthma: Role of Interaction Between Genes and Environment


1
Asthma Role of Interaction Between Genes and
Environment
Fernando D. Martinez, M.D. Arizona Respiratory
Center The University of Arizona
2
Asthma as a Developmental Disease
  • Asthma is likely the result of alterations in the
    developmental pathways that determine normal
    maturation of the immune system and the lungs
  • There are often windows of opportunity during
    development in which environmental exposures
    influence these pathways in susceptible
    individuals

3
The Genomic Era
  • The completion of a...sequence of the human
    genomeis a landmark event. The genomic era is
    now a reality.
  • Grand challenge I-2. Elucidate the organization
    of genetic networksand establish how they
    contribute to cellular and organismal phenotypes

Collins et al, Nature April 24, 2003, page 835.
4
The Genomic Era
  • One useful research resource would be a
    healthy cohort, a large, epidemiologically
    robust group of individuals with unusually good
    health, who could be compared with cohorts of
    individuals with diseases, and who could also be
    intensively studied to reveal alleles protective
    for diabetes, cancer.
    Collins et al, Nature April 24, 2003, page 835.

5
Genetic Happiness
Researchers now believe that our brains are
hard-wired in ways that, at least to some
degree, determine just how happy we're going to
be. Scientists have used advanced imaging
technology to pinpoint the area of the brain --
specifically, the left prefrontal cortex that
serves as the center for positive, optimistic,
and happy feelings. When people naturally have
higher than normal activity in this brain
region, they are more likely to feel positive
moods, and they'll tend to start each day ready
to take on the world In short, it's in the
genes.
WebMD, March 6 2003
6
Genetic Health
  • Are there genes for health? Is there a
    privileged few that were born to be
    disease-free?
  • Is each one of us the imperfect realization of an
    ideal state? Is disease the unnecessary deviation
    from that ideal?
  • But if so, why did natural selection eliminate
    our tails but not hypertension, cancer, asthma?

7
A Useful But Misleading Phenotype
A Drosophila mutant with abnormal wings and a
normal fly (wild type) for comparison.
8
From Genotype to Phenotype Diseases of Genes
Genotype
Phenotype
9
Discrepancies in Results of Genetic Studies of
Asthma
  • The most consistent feature of results of genetic
    studies of asthma is their conspicuous lack of
    any consistency
  • These apparent contradictions are usually
    attributed to type I/type II errors or defective
    design (admixture, population stratification,
    etc).

10
Discrepancies in Results of Environmental Studies
of Asthma
  • Few environmental exposures are consistently
    found to be associated with univocal risk for
    asthma
  • Examples are exposures to allergens and to
    endotoxin results vary by timing, locale, dose,
    phenotypic status, among others

11
What Inconsistent Results of Risk Studies Are
Really Telling Us
  • Inconsistencies among well designed genetic and
    environmental studies of asthma are the expected
    result of profound heterogeneity of complex human
    phenotypes
  • Attempting to overcome these inconsistencies is
    useless and counterproductive they are telling
    us something fundamental about the mechanisms
    that underlie these phenotypes

12
Defining Phenotype
  • A phenotype is the ongoing manifestation of the
    interaction between codes stored in genes and the
    internal and external environment in which the
    products of these genes are expressed
  • Genes are therefore not blueprints for
    phenotypes or simply interpretable instructions
    of a more or less linear program
  • Asthma is not (often) caused by diseases of
    genes, but by genes of diseases

13
Complex Diseases Developmental Transition from
Genotype to Phenotype
Genotype
Development/Epigenetics (gene-gene-cytoplasm)
Integration (phenotype-phenotype)
Plasticity (gene-environment)
Phenotype
14
Epigenetics
  • Epigenetics is an ensemble of processes that
    propagate phenotypic characteristics throughout
    development.
  • These processes derive from either indirect
    effects of gene action (emergent properties) or
    from non-genetic phenomena (e.g., cell-cell or
    hormone-target communication).
  • Schlichting and Pigliucci. Phenotypic
    Evolution, 1997, page 232

15
Context-Dependent Gene Regulation Canalization
and Plasticity
Plastic (heterostasis)
Canalized (homeostasis)
  • Genome structure
  • Embryogenesis
  • Cephalo-caudality
  • Mitosis, meiosis
  • Size
  • Response rates
  • Duration
  • Inheritable disease

16
Developmental Landscape
Waddington, The Strategy of the Genes, Allen
Unwin London 1957
17
Asthma as a Developmental Disease
  • Asthma may be the result of alterations in the
    developmental pathways that determine normal
    maturation of the immune system and the lungs
  • There are often windows of opportunity during
    development when environmental exposures may
    influence these pathways in susceptible
    individuals

18
Maturation of Immune Responses in Infancy
Microbial Exposure
T-Reg Cells
Th1
Th2
Th1
Th2
Early Life
Birth
19
Delayed Maturation of Immune Immune Responses in
Children with Allergies
Microbial Exposure
Th1
Th1
Th2
Th2
Early Life
Birth
20
Complex Diseases Developmental Transition from
Genotype to Phenotype
Genotype
Development/Epigenetics (gene-gene)
Integration (phenotype-phenotype)
Plasticity (gene-environment)
Phenotype
21
Phenotypic Integration
  • Phenotypic integration encompasses the
    covariation between any pair or groups of
    phenotypic traits
  • This new concept arises from the crucial
    importance of the coordination (or lack thereof)
    of many phenotypes to achieve the changes
    occurring during development

22
Asthma by BMI in Females
Asthma
Symptomatic AHR
Frequency
15
20
25
30
35
BMI
Celedon et al., AJRCCM 20011641835
23
Phenotypic Plasticity
  • Phenotypic plasticity is the property of a given
    genetic variation to produce different phenotypes
    in response to distinct environmental exposures
  • In human words to cause asthma, most (if not
    all) asthma genes MUST interact with exposures
    that allow these genes to be expressed as disease

Schlichting and Pigliucci. Phenotypic Evolution,
1997, page 232
24
Phenylketonuria (PKU)
  • PKU is an autosomal recessive disorder, caused by
    mutations in both alleles of the gene for
    phenylalanine hydroxylase (PAH), found on
    chromosome 12
  • Accumulation of phenylalanine in the brain
    causes severe mental retardation for this
    reason, all newborns are screened for this
    disease at birth

Genes and Disease, from the NCBI
25
Genotypic Norms of Reaction
Trait Values
VP VG VE VGE
Environment
26
Genotypic Norms of Reaction for PKU
PKU phenotype
VP VG VE VGE
Phenylalanine content in diet
27
Genotypic Norms of Reaction
Very high heritability
Very low heritability
Trait Values
Environment
28
Genotypic Norms of Reaction
Trait Values
VP VGE
Environment
29
(No Transcript)
30
Norms of Reaction for Seven Different Achillea
Plants Grown at 3 Elevations
31
(No Transcript)
32
Disease Risk
AA BB CC DD EE FF
aa bb cc dd ee ff
33
Environment A
Disease Risk
AA BB CC DD EE FF
aa bb cc dd ee ff
34
Environment B
Disease Risk
AA bb DD EE FF
aa BB dd ee ff
35
Environment C
Disease Risk
AA bb CC ee FF
aa BB cc EE ff
36
Total Serum IgE (IU/Ml) by CD14/-159 by Contact
with Animals
p0.003
p0.012
n.s.
CC
CT
TT
Eder et al, ATS 2003
37
Norms of Reaction for CD14 Genotypes in Humans
CD14/-159CC
CD14/-159CT
IgE
CD14/-159TT
No Animals
Pets No Stables
Stables
Eder et al, ATS 2003
38
Total Serum IgE by CD14/-159 in Rural Europe

Eder et al, ATS 2003
39
PKU Genetic, Developmental or Environmental
Disease?
  • If there were no phenylalanine in normal diets,
    there would be no PKU
  • If there were no PKU gene, there would not be no
    PKU
  • BUT, if accumulation of phenylalanine did not
    cause brain toxicity, there would be no PKU
    either!

40
(No Transcript)
41
How Does Farming Protect Against Asthma?
  • Exposure to microbial products in early life may
    help develop a balanced immune response
  • These products interact with so-called Toll-like
    receptors, which have genetic variants in them
  • Our hypothesis if these variants make people
    less sensitive to the microbial products, they
    will be less protected against asthma

42
Toll-like Receptors (TLR) and Their Ligands
Lipoproteins (di-/triacylated) lipoarabinomannan L
PS (leptospira) LPS (P. gengivalis) PGN (Gram
) zymosan (yeast) GPI anchor (T. cruzi)
nucleotides nucleotide analogs
LPS (Gram -) taxol (plants) F protein (RSV) Hsp60
(host) fibronectin (host)
anti-viral compounds
unmethylated CpG DNA
flagellin
ds RNA
MD-2
TLR4 TLR2 TLR5
TLR9 TLR3 TLR7
TLR6 TLR1
43
Asthma and Allergies by TLR2/-16934 in Children
of Farmers and Non-farmers
Farmers children (n229)
Nonfarmers children (n380)


44
Genotypic Plasticity for Asthma among Farmers and
Non-Farmers
TLR2/AA
Asthma
TLR2/AT-TT
Non-Farmers
Farmers
45
Asthma Genetic, Developmental or Environmental
Disease?
  • If persons with certain genes are exposed to the
    right substances, they are protected against
    asthma
  • BOTH the genes AND the exposure are needed
  • BUT, the exposure HAS to happen at the right time
    during development

46
Asthma Developmental Transition from Genotype to
Phenotype
Genotype
Development/Epigenetics (gene-gene)
Integration (phenotype-phenotype)
Plasticity (gene-environment)
Phenotype
47
So, What Will the Future of Asthma Genetics Be?
  • The future of asthma genetics will be centered
    around prevention
  • The motto will be the right environment for our
    genes AND at the right time
  • Thus, modern genetics and genomics will NOT
    result in Armageddon or Dracula clones, but in
    learning how to better live with the genes we
    were brought to life with

48
The Geno-Phenomic Era
  • Without serious advances in the definition of
    the factors that influence the expression of
    human phenotypes (development, integration,
    plasticity) the promise of the Genome Project to
    elucidate the genetic basis of complex human
    disease will remain largely unfulfilled

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