Transcript Phenotypes

Asthma: Role of Interaction
Between Genes and Environment
Fernando D. Martinez, M.D.
Arizona Respiratory Center
The University of Arizona
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
The Genomic Era

“The completion of a...sequence of the
human genome…is a landmark event. The
genomic era is now a reality.”

Grand challenge I-2. “Elucidate the
organization of genetic networks…and
establish how they contribute to cellular
and organismal phenotypes”
Collins et al, Nature April 24, 2003, page 835.
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.
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
Genetic Health

Are there “genes” for health? Is there a
privileged few that were born to be diseasefree?

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?
A Useful But “Misleading” Phenotype
A Drosophila mutant with abnormal wings and
a normal fly (wild type) for comparison.
From Genotype to Phenotype:
“Diseases of Genes”
Genotype
Phenotype
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).
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
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
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
Complex Diseases:
Developmental Transition
from Genotype to Phenotype
Genotype
Development/Epigenetics
(gene-gene-cytoplasm)
Integration
(phenotypephenotype)
Plasticity
(gene-environment)
Phenotype
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 hormonetarget communication).
Schlichting and Pigliucci. Phenotypic Evolution, 1997, page 232
Context-Dependent Gene Regulation:
Canalization and Plasticity
Plastic (heterostasis)
Canalized (homeostasis)

Genome structure

Size

Embryogenesis

Response rates

Cephalo-caudality

Duration

Mitosis, meiosis

Inheritable disease
Developmental Landscape
Waddington, The Strategy of the Genes, Allen &Unwin London 1957
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
Maturation of Immune Responses
in Infancy
Microbial Exposure
T-Reg Cells
Th1
Th2
Birth
Th1
Th2
Early Life
Delayed Maturation of Immune Immune
Responses in Children with Allergies
Microbial Exposure
Th1
Th1
Th2
Birth
Early Life
Th2
Complex Diseases:
Developmental Transition
from Genotype to Phenotype
Genotype
Development/Epigenetics
(gene-gene)
Integration
(phenotypephenotype)
Plasticity
(gene-environment)
Phenotype
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
Asthma by BMI in Females
0.4
Frequency
Asthma
Symptomatic AHR
0.3
0.2
0.1
0
15
20
25
30
35
BMI
Celedon et al., AJRCCM 2001;164:1835
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
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
Genotypic Norms of Reaction
Trait
Values
VP = VG + VE + VGE
Environment
Genotypic Norms of Reaction for PKU
PKU
phenotype
VP = VG + VE + VGE
Phenylalanine content in diet
Genotypic Norms of Reaction
Very high
heritability
Very low
heritability
Trait
Values
Environment
Genotypic Norms of Reaction
Trait
Values
VP =VGE
Environment
Norms of Reaction for Seven Different
Achillea Plants Grown at 3 Elevations
Disease
Risk
aa
bb
cc
dd
ee
ff…
AA
BB
CC
DD
EE
FF…
Environment A
Disease
Risk
aa
bb
cc
dd
ee
ff…
AA
BB
CC
DD
EE
FF…
Environment B
Disease
Risk
aa
BB
AA
bb
dd
ee
ff…
DD
EE
FF…
Environment C
Disease
Risk
aa
BB
cc
AA
bb
CC
EE
ff…
ee
FF…
Total Serum IgE (IU/Ml) by CD14/-159
by Contact with Animals
Geometric mean (IU/ml)
150
n.s.
p=0.003
p=0.012
120
90
60
CC
CT
30
TT
0
No animals
n=86
Dog/Cat only Stable animals
n=110
n=376
Eder et al, ATS 2003
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
Geometric mean (95%CI)
Total Serum IgE by CD14/-159
in Rural Europe
150
120
CC n=160
CT n=321
TT n=143
90
60
30
0
CC
n=160
CT
n=321
TT
n=143
Eder et al, ATS 2003
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!
Exposure to Stables and/or Farm Milk in
the First Year of Life.
%
E xposed
Non-e xposed
16
14
12
10
8
6
*
*
4
2
0
Asthma ever
A st hma attac ks past 12 mo
Riedler et al, Lancet. 2001 Oct 6;358:1129-33.
* p<0.0001
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
Toll-like Receptors (TLR)
and Their Ligands
Lipoproteins (di-/triacylated)
lipoarabinomannan
nucleotides
LPS
(leptospira)
LPS (Gram -)
nucleotide analogs
LPS
(P.
gengivalis)
taxol (plants)
PGN (Gram +)
F protein (RSV)
unmethylated anti-viral
zymosan (yeast)
Hsp60 (host)
CpG DNA compounds
flagellin
GPI
anchor
(T.
cruzi)
fibronectin (host)
ds RNA
MD-2
TLR4
TLR6
TLR2
TLR1
TLR5
TLR9 TLR3 TLR7
Asthma and Allergies by TLR2/-16934 in
Children of Farmers and Non-farmers
Farmers’ children (n=229)
p=0.023
p=0.012
p=0.004
30
p=0.010
20
TLR2/-16934:
Current hayfever
symptoms
Asthma
diagnosis
0
Atopy
0
Current asthma
symptoms
10
Asthma
diagnosis
10
AA
AT
TT
Current hayfever
symptoms
20
Nonfarmers’ children (n=380)
Atopy
30
% 40
Current asthma
symptoms
% 40
Genotypic Plasticity for Asthma
among Farmers and Non-Farmers
TLR2/AA
Asthma
TLR2/AT-TT
Farmers
Non-Farmers
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
Asthma:
Developmental Transition
from Genotype to Phenotype
Genotype
Development/Epigenetics
(gene-gene)
Integration
(phenotypephenotype)
Plasticity
(gene-environment)
Phenotype
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
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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