asthma: role of interaction between genes and environment fernando d. martinez, m.d. arizona...

Asthma: Role of Interaction Between Genes and Environment

Asthma: Role of Interaction Between Genes and Environment

Fernando D. Martinez, M.D.Fernando D. Martinez, M.D.Arizona Respiratory CenterArizona Respiratory CenterThe University of ArizonaThe University of Arizona

Asthma as a Developmental Disease


Asthma is likely the result of alterations in Asthma is likely the result of alterations in the developmental pathways that the developmental pathways that determine normal maturation of the determine normal maturation of the immune system and the lungsimmune system and the lungs

There are often windows of opportunity There are often windows of opportunity during development in which during development in which environmental exposures influence these environmental exposures influence these pathways in susceptible individuals pathways in susceptible individuals

The Genomic EraThe Genomic EraThe Genomic EraThe Genomic Era

““The completion of a...sequence of the The completion of a...sequence of the human genome…is a landmark event. The human genome…is a landmark event. The genomic era is now a reality.”genomic era is now a reality.”

Grand challenge I-2. “Elucidate the Grand challenge I-2. “Elucidate the organization of genetic networks…and organization of genetic networks…and establish how they contribute to cellular establish how they contribute to cellular and organismal phenotypesand organismal phenotypes””

Collins et al, Nature April 24, 2003, page 835.Collins et al, Nature April 24, 2003, page 835.

The Genomic EraThe Genomic Era

“ “One useful research resource would be a One useful research resource would be a ‘healthy cohort’, a large, epidemiologically ‘healthy cohort’, a large, epidemiologically robust group of individuals with unusually robust group of individuals with unusually good health, who could be compared with good health, who could be compared with cohorts of individuals with diseases, and cohorts of individuals with diseases, and who could also be intensively studied to who could also be intensively studied to reveal alleles protective for diabetes, reveal alleles protective for diabetes, cancer….” cancer….”

Collins et al, Nature April 24, 2003, page 835.Collins et al, Nature April 24, 2003, page 835.

“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 2003WebMD, March 6 2003

Genetic HappinessGenetic Happiness

Genetic HealthGenetic Health

Are there “genes” for health? Is there a Are there “genes” for health? Is there a privileged few that were born to be disease-privileged few that were born to be disease-free?free?

Is each one of us the imperfect realization of Is each one of us the imperfect realization of an ideal state? Is disease the unnecessary an ideal state? Is disease the unnecessary deviation from that ideal?deviation from that ideal?

But if so, why did natural selection eliminate But if so, why did natural selection eliminate our tails but not hypertension, cancer, our tails but not hypertension, cancer, asthma?asthma?

A A DrosophilaDrosophila mutant with abnormal wings and mutant with abnormal wings and a normal fly (wild type) for comparison. a normal fly (wild type) for comparison.

A Useful But “Misleading” PhenotypeA Useful But “Misleading” Phenotype

From Genotype to Phenotype:“Diseases of Genes”

From Genotype to Phenotype:“Diseases of Genes”

GenotypeGenotype

PhenotypePhenotype

Discrepancies in Resultsof Genetic Studies of Asthma

Discrepancies in Resultsof Genetic Studies of Asthma

The most consistent feature of results of The most consistent feature of results of genetic studies of asthma is their genetic studies of asthma is their conspicuous lack of any consistency conspicuous lack of any consistency

These apparent contradictions are usually These apparent contradictions are usually attributed to type I/type II errors or attributed to type I/type II errors or defective design (admixture, population defective design (admixture, population stratification, etc).stratification, etc).

Discrepancies in Resultsof Environmental Studies of Asthma

Discrepancies in Resultsof Environmental Studies of Asthma

Few environmental exposures are Few environmental exposures are consistently found to be associated with consistently found to be associated with univocal risk for asthma univocal risk for asthma

Examples are exposures to allergens and Examples are exposures to allergens and to endotoxin: results vary by timing, to endotoxin: results vary by timing, locale, dose, phenotypic status, among locale, dose, phenotypic status, among othersothers

What Inconsistent Results of Risk Studies Are Really Telling Us

What Inconsistent Results of Risk Studies Are Really Telling Us

Inconsistencies among well designed genetic Inconsistencies among well designed genetic and environmental studies of asthma are the and environmental studies of asthma are the expected result of profound heterogeneity of expected result of profound heterogeneity of complex human phenotypescomplex human phenotypes

Attempting to “overcome” these Attempting to “overcome” these inconsistencies is useless and inconsistencies is useless and counterproductive: they are telling us counterproductive: they are telling us something fundamental about the something fundamental about the mechanisms that underlie these phenotypes mechanisms that underlie these phenotypes

Defining Phenotype Defining Phenotype Defining Phenotype Defining Phenotype

A phenotype is the ongoing manifestation of the A phenotype is the ongoing manifestation of the interaction between codes stored in genes and interaction between codes stored in genes and the internal and external environment in which the internal and external environment in which the products of these genes are expressedthe products of these genes are expressed

Genes are therefore not “blueprints” for Genes are therefore not “blueprints” for phenotypes or simply interpretable instructions phenotypes or simply interpretable instructions of a more or less linear programof a more or less linear program

Asthma is not (often) caused by diseases of Asthma is not (often) caused by diseases of genes, but by genes of diseasesgenes, but by genes of diseases

Complex Diseases:Developmental Transition

from Genotype to Phenotype



GenotypeGenotype

PhenotypePhenotype

IntegrationIntegration(phenotype-(phenotype-phenotype)phenotype)

Development/EpigeneticsDevelopment/Epigenetics(gene-gene-cytoplasm)(gene-gene-cytoplasm)

PlasticityPlasticity(gene-(gene-

environment)environment)

EpigeneticsEpigenetics

Epigenetics is an ensemble of processes Epigenetics is an ensemble of processes that propagate phenotypic characteristics that propagate phenotypic characteristics throughout development.throughout development.

These processes derive from either These processes derive from either indirect effects of gene action (emergent indirect effects of gene action (emergent properties) or from non-genetic properties) or from non-genetic phenomena (e.g., cell-cell or hormone-phenomena (e.g., cell-cell or hormone-target communication).target communication).

Schlichting and Pigliucci. Phenotypic Evolution, 1997, page 232Schlichting and Pigliucci. Phenotypic Evolution, 1997, page 232

Context-Dependent Gene Regulation: Canalization and Plasticity

Context-Dependent Gene Regulation: Canalization and Plasticity

Genome structureGenome structure

EmbryogenesisEmbryogenesis

Cephalo-caudalityCephalo-caudality

Mitosis, meiosisMitosis, meiosis

Size Size

Response ratesResponse rates

DurationDuration

Inheritable diseaseInheritable disease

Canalized (homeostasis)Canalized (homeostasis) Plastic (heterostasis)Plastic (heterostasis)

Developmental LandscapeDevelopmental Landscape

Waddington, The Strategy of the Genes, Allen &Unwin London 1957Waddington, The Strategy of the Genes, Allen &Unwin London 1957



Asthma may be the result of alterations in Asthma may be the result of alterations in the developmental pathways that the developmental pathways that determine normal maturation of the determine normal maturation of the immune system and the lungsimmune system and the lungs

There are often windows of opportunity There are often windows of opportunity during development when environmental during development when environmental exposures may influence these pathways exposures may influence these pathways in susceptible individuals in susceptible individuals

Maturation of Immune Responses Maturation of Immune Responses in Infancyin Infancy

Maturation of Immune Responses Maturation of Immune Responses in Infancyin Infancy

Th1

Th2 Th1 Th2

Birth Early Life

Microbial Exposure

T-Reg Cells

Delayed Maturation of Immune Immune Delayed Maturation of Immune Immune Responses in Children with AllergiesResponses in Children with Allergies

Delayed Maturation of Immune Immune Delayed Maturation of Immune Immune Responses in Children with AllergiesResponses in Children with Allergies

Th1

Th2

Birth

Th1

Th2Early Life

Microbial Exposure





GenotypeGenotype

PhenotypePhenotype


Development/EpigeneticsDevelopment/Epigenetics(gene-gene)(gene-gene)



Phenotypic IntegrationPhenotypic Integration

Phenotypic integration encompasses the Phenotypic integration encompasses the covariation between any pair or groups of covariation between any pair or groups of phenotypic traitsphenotypic traits

This new concept arises from the crucial This new concept arises from the crucial importance of the coordination (or lack importance of the coordination (or lack thereof) of many phenotypes to achieve thereof) of many phenotypes to achieve the changes occurring during the changes occurring during developmentdevelopment

0

0.1

0.2

0.3

0.4

15 20 25 30 35

BMI

Fre

quen

cy

Asthma by BMI in FemalesAsthma by BMI in Females

Asthma

Symptomatic AHR

Celedon et al., AJRCCM 2001;164:1835

Phenotypic PlasticityPhenotypic Plasticity

Phenotypic plasticity is the property of a Phenotypic plasticity is the property of a given genetic variation to produce different given genetic variation to produce different phenotypes in response to distinct phenotypes in response to distinct environmental exposuresenvironmental exposures

In human words: to cause asthma, most (if In human words: to cause asthma, most (if not all) “asthma” genes MUST interact with not all) “asthma” genes MUST interact with exposures that allow these genes to be exposures that allow these genes to be expressed as disease expressed as disease

Schlichting and Pigliucci. Phenotypic Evolution, 1997, page 232Schlichting and Pigliucci. Phenotypic Evolution, 1997, page 232

Phenylketonuria (PKU)Phenylketonuria (PKU)

PKU is an autosomal recessive disorder, PKU is an autosomal recessive disorder, caused by mutations in both alleles of the caused by mutations in both alleles of the gene for phenylalanine hydroxylase (PAH), gene for phenylalanine hydroxylase (PAH), found on chromosome 12found on chromosome 12

Accumulation of phenylalanine in the Accumulation of phenylalanine in the brain causes severe mental retardation; for brain causes severe mental retardation; for this reason, all newborns are screened for this reason, all newborns are screened for this disease at birththis disease at birth

Genes and Disease, from the NCBIGenes and Disease, from the NCBI

Genotypic Norms of Reaction Genotypic Norms of Reaction

EnvironmentEnvironment

Trait Trait ValuesValues

VP = VG + VE + VGE

Genotypic Norms of Reaction for PKU Genotypic Norms of Reaction for PKU

Phenylalanine content in dietPhenylalanine content in diet

PKUPKUphenotypephenotype

VP = VG + VE + VGE




Very low Very low heritabilityheritability

Very highVery high heritability heritability




VP =VGE

Norms of Reaction for Seven Different Norms of Reaction for Seven Different Achillea Plants Grown at 3 ElevationsAchillea Plants Grown at 3 Elevations

AAAABBBBCCCCDDDDEEEE

FF…FF…

aaaabbbbccccddddeeee

ff…ff…

DiseaseDiseaseRiskRisk

AAAABBBBCCCCDDDDEEEE

FF…FF…

aaaabbbbccccddddeeee

ff…ff…


Environment AEnvironment A

AAAAbbbb

DDDDEEEE

FFFF……

aaaaBBBB

ddddeeee

ff…ff…

Disease Disease RiskRisk

Environment BEnvironment B

AAAAbbbbCCCC

eeee FF…FF…

aaaaBBBBcccc

EEEE ff…ff…


Environment CEnvironment C

0

30

60

90

120

150

No animalsn=86

Dog/Cat onlyn=110

Stable animalsn=376

Geo

met

ric m

ean

(IU

/ml)

Total Serum IgE (IU/Ml) by CD14/-159 by Contact with Animals

CC

CT

TT

p=0.003 p=0.012n.s.

Eder et al, ATS 2003Eder et al, ATS 2003

StablesStablesNo AnimalsNo Animals

IgEIgE

PetsPetsNo StablesNo Stables

CD14/-159CCCD14/-159CC

CD14/-159TTCD14/-159TT

Norms of Reaction for CD14 Norms of Reaction for CD14 Genotypes in Humans Genotypes in Humans

CD14/-159CTCD14/-159CT


0

30

60

90

120

150

CC n=160

CT n=321

TT n=143

Geo

met

ric m

ean

(95%

CI)

CC n=160

CT n=321

TT n=143

Total Serum IgE by Total Serum IgE by CD14/-159 CD14/-159

in Rural Europein Rural Europe


PKU: Genetic, Developmental or Environmental Disease?

PKU: Genetic, Developmental or Environmental Disease?

If there were no phenylalanine in normal If there were no phenylalanine in normal diets, there would be no PKU diets, there would be no PKU

If there were no PKU gene, there would not If there were no PKU gene, there would not be no PKUbe no PKU

BUT, if accumulation of phenylalanine did BUT, if accumulation of phenylalanine did not cause brain toxicity, there would be no not cause brain toxicity, there would be no PKU either!PKU either!

Exposure to Stables and/or Farm Milk inthe First Year of Life.

0

2

4

6

8

10

12

14

16

Asthma ever Asthma attacks past 12 mo

E xposedNon-exposed%

Riedler et al, Lancet. 2001 Oct 6;358:1129-33.

* *

* p<0.0001

How Does Farming ProtectAgainst Asthma?

How Does Farming ProtectAgainst Asthma?

Exposure to microbial products in early life may Exposure to microbial products in early life may help develop a balanced immune responsehelp develop a balanced immune response

These products interact with so-called Toll-like These products interact with so-called Toll-like

receptors, which have genetic variants in themreceptors, which have genetic variants in them

Our hypothesis: if these variants make people Our hypothesis: if these variants make people less sensitive to the microbial products, they will less sensitive to the microbial products, they will be less protected against asthmabe less protected against asthma

Toll-like Receptors (TLR) and Their

Ligands

Toll-like Receptors (TLR) and Their

Ligands

TLR4 TLR2 TLR5 TLR9 TLR3 TLR7TLR6 TLR1

MD-2

LPS (Gram -)taxol (plants)

F protein (RSV)Hsp60 (host)

fibronectin (host) ds RNA

unmethylatedCpG DNA

anti-viralcompounds

flagellin

Lipoproteins (di-/triacylated)lipoarabinomannan

LPS (leptospira)LPS (P. gengivalis)

PGN (Gram +)zymosan (yeast)

GPI anchor (T. cruzi)

nucleotidesnucleotide analogs

0

10

20

30

40

0

10

20

30

40

Ast

hma

dia

gnos

is

Cur

rent

ast

hma

sym

ptom

s

Ato

py

Cur

rent

hay

feve

r s

ympt

oms

Cur

rent

hay

feve

r s

ympt

oms

Ato

py

Cur

rent

ast

hma

sym

ptom

s

Ast

hma

dia

gnos

is

p=0.012p=0.004

p=0.023

p=0.010

TLR2/-16934: AA AT TT

Asthma and Allergies by TLR2/-16934 in Children of Farmers and Non-farmers

Farmers’ children (n=229) Nonfarmers’ children (n=380)% %

Genotypic Plasticity for AsthmaGenotypic Plasticity for Asthmaamong Farmers and Non-Farmers among Farmers and Non-Farmers

FarmersFarmers

AsthmaAsthma

TLR2/AATLR2/AA

TLR2/AT-TTTLR2/AT-TT

Non-FarmersNon-Farmers

Asthma: Genetic, Developmental or Environmental Disease?

Asthma: Genetic, Developmental or Environmental Disease?

If persons with certain genes are exposed If persons with certain genes are exposed to the “right” substances, they are to the “right” substances, they are protected against asthma protected against asthma

BOTH the genes AND the exposure are BOTH the genes AND the exposure are neededneeded

BUT, the exposure HAS to happen at the BUT, the exposure HAS to happen at the right time during development right time during development

Asthma:Developmental Transition


Asthma:Developmental Transition


GenotypeGenotype

PhenotypePhenotype


Development/EpigeneticsDevelopment/Epigenetics(gene-gene)(gene-gene)



So, What Will the Future of Asthma Genetics Be?

So, What Will the Future of Asthma Genetics Be?

The future of asthma genetics will be The future of asthma genetics will be centered around preventioncentered around prevention

The motto will be: the right environment The motto will be: the right environment for our genes AND at the right time for our genes AND at the right time

Thus, modern genetics and genomics will Thus, modern genetics and genomics will NOT result in Armageddon or Dracula NOT result in Armageddon or Dracula clones, but in learning how to better live clones, but in learning how to better live with the genes we were brought to life withwith the genes we were brought to life with

The Geno-Phenomic EraThe Geno-Phenomic EraThe Geno-Phenomic EraThe Geno-Phenomic Era

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

http://resp-sci.arizona.edu/~nam/slides.ppthttp://resp-sci.arizona.edu/~nam/slides.ppt

asthma: role of interaction between genes and environment fernando d. martinez, m.d. arizona...

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