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• ERS 2002

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The impact of recent genetic research on the
performance of asthma epidemiology

• Neil Pearce
• Centre for Public Health Research
• Massey University Wellington Campus
• Wellington, New Zealand
• Presented at the ERS Research Seminar on
• Post-genome respiratory epidemiology
• Abbaye des Vaux de Cernay, France
• 25-27 January 2002

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The impact of recent genetic research on the
performance of asthma epidemiology

• Asthma epidemiology
• Theories of asthma causation
• Asthma genetics
• What does this mean for asthma epidemiology?

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Asthma epidemiologyIncreases in asthma
prevalence
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Increases in asthma prevalence
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ISAAC Steering Committee
R Anderson M Burr U Keil D Strachan E von
Mutius S Weiland H Williams
B Björkstén
F Martinez
S Montefort
C Lai
JR Shah
I Asher R Beasley J Crane E Mitchell N Pearce C
Robertson
J Mallol
N Aït-Khaled G Anabwani
gm/08/96 stock_2.ppt
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Study centres and participants 13-14 year age
group

gm/08/96 stock_2.ppt
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12 month period prevalence of asthma symptoms in
13-14 yr old children
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Proportion of children with symptoms of asthma,
allergic rhinoconjunctivitis or atopic eczema
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Key findings from ISAAC

• English-speaking countries have the highest
  asthma prevalence in the world
• There is little variation within the
  English-speaking countries
• Other countries in Latin America are also high
• There is a Northwest-Southeast gradient within
  Europe

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Key findings from ISAAC

• There is an inconsistent correlation of asthma
  prevalence with affluence (as measured by GNP)
• There are some areas (West/East Germany, Hong
  Kong/Guangzhou) with major prevalence differences
  within the same ethnic group
• There is a weak and inconsistent association
  between asthma prevalence and that of other
  atopic conditions such as rhinitis and eczema

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Asthma epidemiologyDo the established risk
factors explain the international patterns and
time trends?

• House dust mite allergen
• Other indoor allergens
• Parental smoking
• Diet
• Air pollution
• Occupational exposures
• Genetic factors

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Air pollution and current wheeze in Asian ISAAC
centres
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Der p 1 levels in mattresses in Hong Kong and
Guangzhou
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Theories of asthma causationthe allergen
hypothesis

• Allergen exposure, particularly in infancy
  produces atopic sensitization
• Continued exposure results in asthma through the
  development of bronchial hyperresponsiveness,
  airway inflammation and reversible airways
  obstruction

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Asthma is an atopic disease

• Is BHR a valid measure of asthma prevalence?
• How much asthma is really attributable to atopy?
• Is allergen exposure a primary cause of asthma?

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BHR and asthma

• Pekkanen J, Pearce N. Defining asthma in
  epidemiological studies. Eur Respir J 1999 14
  951-7.
• Pearce N, Pekkanen J, Beasley R. Role of
  bronchial responsiveness testing in asthma
  prevalence surveys. Thorax 2000 55 352-4.
• BHR validates well against asthma in selected
  clinical populations
• There have only been two population-based studies
  in which BHR and symptoms were validated against
  a clinical diagnosis

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BHR and asthma

• In both studies symptom questionnaires (e.g.
  ISAAC) validated better than BHR or BHR
  symptoms
• BHR is not a good surrogate measure of asthma,
  many asthmatics do not have BHR and vice versa
• BHR testing is most relevant to mechanisms of
  asthma, rather than as a measure of prevalence

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How much asthma is really attributable to atopy?

• Pearce N, Pekkanen J, Beasley R. How much asthma
  is really attributable to atopy? Thorax 1999 54
  268-72.

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Studies in children
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Association of atopy with asthma in individuals

• Most asthmatics are atopic (58 in children and
  54 in adults)
• Many non-asthmatics are atopic also (29 in
  children and 24 in adults)
• The proportion of cases attributable to atopy is
  less than 40 in both children and adults
• Higher estimates can be obtained using total
  serum IgE but these associations may not be
  entirely causal

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Comparisons of populations(Peat et al)
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Association of atopy with asthma in populations

• A few studies show an association between the
  prevalence of atopy and the prevalence of asthma
• Most studies do not
• Population studies provide at best limited and
  inconsistent evidence that atopy is a major cause
  of asthma

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Is allergen exposure a major primary risk factor
for asthma?

• Pearce N, Douwes J, Beasley R. Is allergen
  exposure the major primary cause of asthma?
  Thorax 2000 55 424-31.

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Allergen exposure and asthma

• Only three cohort studies have been conducted
  (both in selected populations) of allergen
  exposure in infancy and asthma risk after age six
  years
• One study (Sporik et al) is positive, but not
  significantly so, Burr et al and Lau et al found
  no association between allergen exposure and
  subsequent asthma risk

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Allergen exposure and asthma

• Cross-sectional studies show weak associations
  with overall population attributable risks of 4
  for Der p 1, 11 for Fel d 1, -4 for Bla g 2 and
  6 for Can f 1
• There was little change in these estimates when
  those adopting allergen avoidance were excluded

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Mean der p 1 levels, and prevalence of HDM atopy
and total atopy in six Australian centres
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Theories of asthma causationThe hygiene
hypothesis

• The increases could be due to increased
  susceptibility to the development of
  sensitization and/or asthma due to other
  exposures (or absence of exposures) in utero and
  in infancy
• In particular, the increases could be occurring
  because our cleaner environment means that we
  have lost the previous protective effect of
  infant infections

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Key features of Westernization

• Small family size is associated with an increased
  risk of atopy and (to a lesser extent) asthma
• Some infections (particularly gastrointestinal)
  early in life reduce the risk of atopy and (to a
  lesser extent) asthma
• Large size at birth is associated with an
  increased risk of atopy and (to a lesser extent)
  asthma
• Changes in diet associated with Westernization
  (e.g. more transfatty acids, fewer vegetables)
  are associated with asthma

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TH1 and TH2 subsets
TH0
ALLERGY HELMINTH
BACTERIA VIRUSES
?
?
TH1
TH2
?
?
IFN gamma IL-2
IL-4, IL-5
?
?
Cytolytic
Induces B cell IgE Production
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Hypotheses

• The increases in asthma prevalence could be due
  to increased exposure to known risk factors
  (particularly house dust mite and other indoor
  allergens)
• The increases could be due to increased
  susceptibility to the development of
  sensitization and/or asthma due to other
  exposures (or absence of exposures) in utero and
  in infancy
• This could be occurring through a reduced TH1 and
  an increased TH2 immune response

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Problems

• We may be replacing one dogma with another
• It is not clear that the new risk factors are
  strong enough to account for the prevalence
  increases (although the package could be)
• Asthma prevalence is higher in Latin American
  countries with (presumably) higher infection
  rates than in Spain or Portugal
• The population evidence is that local allergen
  exposure may merely determine which allergens
  susceptible individuals become sensitized to,
  without causing sensitization itself

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Problems

• The susceptibility hypothesis is conceptualised
  within the allergen-TH1/TH2 paradigm which
  appears to account for at most about one-half of
  asthma cases
• This may be an overestimate because the
  association may not be entirely causal, and
  sensitization may be a consequence of an
  asthmatic predisposition
• It is possible that the package of changes
  involved in increasing affluence and
  Westernization account for the asthma prevalence
  increases, but that this does not involve classic
  atopic (TH2) mechanisms

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Genetic diseases

• It cannot be assumed that a disease is genetic
  because it is inherited
• Even for classic genetic diseases such as
  phenylketonuria (PKU), there is an environmental
  component (e.g. diet)
• All diseases are 100 genetic and 100
  environmental

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Genetic diseases

• When the environmental component is universal but
  the genetic component varies, then we say that
  the condition is entirely genetic
• When the genetic component is universal but the
  environmental component varies then we say that
  the disease is entirely environmental
• In most instances, presumably, both the genetic
  factors and the environmental factors vary, and
  whether we label the disease as genetic or
  environmental depends on our current knowledge

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Genetic diseases

• The greatest potential for population-based
  genetic interventions occurs when
• The disease is known to occur through a single
  well-defined mechanism
• Only a small number of genes are relevant to this
  mechanism
• There is little temporal or geographical variation

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Asthma genetics

• Asthma satisfies none of these conditions
• It occurs through multiple mechanisms that are
  not well understood
• Many genes appear to be related to different
  aspects of the main (allergic) mechanism that has
  been studied to date
• There is major temporal or geographical variation
  that cannot be explained by genetic factors

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Asthma genetics

• Thus, to date asthma genetics has had limited
  success in explaining a significant proportion of
  asthma cases, and even less success in explaining
  the population patterns
• Those associations that have been found have
  often not been reproduced in other populations

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Asthma genetics

• It could be argued that the solution is to use
  narrower disease definitions and intermediate
  phenotypes
• However, the findings may then be generalisable
  to only a small proportion of asthma cases
• In particular, at most half of all asthma cases
  appear to occur through allergic mechanisms
• The major task is to identify the causes of the
  major increases in prevalence that appear to have
  occurred globally.

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Asthma epidemiology

• Genetic factors cannot account for these
  increases, but gene-environment interactions may
  be important.
• In the past we have consistently overestimated
  the importance of genetic factors for health, and
  we have underestimated the ethical and practical
  problems in applying genetic knowledge to
  interventions
• The search for environmental causes of asthma is
  likely to continue to be primary, while the study
  of gene-environment interactions will play an
  important secondary role