Paper 017 Disc

Clinical and Experimental Allergy, 1998, Volume 28, Supplement 5, pages 1620

Genetic factors in asthma severity

I. P. HALL
Division of Therapeutics, University Hospital, Nottingham, UK
Summary
The development of asthma in an individual depends upon the interaction of genetic factors with the
environment. Asthma is a polygenic disease and both genome screening and candidate gene
strategies have identified a number of putative genes that may predispose to the development of
asthma. However, there are few data regarding genes that may either dictate disease severity or
chronicity and genes that dictate response to treatment. Analysing asthma as a categorical variable
will fail to identify genes solely involved in determining disease severity, whereas studies designed to
analyse asthma as a semiquantitative trait may identify these genes in addition to disease-initiating
genes. However, identifying genes specifically involved in the determination of disease severity (e.g.
in airway remodelling) will be ideally performed in cohorts of asthmatics specifically recruited and
using appropriate end points. This review discusses methodological issues concerned with
identifying disease-modifying genes in individuals with asthma, and summarizes the potential
contribution of known candidate genes to the determination of disease severity.

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Introduction

Measuring asthma severity

The clinical manifestation of asthma in an individual

depends upon the combination of genetic predisposition
and environmental exposure. It is clear that asthma is a
polygenic disease and both genome screening strategies
[1,2] and candidate gene approaches are beginning to
identify areas of linkage and specific gene mutations
that contribute to the disease [3,4]. The majority of these
studies have used asthma as a phenotype defined on an
`all or none' basis together with other subphenotypes of
which the most informative have been IgE, bronchial
hyperreactivity and atopy. The asthma phenotype has
been allocated to individuals either on the basis of
questionnaire data or on the basis of a doctor diagnosis
and/or medication requirement. However, this approach
may be over-simplistic. It does not follow that the genes
that predispose an individual to developing an allergic
disease will necessarily determine the severity of that
disease. Hence approaches treating asthma as an `all or
none' diagnosis may potentially miss genes that modify
disease progression or determine response to treatment.
The aim of this review is to consider some of the issues
regarding identifying genes that may contribute to
asthma severity.

In order to begin to assess the potential contribution of

individual genes to asthma severity there is an obvious
requirement to have a suitable index of severity. Such an
index must be easily measured so that it can be applied
to large populations and ideally should be both
reproducible within populations and comparable between different populations.
The easiest approach to attempt to define asthma
severity is to ignore clinical asthma and to use objective
measurements which provide a numerical value. These
subphenotypes have been used in a number of studies.
The most obvious subphenotypes are total IgE, bronchial hyperresponsiveness, an index of skin test positivity (measured from mean wheal diameter), eosinophil
counts and treatment requirements. There are relatively
few data about the longitudinal stability of these
subphenotypes although from the limited data available
particularly on bronchial hyperresponsiveness and skin
test positivity there are obvious changes with time. The
most useful data in this area have been generated by the
Dutch group who also looked at the stability of the
asthma phenotype in a cohort of Dutch families: they
found that there is significant cross-over between the
asthma and non-asthma groups and also between those
individuals with bronchial hyperreactivity and those
without bronchial hyperreactivity over a period of 20
years [5]. Other subphenotypes are likely to be more

Correspondence: Dr I. P. Hall, Division of Therapeutics, University

Hospital, Nottingham, NG7 2UH, UK.
# 1998 Blackwell Science Ltd

16

Paper 017 Disc

Genetic factors in asthma severity

variable; IgE varies markedly with time and may also

vary with season in individuals sensitive to aeroallergens, and both eosinophil counts and treatment will
vary markedly with time.
In addition to the long-term stability of the phenotype
it is important to consider the repeatability of methods
used to define phenotypes. Estimates for repeatability of
questionnaire data in the UK are around 8595% [6]
and the repeatability of histamine PC20 measurements is
of the order of two doubling doses [7]. Hence it is clear
that whilst subphenotypes such as IgE or the slope of a
histamine or methacholine challenge dose response will
provide a quantitative absolute value it is also clear that
these values will vary significantly with time with
individuals.
Asthma as a semiquantitative trait
Whilst the majority of studies reporting linkage or
association of genetic markers in asthmatic populations
have reported on asthma as an `all or none' phenomenon
there has been interest in developing quantitative
scoring systems to define asthma severity. Again the
fundamental requirement for such a scoring system is
that it is reproducible within a population over time and
reproducible between different populations. One particular advantage of a scoring system that covers a whole
population (i.e. both asthmatic and non-asthmatic) is
that it deals effectively with those individuals who have
`probable' asthma. To attempt to identify the major
factors contributing to the asthma phenotype Morton
and colleagues examined traits relating to atopy and
asthma in a random cohort of 130 families with three or
more children in the south of England [8]. In practice
they found that bronchial reactivity was the major
determinant amongst the variables examined contributing to the asthma phenotype. This study also provided
useful information on the degree of correlation between
the different traits studied (Table 1).
Using information derived from this kind of approach
it is possible to develop a simple scoring system for
asthma severity. The big advantage of this approach is
that because disease severity is being taken into account
Table 1 Trait correlations in a random cohort
of 130 UK families (adapted from [8])

17

in deriving the data used for analysis, genes important in

contributing to disease severity rather than the initiation
of the disease process, will also be identified. This
quantitative approach can also work with categorical
variable such as IgE and BHR. For example, because
log IgE is unimodally distributed in the population
defining a population as having elevated IgE levels
based upon an arbitrary cut off value is artificial. By
using the entire range of values (e.g. log total IgE or a
BHR slope) one is able to analyse a given trait as a QTL
(quantitative trait locus).
Pathophysiological considerations
If one is going to distinguish between genes potentially
initiating a disease process and those that, whilst not
important in disease initiation, may determine disease
severity, it is useful to consider potential candidates for
genes determining severity. The most likely candidates
for `initiating' genes are those concerned with control of
IgE and antigen presentation. For example, intuitively
one would think that a mutation in a gene that was
important for IgE isotype switching in B cells would
predispose an individual to having elevated IgE levels
but may not ultimately be important in determining
disease severity. However, in an individual with asthma
a mutation in a gene important for determining
treatment response or the extent of airway remodelling
would potentially be more important for determining
asthma severity than for predisposing to the disease
itself. Such considerations are important in designing
studies with the aim of assessing genes that may be
important in asthma severity. A number of individuals
with asthma will eventually develop irreversible airway
obstruction as a consequence of airway remodelling, key
features of which include basal membrane thickening,
airway smooth muscle hypertrophy and subepithelial
fibrosis. Attractive candidates for disease-modifying
genes which might predispose to airway remodelling
would be those concerned with collagen and matrix
deposition in the airway wall. Mutations are already
known in a number of potential candidate genes (e.g.
TGFb). However, to define the importance of such

Log IgE
Bronchial response
Skin prick
Wheeze
Eczema
Hay fever
Atopy
Asthma

IGE
1.00

BR
0.35
1.00

# 1998 Blackwell Science Ltd, Clinical and Experimental Allergy, 28, Supplement 5, 1620

SP
0.54
0.39
1.00

WZ
0.37
0.63
0.44
1.00

EZ
0.24
0.09
0.20
0.21
1.00

HF
0.33
0.29
0.44
0.35
0.15
1.00

AY
0.98
0.46
0.69
0.48
0.27
0.41
1.00

AS
0.38
0.98
0.44
0.78
0.13
0.33
0.50
1.00

Paper 017 Disc

18

I. P. Hall

mutations to determining asthma severity one would

need to use as a phenotype an appropriate marker in
clinical studies. Although ideally serial bronchial biopsies would provide this kind of data, from a practical
point of view decline in FEV1 in a cohort of asthmatics
would be the easiest data to collect. At present very few
studies are utilizing this kind of approach which may
become increasingly important, and hence the ability to
examine candidate genes which may contribute to the
development of airway remodelling is limited. Table 2
gives a list of some potential gene families that are
candidates for asthma disease severity genes. Other gene
families (e.g. Th2 cytokine genes) may also contribute to
disease severity and/or chronicity, but their main
contribution is likely to be in disease initiation.
Whereas looking at disease-modifying genes responsible for airway remodelling will require studies over
several years, response to treatment is much easier to
look at. This pharmacogenetic approach to asthma is
likely to become increasingly important with the
recognition that common polymorphisms within genes
Table 2 Examples of potential candidate gene families for
disease-modifying effects in asthmatics
Airway remodelling
Collagen and matrix deposition
Proinflammatory mediators and their receptors
Mitogen and mitogen receptors (e.g. PDGF)
Chronic airway inflammation
Chemokines and chemokine receptors
Integrin receptors
Inflammatory genes (e.g. NO synthase, phospholipases,
5-LO, etc.)
Treatment response
b2-adrenoceptor
Glucocorticoid receptor
Muscarinic receptors

such as the b2-adrenoceptor may well determine

treatment response in asthmatic patients and hence
indirectly affect disease severity. This is covered in more
detail below.
Candidate genes in allergic disease and their potential
contribution to asthma severity
Table 3 shows candidate genes with known mutations
that have been proposed to be important in the development of atopy and/or asthma and its subphenotypes.
Reviewing candidate genes with known mutations that
have been associated with allergic disease it is clear that
the majority of these genes will be expected to be
involved in the control of IgE and/or Th2 mediated
inflammatory responses. As such, given that mutations
in these genes would be expected to predispose to
asthma per se it is perhaps not surprising that positive
results have been obtained looking at mutations in these
genes, using endpoints likely to identify disease-initiating genes. There have been many negative studies that
have looked at other genes that might potentially be considered to be disease-modifying but it may be premature
to discard these as contributory genes given that severity
was not specifically examined in many of these studies.
Pharmacogenetic studies
One obvious way in which genetic factors may influence
asthma severity is by determining treatment responses.
This possibility has been specifically examined in
asthmatics with respect to responses to steroids and to
b2 adrenoceptor agonists to date. There is a small group
of individuals who do not appear to respond to steroid
even at a high dose: such patients have been labelled as
being steroid-resistant asthmatics. In practice there
appears to be a continuum of steroid responsiveness

Table 3 Candidate genes for asthma and their potential contribution to asthma severity
Chromosome

Candidate gene

Association

IL-4
IL-9
b2AR

HLA
TNFa
5-LO
CC10
FCeRIb
TCRa
IL-4R

IgE
IgE
IgE, BHR,
treatment response,
nocturnal asthma
Specific IgE
? Asthma
Asthma
Asthma
Atopy, IgE, BHR
Specific IgE
Atopy

10
11
14
16

Potential contribution
to disease severity

Ref

Low
Low
High

[9,10]
[11]
[1216]

Low
High
High
High
Low
Low
Low

[17]
[18]
[19]
[20]
[2124]
[25]
[26]

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Paper 017 Disc

Genetic factors in asthma severity

and such patients may just represent one extreme end of

the distribution. A number of attempts have been made
to define the molecular basis of steroid resistance including sequencing the glucocorticoid receptor from a
number of such patients [27]. To date no specific mutation
has been identified that determines steroid resistance,
although this work is ongoing. Obviously, relevant
mutations do not have to be within the coding region of
the glucocorticoid receptor gene itself, but could be in
genes for products in downstream signalling pathways.
Our group has concentrated on assessing the contribution of b2-adrenoceptor polymorphism to allergic
disease. Initial studies demonstrated that the glutamate
27 b2-adrenoceptor polymorphism was associated with
lower IgE levels and less reactive airways in asthmatic
subjects [13,14], although it is possible that these
findings are due to linkage disequilibrium with other
genes close by on 5q.31 given that both IgE and BHR
have been linked to this region of 5q by other groups
[10,11]. More recently we have studied the response to
long-acting b-agonists of individuals who are homozygous for the glycine 16 b2-adrenoceptor variant: in
vitro this polymorphism confers increased levels of
downregulation following agonist exposure. We found
such subjects to develop tachyphylaxis to the bronchodilator effects of long-acting b-agonists following
chronic dosing with oral formoterol, although whether
this effect occurs with clinically relevant doses of inhaled
long-acting b-agonists remains to be determined [16].
The glycine 16 form of the receptor is also associated
with nocturnal fall in FEV1 [15].
One other study has been reported which is potentially relevant to asthma pharmacogenetics. Drazen's
group have recently described a promoter polymorphism in the 5 lipoxygenase gene that alters transcription
in in vitro systems [19]. With the development of 5-LO
inhibitors for the treatment of asthma it will be
important to determine whether polymorphisms affecting
gene transcription will determine response to treatment.
Conclusions
Whilst genetic studies have made considerable progress
in identifying both chromosomal areas of linkage and
mutations in candidate genes that may be relevant to
allergic disease, the majority of these studies have
concentrated on the contribution of these genetic factors
to the risk of developing asthma per se. Few studies to
date have addressed the question of disease-modifying
genes in asthma and the possibility that genetic factors
may be important determinants of treatment response.
There are important potential clinical consequences of
identifying these genes. For example if individuals with

19

relatively mild asthma are at high risk of developing

irreversible airflow obstruction in time due to airway
remodelling, it might be appropriate to treat them at an
early stage with more aggressive therapy. Similarly if
subgroups of asthmatics can be identified who respond
better to one treatment, then therapy can be tailored
according to an individual's genetic make up. In order
to identify these disease-modifying and treatmentresponse determining genes, studies will need to be
designed specifically to examine these factors.
Acknowledgements
IPH is a National Asthma Campaign Senior Research
Fellow.
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