Download Genetics of allergic disease

Genetics of allergic disease
Marlies Feijen*\ Jorrit Gerritsen* and Dirkje S Postma*
*Department of Pulmonary Rehabilitation, Beatrixoord Rehabilitation Centre, Haren,
The Netherlands, ^Department of Pediatric Pulmonology, Beatrix Children's Clinic, The
Netherlands, ^Department of Pulmonology, University Hospital Groningen, The Netherlands
Atopy can express itself as asthma, rhinitis and eczema. The presence of atopy
can be assessed by increased levels of total serum IgE and specific IgE to
common allergens, skin test positivity and increased numbers of peripheral
blood eosinophils. Genetic studies indicate that multiple genes are involved in
the pathogenesis of atopy and that different genes regulate the presence of
increased levels of serum total IgE and specific IgE. Linkage of these traits to
chromosomal regions likely to contain atopic susceptibility genes has been
replicated in several studies. Genome-wide screens have identified several new
chromosomal locations that are likely to contain atopic genes. These regions
also contain candidate genes. Moreover, the available literature suggests that
multiple, yet different genes may be involved in the translation of atopy to a
distinct clinical phenotype. We anticipate that understanding of the genetic
basis of atopy will lead to new therapeutic interventions and early diagnosis.
It has now been widely accepted that atopy constitutes a genetic disease,
yet the exact genes and their loci have not been established so far. More
than one gene is most likely involved in the expression of atopy and their
Correspondence to:
Prof. Dr Dirkje S Postma.
Department of
Pulmonology, University
Hospital Groningen,
PO Box 30.001, 9700 RB
Groningen,
The Netherlands
Fig. 1 The phenotypic heterogeneity of atopy. The outer box represents a general population:
approximately 40% is atopic as defined by skin test posrtivity. Allergic rhinrtis has a population
prevalence of 20%. There is a considerable overlap between asthma and rhinitis; however, not
all asthmatics are atopic Atopic eczema has also an overlap with asthma and allergic rhinitis.
Please note that figures are estimations for a population of children and adults.
British Medical Bulletin 2000; 56 (No. 4): 894-907
O The British Council 2000
Genetics of allergic disease
interaction may result in different disease expressions such as asthma,
rhinitis or atopic dermatitis (Fig. 1).
The prevalence of atopy, asthma, rhinitis and atopic eczema in childhood
are 40%, 10-20%, 20% and 10-20%, respectively. It has been well
established that the prevalence of atopic diseases is increasing1. This rise in
prevalence of atopy can not simply be explained by genetic factors alone,
because it has occurred within one or two generations. Thus the clinical
expression of the atopic trait has to be also dependent on environmental
factors. Important environmental factors in the development of atopic
diseases are allergen exposure, (maternal) smoking, breast feeding, Western
life-style and possibly lack of infections or hygiene2.
Phenotypes of atopy
Atopy can be defined as a prolonged increased production of IgE as a
response on exposure to common allergens. Atopy can be assessed by
increased levels of total serum IgE and specific IgE to common allergens
and by skin test positivity to inhalant or food allergens. Furthermore, it
can be suggested that atopy is present when increased levels of
peripheral blood eosinophils exist. The clinical expression of atopy
includes asthma, rhinitis and dermatitis. Asthma has been defined as a
chronic inflammatory disease in the airways of the lung, characterised
by variable airway obstruction and airway hyper-responsiveness
accompanied by symptoms such as wheeze, breathlessness or cough.
Asthma generally develops in childhood, but symptoms occasionally
start in adulthood. Allergic rhinitis can be defined as a recurrent or
persistent inflammation of the nostrils with one or more of the following
symptoms: nasal congestion, rhinorrhoea, sneezing and itching. The
most common form of allergic rhinitis, i.e. hay fever, starts around the
age of 7 years, but the onset can also be earlier or later in life. Atopic
dermatitis is a disease most prominent in early childhood, it is
characterised by an itchy red rash that has an easily broken surface.
The genetic basis of atopic disease
Family studies
It has long been known that asthma clusters in families. Until recently
the route of inheritance was not known. Familial aggregation studies are
the logical first step to determine the mode of inheritance. This can
either be performed by twin studies or in families ascertained by a
proband with the phenotype under study. Significant aggregation of
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asthma and atopic phenotypes in families screened by an asthmatic
proband has been described3.
Twin studies
Twin studies are especially important to estimate both the genetic and
environmental contribution to complex traits. Monozygotic (MZ) and
dizygotic (DZ) twins are compared for similarities and differences
between these twin types. MZ twins share 100% of their genetic
information and DZ twins share 50% on average. Thus, MZ twins
should resemble each other to a greater extent than DZ twins if a trait
is influenced by genetic factors. The major assumptions of twin studies
are that the twins are samples of the same gene pool, that they are
representative of the general population, that self-reported zygosity is
correct in questionnaire-based studies and that the environment for both
MZ and DZ twins is similar.
Twin studies have provided evidence of a considerable genetic
component of asthma, hay fever and eczema4""*. Atopic phenotypes such
as elevated serum total IgE and positive skin tests were studied by Hopp
and co-workers and genetic contribution to both of the phenotypes was
suggested7.
Table 1 provides an overview on atopic twin studies and shows that
atopy itself (IgE and positive skin test) is genetically determined as well
as asthma, rhinitis and eczema (modified table, references from review
article by Los et al.8). Heritability lies in general between 0.60 and 0.70
and monozygotic twins have always a higher concordance of the trait
under study than dizygotic twins.
Segregation analyses
Segregation analyses are used to model inheritance patterns in families.
The distribution of a disease is studied in families and the observed
frequency of the disorder in offspring and siblings is compared to the
expected distribution using different genetic models of inheritance (e.g.
dominant, co-dominant, recessive or polygenic).
Different genetic models have been found for total serum IgE. Several
explanations may be given for these different findings. The first
explanation may be the variable definition of atopy between studies.
Secondly, the ascertainment of families for segregation studies may play
a role. In families screened for asthma, estimates on frequencies of alleles
regulating total serum IgE are expected to be higher than in families
sampled randomly from the general population. A final explanation may
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Table 1 Twin studies of atopic traits
Phenotype
First
author
Population
Total IgE
Hopp
Hanson
US, A and B
US apart, A
US together, A
Finland, A
107
70
61
158
Specific IgE
Hanson
US apart, A
US together. A
26
14
Skin test
Hopp
Hanson
US, B and C
US apart, A
US together, A
107
39
41
0.82
Edfors-Lubbs
Sweden, A
6996
0 65
0.25*
Hopp
Duffy
US, B and C
Australia, A
107
3808
0.65
0.24*
Nieminen
Finland, A
13.888
0.43-
Lichtenstein
Sweden, C
Harris
Laitinen
Skadhauge
Norway, B
Finland, B
Denmark,
434 M
456 F
2559
1713
11.688
Asthma
B
A
Hayfever
Eczema
Urticaria
Number of
twin pairs
MZ
correlation
DZ
correlation
0.82
0.64
0.42
0.56
0.52*
0.49*
0.26
0.37*
Probandwise
concordance
MZ/DZ
H
Comments
0.61
Twins raised apart
Twins raised together
Twins raised together
0 50/0
0.50/0.33
Twins raised apart
Twins raised apart
0.72
0.46*
0.55/0.50
0.70/0.28
0.19#/0.05#*
0.50#/0.33#
0.72
0.60-0.75
0.25-*
0.13/0.07
0.36
0 75
0.76
0.21
0.45
0.62/0.26*
0.41/0.18*
0.45/0.12*
0.42/0.19*
0.76
0.62
0.75
0.79
0.73
1929 M
2131 F
1867 M
2110 F
0.76
0.71
0.81
0.65
0.36
0.47
0.37
0.15
0.48/0.19*
0.42/0.26*
0.51/0.16*
0.38/0.09*
21.4#/13.6#*
Edfors-Lubbs
Sweden, A
6996
0.45-
0.25-*
Duffy
Australia, A
3808
0.61
0.25*
Lichtenstein
Sweden, C
434 M
456 F
0 60/0.43*
0.59/0.34*
Edfors-Lubbs
Sweden, C
6996
15.4#/4.5#*
Lichtenstein
Sweden, C
434 M
456 F
0.54/0.35*
0.73/0.4O*
0.74
0.71
Lichtenstein
Sweden, C
434 M
456 F
0.52/0.33*
0.68/0.38*
0.54
0.60
0 60-0.75
0.33
0.70
Population study, selfreported asthma
Questionnaire
Population study, selfreported asthma
Population study,
doctor's diagnosis of
asthma
Questionnaire
Population study
Parental/twin design
Population study, selfreported asthma
Population study, selfreported hayfever
Population study, selfreported hayfever
Questionnaire
Population study, selfreported eczema
Questionnaire
Questionnaire
'Statistically significant differences between monozygous (MZ) and dizygous pairs. A, adults; B, young adults; C children; M, male; F,
female. -Correlation is calculated by Duffy etal1. #Concordance: pairwise concordance. H: heritability.
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be genetic heterogeneity. This means that in different populations, separate
genes act in the regulation of these phenotypes. To date, this cannot be
investigated since the exact locations of these genes are still unknown.
Using a single locus approach, the best fitting models for high serum
IgE levels were the models of a major Mendelian gene, either codominant, recessive, mixed model of recessive inheritance, dominant, or
in two other studies of polygenic inheritance. In a study of 243
Australian nuclear families, evidence for recessive inheritance of total
serum IgE and significant residual familial correlations were found9.
However, these correlations were not significant when the presence of
the specific immune response was accounted for in the analysis.
Therefore, it suggests that regulation of total serum IgE is genetically
independent from the regulation of allergen specific IgE. A two locus
model on IgE in 92 Dutch families screened through a proband with
asthma provided a significantly better fit of the data than a one-locus
model10. In addition, evidence was presented for two unlinked loci
regulating total serum IgE in these families. The first locus alone explained
50.6% of the variance of the level of total serum IgE, the second 19%.
Considered jointly, the two loci accounted for 78.4% of the variability of
total serum IgE. No data on the segregation of skin test positivity or
specific IgE levels to allergens as a representative for atopy have been
presented so far.
In the European Community Respiratory Health Survey of 13,963
asthma patients, the complex segregation analysis of the asthma phenotype provides evidence for a two-allele gene with co-dominant inheritance11. Other studies on aggregation of asthma and wheeze in families are
summarised in Table 2 (for references see the review article by Los et al.s).
The segregation of asthma in these families appears to be predominantly
consistent with the action of multiple genes with a small effect.
In summary, segregation analyses of asthma or atopy, when expressed
as total serum IgE, confirms a genetic trait, but the mode of inheritance
is yet uncertain as are the number of genes involved. There are no data
available on eczema and rhinitis.
Linkage
Linkage analysis is used to determine a chromosomal region which cosegregates with a certain trait within families. The likelihood that a trait
co-segregates with a marker is expressed as a LOD score, i.e. the log of
the ratio of the likelihood of linkage and the likelihood of no linkage. A
value of +3 is traditionally taken as evidence for linkage and a value of
-2 is considered evidence against linkage. Linkage analysis requires
pedigree data as opposed to association studies in which unrelated cases
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Table 2 Segregation analyses of atopic traits
Phenotype
First author Year
Number of
families/
population
Genetic model
Total IgE
Gerrard
173 USA
Model major gene
Dominant allele suppresses
high levels of IgE
0.43
Selected population for
ragweed allergy
Blumenthal 1981
3 USA
Major gene with polygenic
transmission
0.43
Extended families selected for
ragweed allergy
Meyers
1982
23 USA
Mendelian co-dominant model
No selection for allergy. Amish
in-bred
Hasstedt
1983
5 USA
No major gene, polygenetic
inheritance
Selected population for
ragweed allergy
Meyers
1987
42 USA
Mixed model with recessive
inheritance of high IgE levels
Martinez
1994
291 USA
Major gene, co-dominant
inheritance for high IgE levels
Hispanic and non-Hispanic
No selection for allergy
Lawrence
1994
131 UK
Polygenic model
Random population sample
Xu
1995
92 The
Netherlands
Two locus recessive model
with epistasis
Families ascertained through
a proband with asthma
Dizier
1995
234 Australia
Recessive major gene controlling
high IgE levels
No selection for allergy
Panhuysen
1996
92 The
Netherlands
Two-locus recessive model
Families ascertained through a
proband with asthma
Lawrence
1994
131 UK
Mixed model, two-locus model
Holberg
1996
906 USA
Polygenetic or oligogenetic
model, not a single two-allele
gene
Questionnaire, physician
diagnosed asthma
ECRHSG
1997
13.963 Europe
Two-allele gene with
co-dominant inheritance
Questionnaire, self-reported
asthma
Jenkins
1997
7,394 Australia
Oligogenetic model
Questionnaire, population of
school children
Chen
1998
309 USA
Single locus model
Contribution of polygenes
and environment
Questionnaire, self-reported
wheeze
Asthma
1973
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Hertitability
0.36
0.28-0.63
Comments
No selection for allergy
Common genes of small effect
Questionnaire, populationbased sample
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and controls are needed. To study linkage using the LOD score
approach, a genetic model has to be specified for different parameters
such as mode of inheritance, allele frequencies and penetrance. Sometimes these parameters can be estimated from segregation analyses,
which is preferable; but, in most cases, the parameters are not known.
No specification of a genetic model is needed in non-parametric
approaches such as the sibling pair analysis and affected relative pair
analysis. These methods test whether the inheritance of a chromosomal
region is not consistent with random segregation. If this is the case,
affected relatives inherit identical copies of alleles in this region more
often than would be expected by chance12. The observed and expected
distributions of alleles can be tested with a x2-test.
In general, evidence for linkage is assumed to be present when the
reviewed linkage from one study has been replicated by others.
Identifying atopic disease genes
In identifying genes there are two general approaches. In the genomewide screen all chromosomes are searched until the approximate
location of the gene is discovered. The localisation of the gene is
progressively refined until the gene itself is isolated by linking the
inheritance of specific chromosomal regions with the inheritance of
disease. This approach is often referred to as positional cloning. The
candidate gene approach is used when a gene is a plausible candidate for
being the disease gene because of its function. The strategy is to find
polymorphisms in a known gene and to compare the frequency of alleles
in cases and controls. The finding of a positive association of an allele
and a trait can be interpreted in three ways12: (i) the allele of interest is
the relevant mutation in the disease gene; (ii) the allele is in linkage
disequilibrium, which means that it is physically very close to the gene;
or (iii) the association is a result of population admixture. This occurs if
a certain trait has a higher prevalence in an ethnic subgroup within a
mixed population. Any allele with a higher frequency within this
subgroup will show association with the trait.
Genome-wide search
Recently, genome-wide searches have contributed
mapping of atopic genes by conducting searches
populations. Families were recruited in Western
Germany, The Netherlands and from the US (both
Caucasians, Hispanics and Hutterites)3'13.
900
significantly to the
in different human
Australia, Sweden,
African Americans,
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Genetics of allergic disease
Table 3 Replication of linkage of atopic traits
Chromosome
Atopy broadly
defined
IgE
Specific IgE
Skin prick
test
Eosinophilia
Asthma
Eczema
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
Evidence for linkage to multiple chromosomal regions was reported in
each study. Linkage by multiple groups were found on chromosomes 1,2q,
3,4, 5q, 6p, 7, 9, l l q , 12q, 13q, 14,16 and 17q. 'Novel' regions of interest
are 17p, 19 and 21 because they were only observed in one study.
Linkage and association of atopy
Table 3 shows the replicated linkages on the different atopic traits.
Genome-wide screens show many regions of interest, but just a few
linkages have been replicated.
Atopy
Linkage for atopy (broadly defined) was found on chromosome 5, 6, 11,
13. Only the linkage to chromosome 11 has been replicated. Cookson and
co-workers reported linkage of a broadly defined atopic phenotype to
markers on chromosome llq 1 4 . Seven families were studied, and most of
the LOD score was contributed by one single family using an autosomal
dominant mode of inheritance. The investigators confirmed their findings
in other samples. In addition, other studies from The Netherlands,
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Germany, Japan and Australia found evidence for linkage between an atopic
phenotype and markers on chromosome llq 8 . Sequence variants in the highaffinity IgE receptor (FceR) gene on chromosome 11 may increase the risk for
development of atopy3. Linkage of chromosome l l q to atopy and asthma
remains controversial due to multiple failures to replicate the linkage in
several other populations. Subsequent work of Cookson et al. suggested that
the linkage in other studies may have been obscured by maternal
inheritance15. Possible explanations for maternal inheritance of atopy are
paternal imprinting (a process by which a particular gene is differentially
activated or silenced, depending on the sex of the parent from whom it was
inherited) or maternal modification of the developing immune response.
Total serum IgE
Linkage of total serum IgE to chromosomes 1, 2, 4, 5, 6, 7, 9, 11, 12, 13,
14, 15 and 16 has been found by several research groups. Replication of
significant linkage has been found to chromosomes 5, 11 and 12.
In 199A, Marsh et al. were the first to report linkage between serum total
IgE levels and chromosome 5q in an American Amish population16. Meyers
et al. replicated this finding in a study of Dutch families17. More studies have
replicated linkages on chromosome 5 whereas others could not8. This can
be due to different populations, definitions of phenotypes, founder effects,
admixture, and possibly varying environmental influences.
Specific IgE
Linkage for specific IgE has been found to chromosomes 1, 2, 4, 6, 7, 9,
and 12. There is only limited data available with regard to linkage of
specific IgE to particular chromosomal regions. Most linkages are not
significant, i.e. they do not reach the maximum LOD score of 3.
Furthermore, significancies are very low. Summary of the available
literature shows that the required replication of linkage to a
chromosomal area is still not found.
Skin prick test
Linkage for skin prick tests was found on chromosomes 1, 3, 6, 9, 11
and 16. Replication of linkage of a positive skin prick test existed for
chromosomes 1 and 11. Ober was the first to investigate skin prick tests
as an atopic phenotype by itself13. Other investigators have always used
a composite score of atopy, including skin prick test.
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Peripheral blood eosinophilia
Linkage for peripheral blood eosinophilia was reported on
chromosomes 1, 3, 4, 5, 6, 7, 11, 14 and 16. Linkage of eosinophilia to
chromosome 6 is significant and has been replicated.
Asthma
Linkage for asthma was found on chromosomes 1, 2, 3, 5, 6, 9,11-14,17,
19 and 21. Evidence for linkage and association for both asthma and total
IgE to chromosome 12q was reported in an Afro-Caribbean population18.
Other studies confirmed a linkage for IgE or asthma on chromosome 12q.
An interesting finding is that the chromosomal regions on 12q implicated
in these studies are not exactly the same3. Further studies are needed to fine
map this region and may answer the question whether one or more regions
on 12q are implicated in asthma and atopy.
Several candidate genes map to this wide region such as interferongamma, IGF1 (promotes differentiation of both B and T lymphocytes), a
mast cell growth factor and the P-subunit of nuclear factor-Y (possibly upregulating transcription of both EL-4 and the HLA genes). For references,
see Wiesch et aP.
Atopic eczema
Linkage of atopic eczema (AE) has been reported on chromosome 5q31 19 .
There are only a few genetic studies on atopic eczema. Shirwaka et al.
confirmed the association between FceRIp on chromosome I l q l 3 and atopy
underlying AE (for references see Tanaka and co-workers20). Significant
association of AE and mast-cell chymase (MCC; a serine protease secreted by
skin mast cells) on 14qll has also been reported21. Recently, an association
between AE and a functional mutation in the promoter region of the C-C
chemokine RANTES was found in children from Germany22.
Allergic rhinitis
No reports are available about linkage of allergic rhinitis.
Asthma and atopy genes
When reviewing the literature there are some interesting and promising
polymorphisms in genes related to atopy, for instance the CD 14 polymorphism, IL-4, IL-13 and p2-receptor.
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CD14
The CD 14 gene is located on chromosome 5q31, expressed on the
surface of macrophages and monocytes, and is also present in serum in
a soluble form (sCD14). CD14 is an important high affinity receptor for
lipopolysaccharide (LPS) and other bacterial wall products. LPS
exposition by bacterial infections in infancy may shift the Th-l/Th-2
balance in favour of Th-1 type immune response, thereby suppressing
the Th-2 response, which leads to atopy23. Binding of LPS to CD14 can
provide activation signals for Th-1 maturation. IgE synthesis is
controlled by inhibitory cytokines from Th-1 cells and by stimulatory
cytokines provided by Th-2 cells24.
Baldini et al. identified a C-T base change polymorphism in the 5'
regulatory region of the CD 14 gene that was associated with low levels
of total serum IgE24.
IL-4and IL-13
There are many candidate genes for atopy on chromosome 5q, such as
a cluster of cytokine genes IL-3, IL-4, IL-5, IL-9 and IL-13. These
cytokines are mediators of inflammation in atopy; IL-4 is an important
mediator in regulating the production of IgE and skewing the Th-l/Th2 balance to Th-2. IL-13 acts on B-cells to produce IgE and there is
increasing evidence that IL-13 is crucial in inducing asthma in animal
models (for references see Shirakawa et al.25). Five variants have been
reported in the IL-4 promoter region, four of them being very rare.
Recently, two variants of IL-13 have been identified, a promoter
polymorphism associated with increased risk of allergic asthma as well
as a coding variant (glnllOarg) of IL-13 that is associated with both
atopic and non-atopic asthma in a British and a Japanese population25.
IL-4 and IL-13 operate through the IL-4 and IL-13 receptor, both
receptors share the IL-4Ra chain25. IL-4 binds to both types of receptors
through the IL-4Ra chain, whereas IL-13 can bind only to the IL-13
receptor. The IL-4 receptor can be expressed on both B- and T-cells, the
IL-13 receptor only on B-cells. Thus, IL-4 can stimulate both B- and Tcells, whereas IL-13 can activate B-cells only. Both receptors activate
STAT6 (signal transducer and activator of transcription 6), the IL4Ra-STAT6 interaction is essential for IL-4 and IL-13 signalling. STAT6
induces GATA3 activation and enables Th-2 cells to maintain their Th2 characteristics, while inducing B-cells to produce IgE. Therefore, the
observation that polymorphisms in these genes are associated with
asthma has important implications for both the understanding of
asthma and the possibility of devising new strategies for prevention or
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amelioration of the disease. Finally, a strong linkage has been found
between atopy and flanking markers to IL-4R on chromosome 16pl2.
$2-Adrenergic receptor
P2-Adrenergic receptors are localised on airway smooth muscle,
epithelium and inflammatory cells (mast cells, macrophages, eosinophils
and T-lymphocytes). P2-Adrenergic receptor function is mainly regulated
by circulating epinephrine and mediates most of the effects of (32agonists on airway function. The P2-adrenergic receptor (P2AR) gene is
localised on chromosome 5q 31-32. This gene is intronless and has a
coding block consisting of 1239 nucleic acids. Nine known
polymorphisms varying within the normal population are situated in
this region, and four polymorphisms result in amino acids variations on
positions 16, 27, 34, and 164. One polymorphism has been identified in
the 5' leader cistron sequence, a peptide that modifies P2AR translation.
Although no differences in the polymorphism frequencies were found in
asthmatics compared with non-asthmatic controls, cell and transgenic
mouse studies have shown altered function or regulation of the P2AR
(for references see Liggett26).
Two variants may play a role in asthma treatment. The first is the
glyl6 variant which is a common polymorphism in the general
population. Tan and co-workers reported that homozygous individuals
with this variant showed reduced treatment response following either
acute or chronic exposure to P2-agonists. Secondly, ilel64 is an example
of a rare polymorphism, which may be important since in vitro
functional studies have demonstrated that the ilel64 receptor has an
approximately 3-fold decreased affinity for P2-agonists.
P2AR polymorphisms can have a pharmacogenetic effect or act as
disease-modifiers. For instance, P2-adrenergic receptor associations have
been found with nocturnal asthma, bronchial hyper-responsiveness,
increased IgE levels, and asthma severity.
5-Lipoxygenase
The core promotor of the 5-lipoxygenase (ALOX5) gene is localised on
chromosome 10qll.2 27 . The level of ALOX5 activity determines to a.
certain extent the level of bronchoconstrictor leukotrienes in the
airways. This gene is the first to provide evidence that pharmacogenetics
can be applied to asthma. One study showed that The ALOX5 locus
contains 3-6 tandem repeats of the Spl-binding motif GGGCGG.
Asthma patients without the wild type (5 tandem repeats) allele do not
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improve or improve to a smaller extent when treated with a drug which
mechanism of action is the inhibition of AL0X5. Thus treatment
response is to a certain extent determined by genetic variants in the 5lipoxygenase gene.
Implications of results of the available studies and future
directions
Atopy has different disease expressions such as asthma, rhinitis and
eczema which all have been shown to contain a significant genetic
contribution. The available literature shows that linkage of the different
measures of atopy are found on distinct chromosomes. Whereas
replicated linkage exists on chromosome 11 for a broadly defined atopy
phenotype, for total serum IgE and skin prick tests, this is not the case
for specific IgE. Linkage of total serum IgE has been replicated for
chromosomes 4-7, yet no linkage whatsoever or no replication has been
found for specific IgE or skin prick test. Thus, either different genes are
to be involved in the regulation of total IgE and allergen specific
responses or one (or more) gene may interact with the environment or
both. Furthermore, distinct combinations of genes may result in
different disease expressions such as asthma, rhinitis and atopic
dermatitis. For instance it is hypothetical, but not totally improbable,
that genes for atopy and airway hyper-responsiveness are to be present
in case of the clinical expression of asthma, yet the latter genes are not
mandatory for eczema (or even rhinitis).
Several candidate genes have been identified, yet more atopic genes are
to be discovered in the future. These genes will give us more insight of
the pathophysiological mechanisms of atopic disease. It can be expected
that this will lead to new and more effective therapeutic interventions,
new methods for early diagnosis, development for disease prevention in
susceptible individuals and more insight in the pharmacogenetics.
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1
2
3
4
5
6
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