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The genetic component of asthma,
The genetic analyses were conducted by the following members of the Genetics teams (listed by alphabetical order): C. Besse-Schmittler, F. Demenais, M.H. Dizier, J. Feingold, M. Guilloud-Bataille, J. Hochez, G. Hyne, M. Lathrop, M. Luilier-Lacombe, F. Meunier, F. Sampogna, V. Parent, N. Thobie. |
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The main objectives of the French cooperative Epidemiologic Study of the Genetics and Environment of Asthma (EGEA) are to identify the genetic and environmental factors involved in asthma, bronchial hyperresponsiveness (BHR) and atopy and to elucidate the gene-environment interactions, while taking into account the heterogeneity of these traits. To achieve these goals, this study was designed to include a case-control study and a family study (1). Patients with asthma (probands), aged 7 to 65, were ascertained from chest clinics of six hospitals located in five French cities (Paris, Lyon, Grenoble, Marseille, Montpellier). These probands, their first-degree relatives and spouses were examined with a standard protocol, based on international standardized tools. Control subjects (population and hospital-based), matched with the probands for sex, age-class, month of examination, and place of living, were evaluated with the same protocol. The study population includes 348 asthmatic probands (213 adults and 135 children) and their family members and 416 controls, making a total of 1,854 subjects. To get a sample of families with at least two asthmatic siblings large enough for linkage studies of asthma, an additional set of 40 families was collected to make a total of 114 families fulfilling this selection criterion (74 families being part of the original family sample). All subjects answered a detailed questionnaire on respiratory and allergic symptoms, medical history including childhood infections, and environmental factors during childhood and adult life (mainly, exposure to various types of allergens, smoking habits, type of heating and cooking fuel, occupational exposures). The following tests were performed : methacholine bronchial challenge for sujects with FEV1 > 80% predicted and bronchodilatator test for others, skin prick tests to 11 allergens, total immunoglobulin E (IgE) levels, multiRAST Phadiatop, leukocyte differential count. A repository of DNA samples for all subjects was established.
It is now well known that genetic factors predispose to asthma and atopy but the exact nature of this genetic component is still imprecise. The genetics determinants of this complex disease are likely to be multiple and to play a role at different stages of the pathological process: some genes may control basal IgE production, others may be involved in the allergic response (skin tests, specific IgE) and/or bronchial responsiveness, and finally there may be genes causing asthma. These genes may act specifically on a given phenotype or may have a pleiotropic effect on several phenotypes. To identify the genetic determinants of asthma and intermediate phenotypes, different approaches can be used which include the study of the familial transmission of these phenotypes (segregation analyses) and approaches taking into account the information provided by genetic markers (linkage and association studies). Most segregation analyses have focused on total IgE levels and have led to contradictory results with some studies showing evidence for a major gene effect while others suggesting a polygenic model and/or genetic heterogeneity (see 2 for a review). No clear major gene effect has yet been demonstrated to account for the familial aggregation of BHR or asthma (3, 4). Linkages and/or associations of genetic markers with atopy, BHR and/or asthma were first reported in candidate regions and included the 6p region with the HLA complex and the Tumor Necrosis Factor a gene (TNF-a ), the 11q region with the gene coding for the b sub-unit of the high-affinity IgE receptor (FCe R1), the T-cell receptor a gene on chromosome 14, the 5q region bearing numerous candidate genes among which the interleukin (IL-3,4, 5, 9, 13) cluster and the b2- adrenergic receptor gene, the 12q region containing the genes for interferon-g (IFNg ), a mast cell growth factor (MGF) and an insulin-like growth factor (IGF1) (5, 6). Moreover, two recent genome-wide searches have indicated new regions of linkage with quantitative traits underlying asthma in Australian and British families (7) and with asthma in different ethnic groups from the US (8). All these studies clearly show the complexity of the genetic mechanisms involved in asthma and associated phenotypes with the additional difficulty encountered to replicate results in separate populations.
The search for genes predisposing to asthma, BHR and atopy in the EGEA study has first begun by a genome-wide search in the sample of 114 nuclear familes with at least two asthmatic children. A two-stage strategy was used with an initial genome screen in a first set of 49 families (46 used for linkage analyses with no parent-child incompatibility) and replication of potential linkages in a second set of 65 families (61 used for linkage analyses). A total of 227 individuals belonging to the first set of families were genotyped for 263 microsatellites markers located at intervals of 15-20 cM over the whole genome. Linkage analyses were carried out by sib-pair model-free methods, as implemented in the computer programs SIBPAL, ANALYZE and MAPMAKER/SIBS. The following phenotypes were analyzed: asthma (52 sib-pairs), bronchial hyperresponsiveness (BHR, 29 pairs), skin test response (positivity defined by a difference of the diameter of the weal at one allergen compared to the negative control of ³ 3 mm; 49 pairs), Immunoglobulin E levels (IgE, 70 pairs), atopy (IgE levels > 100 UI/ml and/or positive skin test; 59 pairs), eosinophil counts (68 pairs). These analyses showed 15 regions of potential linkages with at least one of the phenotypes studied, five of these regions being significant at the 1% level and ten others leading to a p-value ranging between 1% and 5%. A few linkage regions, especially on chromosomes 6, 7, 11, 12 and 13, were previously reported in the literature and new ones were also detected. Confirmation of these results is currently being investigated in the second set of families. Moreover, candidate regions will be explored specifically.
Concurrently, segregation analyses of intermediate phenotypes associated with asthma are carried out in the total EGEA family sample (335 families with at least three blood-relatives examined). These analyses are conducted with the regressive models which allow to search for major gene effects in presence of other unspecified sources of familial covariation (genetic and/or environmental) as well as measured risk factors (e.g. age, sex, smoking habits) which may interact with the major gene. These analyses may help in refining the phenotypes by indicating the associated risk factors to be taken into account in further genetic analyses and lead to the detection of major gene effects which can then be assigned to chromosomal regions by linkage with greater power. Preliminary results indicate the segregation of a dominant gene for total IgE in these families. Univariate as well as multivariate analyses of the different asthma-associated phenotypes are pursued. Combined segregation-linkage analyses will then be applied to better dissect the genetic pathways involved and to elucidate gene-environment interactions in the pathogenesis of asthma and atopy. Future work will also involve the search for polymorphisms within linked regions that are associated with asthma, BHR and/or atopy to be further explored by functional studies.
Supported by a convention INSERM-MSD.
References
Ref (1): Epidemiological study of the genetics and environmentof asthma, bronchial responsiveness and atopy. Phenotype issues. (partial abstract from http://www.healthy.net/library/search/medline.htm )
None available
... for the complete abstract, please enquire http://www.healthy.net/library/search/medline.htm
Ref (2): Detection of a recessive major gene for high IgE levels acting independently of specific response to allergens.(partial abstract from http://www.healthy.net/library/search/medline.htm )
Author Dizier MH; Hill M; James A; Faux J; Ryan G; le Souef P;
Lathrop M; Musk AW; Demenais F; Cookson W
Address INSERM U155, Paris, France.
Source Genet Epidemiol, 12(1):93-105 1995
Abstract : The
genetic control of the total IgE, the immunoglobulins E involved
in allergy, remains still unclear. Although high IgE levels were
found to be determined by a recessive major gene in several
studies, other modes of inheritance were also reported. Moreover,
at least two different genetic mechanisms controlling the IgE
regulation have been suggested: one involved in the specific IgE
response and the other one in the nonspecific response. To better
understand the genetic mechanisms controlling IgE variation, we
performed segregation analysis of IgE levels by ignoring or
taking into account the specific response to allergens (SRA).
Analyses were conducted using the class D regressive model, in a
sample of 234 Australian nuclear families randomly selected
during the winter months, when IgE levels are the lowest (basal).
SRA, when included as a covariate in the model, was defined by
one of the three following criteria: (1) raised specific IgE
level for one or more allergens, (2) positive skin test for one
or more allergens, and (3) at least one of the (1) or (2)
criteria. When the presence of SRA is ignored, the familial
transmission of total IgE level is compatible with the
segregation of a recessive major gene and residual familial
correlations.....
... for the complete abstract, please enquire http://www.healthy.net/library/search/medline.htm
Ref (3): Segregation analysis of physician-diagnosed asthma in Hispanic and non-Hispanic white families. (partial abstract from http://www.healthy.net/library/search/medline.htm )
Title Segregation analysis of physician-diagnosed asthma in
Hispanic and non-Hispanic white families. A recessive component?
Author Holberg CJ; Elston RC; Halonen M; Wright AL; Taussig LM;
Morgan WJ; Martinez FD
Address Respiratory Sciences Center, University of Arizona Health
Sciences Center, Tucson 85724, USA.
Source Am J Respir Crit Care Med, 154(1):144-50 1996 Jul
Abstract : The
inheritance of asthma, evident from its high family concordance,
is not well understood. To investigate whether asthma may be
inherited through a major gene with two alleles, segregation
analyses were conducted in 3,369 individuals from 906 nuclear
families enrolled, without selection, in a longitudinal study of
respiratory health in Tucson, Arizona. Physician-diagnosed asthma
and its age of onset were ascertained for each family member when
children were at a mean age of 7 yr. Age of asthma diagnosis was
allowed for in analyses, and the impact of the covariate total
serum IgE level on age of onset was examined. Segregation
analyses were conducted with and without residual family effects,
with and without the covariate IgE. The hypothesis of a single
two-allele locus for asthma was rejected. However, depending on
the method of assessment of the residual familial effects, either
a polygenic/multifactorial mode of inheritance alone, or an
oligogenic model with some evidence of a recessive component
present in the population with the high frequency of 0.67, were
compatible with the data....
... for the complete abstract, please enquire http://www.healthy.net/library/search/medline.htm
Ref (4): Regressive logistic modeling of familial aggregation for asthma in 7,934 population-based nuclear families. (partial abstract from http://www.healthy.net/library/search/medline.htm )
Author Jenkins MA; Hopper JL; Giles GG
Address Department of Public Health and Community Medicine,
University of Melbourne, Victoria, Australia.
Source Genet Epidemiol, 14(3):317-32 1997
Abstract : The aim
of this population-based study was to determine whether asthma
aggregates in families, and if so, whether aggregation was
consistent with environmental and/or genetic etiologies. Data
were from 7,394 nuclear families (41,506 individuals) from the
1968 Tasmanian Asthma Survey, in which all Tasmanian
schoolchildren born in 1961 were surveyed by respiratory
questionnaire completed by their parents. Similar data were
obtained for parents and siblings of probands. For a child,
having ever had asthma was predicted by a parent or sibling
having ever had asthma; odds ratio (OR) = 3.13 (95% confidence
interval [CI] 2.82-3.48) for mother, 2.99 (2.69-3.32) for father,
and 3.47 (3.23-3.72) for a sibling. Regressive logistic modeling
showed that, in addition to parent-offspring effects, the data
were consistent with the existence of an unmeasured factor shared
by siblings, evident in 15% (SE 2%) of families and associated
with a conditional OR of 9.68 (8.27-11.32). Familial aggregation
was best described by a general oligogenic model with
non-Mendelian transmission probabilities. Of the Mendelian
models, a codominant model with an allele frequency of 16% (SE
0.3%) was preferred. Under a dominant model there was evidence
for additional parent-offspring and sibling effects of similar
magnitude. It is unlikely that there is one major loci
influencing asthma susceptibility; the overall effects of asthma
genes in the population are more likely to be inherited
codominantly, at least for the majority of loci of major
etiological importance....
... for the complete abstract, please enquire http://www.healthy.net/library/search/medline.htm
Ref (5): The genetics of asthma in 'Genetic Approaches to Noncommunicable Diseases' (partial abstract from http://www.healthy.net/library/search/medline.htm )
None available
... for the complete abstract, please enquire http://www.healthy.net/library/search/medline.htm
Ref (6): Asthma genetics: waiting to exhale. (partial abstract from http://www.healthy.net/library/search/medline.htm )
None available
... for the complete abstract, please enquire http://www.healthy.net/library/search/medline.htm
Ref (7): A genome wide search for quantitative trait loci underlying asthma. (partial abstract from http://www.healthy.net/library/search/medline.htm )
Author : Daniels SE; Bhattacharrya S; James A; Leaves NI;
Young A; Hill MR; Faux JA; Ryan GF; le Söuef PN; Lathrop GM;
Musk AW; Cookson WO
Address Wellcome Trust Centre for Human Genetic Disease,
University of Oxford, UK.
Source : Nature, 383(6597):247-50 1996 Sep 19
Abstract
Asthma now affects one child in seven in the United Kingdom. Most
cases (95%) of childhood asthma are associated with atopy, the
immunoglobulin E (IgE)-mediated familial syndrome of allergic
asthma, eczema and rhinitis. Segregation analysis has
consistently suggested the presence of major genes influencing
atopy and IgE levels, with the expectation that these genes may
be identified by positional cloning or the examination of
candidate genes. Here we report the results of a genome-wide
search for linkage to one qualitative and four quantitative
traits associated with allergic (atopic) asthma. We have
identified six potential linkages (P<0.001), five of which are
to quantitative traits. Monte Carlo simulations show that 1.6
false-positive linkages at this level of significance would be
expected from the data. One linkage, to chromosome 11q13, has
been established previously. Three of the new loci show evidence
of linkage to a second panel of families, in which maternal
effects and pleiotropy of linked phenotypes are seen....
... for the complete abstract, please enquire http://www.healthy.net/library/search/medline.htm
Ref (8): A genome-wide search for asthma susceptibility genes loci in ethnically diverse populations. (partial abstract from http://www.healthy.net/library/search/medline.htm )
Author : The Collaborative Study on the Genetics of Asthma
(CSGA).
Source : Nat Genet, 15(4):389-92 1997 Apr
Abstract : Asthma
is an inflammatory airways disease associated with intermittent
respiratory symptoms, bronchial hyper-responsiveness (BHR) and
reversible airflow obstruction and is phenotypically
heterogeneous. Patterns of clustering and segregation analyses in
asthma families have suggested a genetic component to asthma.
Previous studies reported linkage of BHR and atopy to chromosomes
5q (refs 7-9), 6p (refs 10-12), 11q (refs 13-15), 14q (ref. 16),
and 12q (ref. 17) using candidate gene approaches. However, the
relative roles of these genes in the pathogenesis of asthma or
atopy are difficult to assess outside of the context of a
genome-wide search. One genome-wide search in atopic sib pairs
has been reported, however, only 12% of their subjects had
asthma. We conducted a genome-wide search in 140 families with
> or = 2 asthmatic sibs, from three racial groups and report
evidence for linkage to six novel regions: 5p15 (P = 0.0008) and
17p11.1-q11.2 (P = 0.0015) in African Americans; 11p15 (P =
0.0089) and 19q13 (P = 0.0013) in Caucasians; 2q33 (P = 0.0005)
and 21q21 (P = 0.0040) in Hispanics...
... for the complete abstract, please enquire http://www.healthy.net/library/search/medline.htm
. 
Enfumosa Congrès Conçue et réalisée par: Michel Godard (at) Top
Date de création: 5 Décembre 1997-Dernière mise à jour: 28/07/99
