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Genetics is the study of inheritance, its patterns and consequences. Over the past 20 years, the study of genetic influences on common human diseases has expanded to include the study of well-defined phenotypes with analysis of DNA-based markers distributed along the entire genome to determine which specific genes determine a given biological characteristic. This process, known as linkage analysis followed by positional cloning, has been applied successfully to identify the genes causing a variety of disorders that follow a classical Mendelian pattern of inheritance, such as cystic fibrosis (1). More recently, genetic loci associated with complex disorders, which do not follow such clear Mendelian patterns, are beginning to be identified (5). The promise of genetics as it relates to asthma is to identify the genes that influence expression of the phenotypic characteristics recognized as asthma; simply stated, to identify asthma genes.
The 1997 Transatlantic Airway Conference addressed the broad topic of "The Genetics of Asthma." This Summary introduces the topics discussed at the conference; full descriptions of each presentation make up the rest of this supplement. However, since the language of genetics is quite specialized and may be unfamiliar to pulmonary physicians and scientists, we provide, in Table 1, a number of very brief definitions to help the reader understand the information in this supplement.
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There are four general approaches that have been used to provide insight into the genetic influences on various complex human disorders. These approaches include animal models, family aggregation studies, linkage analysis, and association studies.
Animal Models
Animal models use animals that either manifest the disease phenotype naturally or through genetic manipulation. The animals are chosen for their different capacities to manifest specific aspects of a given phenotype, such as airway responsiveness (8). The required information is derived by examining the phenotypic expression of the relevant trait in animals bred from crosses between two progenitor strains that differ substantially in expression of the trait. This is most conveniently done by examining matings between different inbred strains of animals; since extensive genetic information is currently available for mice, various murine strains are usually the experimental animals. At the conference, and in this supplement, there are five papers related to animal models. In the first paper, Dr. Beier and colleagues (9) describe how animal models can be used to dissect complex traits. Dr. Beier points out how animal models can be used to identify genes, but also points out the significant difficulties that may arise in these apparently simple genetic systems. In particular, the issue of epistasis, which occurs when the effects of a trait-inducing gene are modified by another gene, is addressed. The important message here is that even in "simple" animal models, unraveling the genetic basis for a given trait can be difficult.
The reports by Pauwels (10) and Vargaftig (11) do not use genetic approaches; instead, they describe the phenotypic changes that can be induced by environmental manipulation in animal models. These changes thereby provide important calibration points for examining the genetic variation in the response observed among various mouse strains. Furthermore, these studies provide an overview of how these particular animal models relate to human disease.
In the papers by De Sanctis and Drazen (12) and Wills-Karp and Ewart (13), genetic approaches to two different aspects of the asthma phenotype are examined. DeSanctis and
Drazen examine the variation in airway responsiveness to infused methacholine among various inbred mouse strains. They
demonstrate that genetic analysis can be used to help localize
regions of the mouse genome linked to the phenotypic trait of
airway hyperresponsiveness. Wills-Karp and Ewart examine
how induced airway hyperresponsiveness
i.e., hyperresponsiveness induced by exposure to specific antigenscan differ
among various mouse strains and how asthmatic airway and T-cell biology can be integrated and tested in an animal
model. In none of these animal models has a "gene" been
identified; rather, regions of the mouse genome that are linked
to various asthma-related traits have been identified. Finding
the genes at each locus is the next big step.
Human Asthma
The remainder of the conference dealt with the genetics of human asthma. As our knowledge about genetic studies has expanded, our appreciation of the problems, pitfalls, and potential of genetic analysis for finding causative and modifying genes has increased substantially. The paper by Schork (14) outlines some of these problems as well as potential solutions. Indeed, many of the studies in this supplement use approaches outlined by Schork, including family aggregation, association, and linkage studies, to help find genes related to asthma.
Genome-Wide Searches for Linkage
The articles by Bleecker and colleagues (15) and by Cookson and Moffat (16) each report the results of linkage analyses: Bleecker and co-workers in U.S. and Dutch populations, and Cookson and co-workers in English and Australian populations. Each of these studies outlines how a group of families was identified, how the asthma phenotype was defined, and how materials for genetic analysis were obtained. By analyzing relationships between the asthmatic phenotype and the genotype, both groups of investigators have identified potential loci on chromosomes 5, 6, 12, and 14; there are additional loci identified by one group, but not the other. However, the identification of a number of the same linked loci by both groups is encouraging and indicates the degree to which progress is being made. The paper by Kauffman and co-workers (17) describes strategies being used in France to find families and to search for asthma genes in this population. Slutsky and co-workers (18) describe an approach that has been successfully used in other disorders: the study of isolated populations with relatively high disease frequency. Slutsky and co-workers describe the segregation of asthma phenotypes on an isolated island, Tristan da Cunha; in a sense, this is a study of asthma aggregation in a large family. They demonstrate a high asthma frequency and outline a strategy for studying these families in a search for asthma genes.
Association Studies
Association studies determine the relationship between the presence of certain disease characteristics and the presence of specific marker genotypes. This strategy has been used successfully for the phenotypes of asthma (physician-diagnosed) and IgE levels by examining loci on chromosomes 5 and 12, as described by Marsh (19). His studies indicate a fairly strong association between measures of atopy, such as IgE or skin tests, and specific alleles of these loci. Martinez (20) reports associations among various specific aspects of the asthma phenotype, as they relate to populations in the southwestern United States, and certain loci known to modify the asthma response. Thomas and colleagues (21) provide data showing an association between specific alleles on chromosomes 5, 11, and 12 and various aspects of the asthma phenotype. Mapp and colleagues (22) use a different kind of approach, in which associations between specific alleles in the HLA locus and various aspects of the occupational asthma phenotype are related.
The methods outline by Rosenwasser and Borish (23) and by Liggett (24) represent a different approach to association studies. These investigators have examined specific known asthma candidate genes for changes in their sequence that could modify their biological function. Thus, they use the presence of these naturally occurring mutations in well-controlled in vitro experiments designed to determine if these natural mutations modify gene function. Once a mutation with a functional effect is identified, they attempt to relate the gene mutations to various aspects of the asthma phenotype, with the knowledge that the specific mutation may have direct functional significance.
Conclusions
Review of the data presented at the meeting led to the following general conclusions. Clearly, there are strongly inherited components of the asthma phenotype; the specific genes responsible for these inherited components have yet to be identified. Certain regions of the murine and human genome have been identified as likely to contain the specific genes responsible for transmission of these asthma-related traits. As molecular biology and statistical genetics methods improve, it is likely that the specific genes at such loci will be identified. In this regard it is important to note that all data currently suggest, in both animal and human models, that asthma is most likely to be transmitted by multiple genes. These multiple genetic influences likely include different genes in different individuals leading to the same phenotype (locus heterogeneity) and multiple genes acting in the same individual (oligogenic or polygenic inheritance) to express the asthma phenotype. Furthermore, there is strong reason to believe that genes will be identified that can modify asthma severity or response to standard asthma treatments, even though they may not cause asthma per se. The identification of the primary asthma genes, asthma severity-modifying genes, and asthma treatment-modifying genes will provide clinicians and physicians with important tools in the diagnosis and management of asthma. The data presented at this conference clearly demonstrate that genetic analysis of asthma is feasible and will modify our thinking and practice in the years to come.
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Footnotes |
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Correspondence and requests for reprints should be addressed to Jeffrey M. Drazen, M.D., Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115.
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TOP
Article
REFERENCES
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1.
Collins, F. S..
1992.
Cystic fibrosis: molecular biology and therapeutic implications.
Science
256:
774-779
2.
Kerem, B.,
J. M. Rommens,
J. A. Buchanan,
D. Markiewicz,
T. K. Cox,
A. Chakravarti,
M. Buchwald, and
L. C. Tsui.
1989.
Identification of
the cystic fibrosis gene: genetic analysis.
Science
245:
1073-1080
3.
Riordan, J. R.,
J. M. Rommens,
B. Kerem,
N. Alon,
R. Rozmahel,
Z. Grzelczak,
J. Zielenski,
S. Lok,
N. Plavsic,
J. L. Chou,
M. L. Drumm,
M. C. Iannuzzi,
F. S. Collins, and
L.-C. Tsui.
1989.
Identification of the
cystic fibrosis gene: cloning and characterization of complementary DNA [published erratum appears in Science 1989 245(4925):1437].
Science
245:
1066-1073
4.
Rommens, J. M.,
M. C. Iannuzzi,
B. Kerem,
M. L. Drumm,
G. Melmer,
M. Dean,
R. Rozmahel,
J. L. Cole,
D. Kennedy,
N. Hidaka,
M. Zsiga,
M. Buchwald,
J. R. Riordan,
L.-C. Tsui, and
F. S. Collins.
1989.
Identification of the cystic fibrosis gene: chromosome walking and jumping.
Science
245:
1059-1065
5. Rowe, R. E., B. Wapelhorst, G. I. Bell, N. Risch, R. S. Spielman, and P. Concannon. 1995. Linkage and association between insulin-dependent diabetes mellitus (IDDM) susceptibility and markers near the glucokinase gene on chromosome 7. Nat. Genet. 10: 240-242 [Medline].
6. Schwab, S. G., M. Albus, J. Hallmayer, S. Honig, M. Borrmann, D. Lichtermann, R. P. Ebstein, M. Ackenheil, B. Lerer, N. Risch, W. Maier, and D. B. Wilenhauer. 1995. Evaluation of a susceptibility gene for schizophrenia on chromosome 6p by multipoint affected sib-pair linkage analysis. Nat. Genet. 11: 325-327 [Medline].
7. Moises, H. W., L. Yang, H. Kristbjarnarson, C. Wiese, W. Byerley, F. Macciardi, V. Arolt, D. Blackwood, X. Liu, B. Sjogren, H. N. Aschauer, H.-G. Hwu, K. Jang, W. J. Livesley, J. L. Kennedy, T. Zoega, O. Ivarsson, M.-T. Bui, M.-H. Yu, B. Havsteen, D. Commenges, J. Weissenbach, E. Schwinger, I. I. Gottesman, A. J. Pakstis, L. Wetterberg, K. K. Kidd, and T. Helgason. 1995. An international two-stage genome-wide search for schizophrenia susceptibility genes. Nat. Genet. 11: 321-324 [Medline].
8. Levitt, R. C., and W. Mitzner. 1988. Expression of airway hyperreactivity to acetylcholine as a simple autosomal recessive trait in mice. FASEB J. 2: 2605-2608 [Abstract].
9.
Iakoubova, O. A.,
H. Dushkin, and
D. R. Beier.
1997.
Genetic analysis
of a quantitative trait in a mouse model of polycystic kidney disease.
Am. J. Respir. Crit. Care Med.
156:
S72-S77
10.
Pauwels, R. A.,
G. J. Brusselle, and
J. C. Kips.
1997.
Cytokine manipulation in animal models of asthma.
Am. J. Respir. Crit. Care Med.
156:
S78-S81
11.
Vargaftig, B. B..
1997.
Modifications of experimental bronchopulmonary
hyperresponsiveness.
Am. J. Respir. Crit. Care Med.
156:
S97-S102
12.
DeSanctis, G. T., and
J. M. Drazen.
1997.
Genetics of native airway responsiveness in mice.
Am. J. Respir. Crit. Care Med.
156:
S82-S88
13.
Wills-Karp, M., and
S. L. Ewart.
1997.
The genetics of allergen-induced
airway hyperresponsiveness in mice.
Am. J. Respir. Crit. Care Med.
156:
S89-S96
14.
Schork, N. J..
1997.
Genetics of complex disease: approaches, problems,
and solutions.
Am. J. Respir. Crit. Care Med.
156:
S103-S109
15.
Bleecker, E. R.,
D. S. Postma, and
D. A. Meyers.
1997.
Evidence for
multiple genetic susceptibility loci for asthma.
Am. J. Respir. Crit.
Care Med.
156:
S113-S116
16.
Moffatt, M. F., and
W. O. C. M. Cookson.
1997.
Linkage and candidate
gene studies in asthma.
Am. J. Respir. Crit. Care Med.
156:
S110-S112
17.
Kauffmann, F.,
M. Dizier,
I. Pin,
E. Paty,
F. Gormand,
D. Vervloet,
J. Bousquet,
F. Neukirch,
I. Annesi,
M. Oryszczyn,
M. Lathrop,
F. Demenais,
A. Lockhart, and
J. Feingold.
1997.
Epidemiological study of
the genetics and environment of asthma, bronchial hyperresponsiveness, and atopy: phenotype issues.
Am. J. Respir. Crit. Care Med.
156:
S123-S129
18.
Slutsky, A. S.,
N. Zamel, and
the University of Toronto Genetics of
Asthma Research Group.
1997.
Genetics of asthma: The University of
Toronto Program.
Am. J. Respir. Crit. Care Med.
156:
S130-S132
19.
Marsh, D. G..
1997.
Approaches toward the genetic analysis of complex
traits: asthma and atopy.
Am. J. Respir. Crit. Care Med.
156:
S133-S138
20.
Martinez, F. D..
1997.
Complexities of the genetics of asthma.
Am. J. Respir. Crit. Care Med.
156:
S117-S122
21.
Thomas, N. S.,
J. Wilkinson, and
S. T. Holgate.
1997.
The candidate region approach to the genetics of asthma and allergy.
Am. J. Respir.
Crit. Care Med.
156:
S144-S151
22.
Mapp, C. E.,
A. Balboni,
R. Baricordi, and
L. M. Fabbri.
1997.
Human
leukocyte antigen associations in occupational asthma induced by isocyanates.
Am. J. Respir. Crit. Care Med.
156:
S139-S143
23.
Rosenwasser, L. J., and
L. Borish.
1997.
Genetics of atopy and asthma:
the rationale behind promoter-based candidate gene studies (IL-4 and
IL-10).
Am. J. Respir. Crit. Care Med.
156:
S152-S155
24.
Liggett, S. B..
1997.
Polymorphisms of the 
2-adrenergic receptor and
asthma.
Am. J. Respir. Crit. Care Med.
156:
S156-S162
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