The Genetics of Asthma
The Important Questions

ANDREW J. SANDFORD and PETER D. PARÉ

University of British Columbia Pulmonary Research Laboratory, St. Paul's Hospital, Vancouver, British Columbia, Canada

	INTRODUCTION

TOP INTRODUCTION WHAT IS KNOWN? WHAT IS PARTLY KNOWN? WHAT IMPORTANT QUESTIONS REMAIN... REFERENCES

Although it has been known for a long time that asthma and the other atopic disorders (rhinitis and allergic dermatitis) are familial, the last two decades have seen an exponential increase in research designed to prove a genetic contribution to their pathogenesis and to identify candidate loci and genes (Figure 1). Asthma and allergy are complex genetic disorders that do not conform to a simple Mendelian pattern of inheritance. Like atherosclerosis, hypertension, diabetes, and the major psychoses, these complex genetic disorders are common and contribute the major burden of illness in western populations.

View larger version (34K): [in this window] [in a new window]   Figure 1.   The number of papers dealing with the genetics of asthma and allergy over the past 3.5 decades.

Until recently the idea of localizing and identifying the genes that contribute to the familial concordance of asthma and allergy was purely theoretical. However, the revolution in molecular genetics has now made it likely that specific DNA sequence variants will be identified that constitute the genetic risk factors for the development of asthma and allergy. With the explosion in interest and capacity to examine the genetic components of asthma and allergy, it is important to reflect on what we know now and what are the important questions to address in the coming decades.

	WHAT IS KNOWN?

TOP INTRODUCTION WHAT IS KNOWN? WHAT IS PARTLY KNOWN? WHAT IMPORTANT QUESTIONS REMAIN... REFERENCES

The Familial Association of Asthma and Allergy Has a Genetic Component

Familial concordance of a disorder can be due to shared environment as well as shared genes. Twin studies can help to determine the relative contribution of shared environment and shared genes to a phenotype. In twin studies the concordance of the phenotype in monozygotic and dizygotic twins is compared and when possible, concordance is also compared in twins who were reared together or apart. Another experimental design that can identify a genetic component to the trait of interest is segregation analysis. In segregation analysis the transmission of a trait is examined in families to see if it conforms to a genetic or environmental pattern. There are now numerous studies of the pattern of inheritance of asthma (1- 8), rhinitis (3, 7), allergic dermatitis (3, 10), and serum IgE levels (11, 12) and these have clearly shown that the familial concordance is at least partly due to shared genes. Many authors have concluded that the genetic contribution to these diseases is more important than environmental influences.

Asthma and Allergy Show Polygenic Inheritance and Genetic Heterogeneity

Despite the evidence that asthma and allergy are heritable, segregation analyses of these phenotypes have not identified a consistent Mendelian pattern, such as dominant, recessive, or sex linked (13). A non-Mendelian pattern of inheritance is characteristic of complex genetic disorders. Such a pattern is not an indication of non-Mendelian segregation of susceptibility genes, but rather indicates that multiple independent segregating genes are required for phenotypic expression (polygenic inheritance). Another characteristic of complex genetic disorders such as asthma and allergy is that there is genetic heterogeneity, i.e., different combinations of gene variants contribute to the phenotype in different families.

Inheritance of Atopic Disorder Is End-organ Specific

In addition to the familial concordance of allergic disorders, there is evidence to suggest that the specific end-organ manifestation, i.e., the airways, the nose, or the skin for asthma, allergic rhinitis, and atopic dermatitis, respectively, is in part familial (7, 9). This suggests that although inheritance of an exaggerated IgE response may underlie all these conditions, separate genes predispose to specific clinical manifestations of the allergic phenotype.

Specific Regions of the Human Genome Harbor Susceptibility Genes for Asthma and Allergy

Since 1989, when Cookson, Hopkin, and coworkers first reported that they had identified a locus containing an atopy gene on chromosome 11q (18), there have been important advances in incriminating specific loci in the human genome that harbor genes that contribute to asthma and allergy. Initially, the linked loci were identified by classic linkage analysis in multigeneration families. More recently the affected sib-pair method (which detects excessive sharing of parental alleles) has been used for gene localization. Other investigators have examined specific candidates by association approaches such as case-control studies.

These methods have identified several loci that may be involved in the pathogenesis of allergy and asthma (see Table 1). However, in common with other complex diseases, independent investigators were not able to reproduce many of these results. There are several explanations for this including genetic heterogeneity, differences in phenotype definition, and lack of a consensus over the appropriate significance levels to use in these studies. To date, six loci have been implicated by independent investigators. On chromosome 6p21, there is an important region that contains the genes for the major histocompatibility (MHC) molecules as well as the tumor necrosis factor  (TNF-) and lymphotoxin genes. This area of chromosome 6 has been repeatedly identified in linkage and association studies. Most of the data concerns the association of specific MHC genotypes with sensitization to specific aeroallergens (19). On chromosome 5q there are many candidate genes for asthma and allergy such as the interleukin 4 and ₂-adrenergic receptor genes. Many studies have shown linkage and association to this region (23, 27). Chromosome 11q13 has been linked to a variety of different phenotypes and the  chain of the high-affinity IgE receptor has been proposed as a candidate for this linkage (31, 32, 38, 40). The region containing the interleukin 4 receptor  chain (16p12) has also been implicated in IgE responsiveness (49). Chromosomes 13q (23, 28, 37, 43) and 12q (28, 37, 52, 53) have also been linked to asthma and related phenotypes but the linked regions contain no known candidates.

Linkage has been replicated in all these regions and for most of them multiple candidate genes have been suggested as the reason for the linkage. However, no DNA sequence variations that alter protein expression or function have been definitively incriminated as "asthma mutations."

	WHAT IS PARTLY KNOWN?

TOP INTRODUCTION WHAT IS KNOWN? WHAT IS PARTLY KNOWN? WHAT IMPORTANT QUESTIONS REMAIN... REFERENCES

The process of gene identification in complex genetic disorders involves initial linkage studies that allow identification of broad regions of the human genome that are linked to a phenotype. This is followed by finer mapping of the linked loci to smaller regions and the development of a physical map of the region in which the order and spacing of genes are described.

This step is followed by the arduous task of identifying DNA sequence variation in the genes within the linked loci. Ultimately, proof of a disease-causing mutation rests on the strength of association of specific gene polymorphisms and disease expression. In asthma genetics research we are at a stage at which a number of replicated linked loci have been identified and fine mapping, gene identification, and polymorphism localization are in progress in a number of laboratories. Of the multiple candidate genes located in these regions a few specific polymorphisms have been associated with asthma and allergy phenotypes.

The ₂-Adrenergic Receptor Gene

The ₂-adrenergic receptor gene (ADR) is on chromosome 5q within the region that had been linked to asthma and allergy phenotypes. A number of variants in the ADR gene have been identified that alter receptor function. The most prevalent of these are the Arg-16  Gly and the Gln-27  Glu polymorphisms, which influence the downregulation of the receptor in response to agonist. These polymorphisms have been associated with several phenotypes including measures of asthma severity, bronchial responsiveness, and response to bronchodilators (54).

The Gly-16/Gln-27 haplotype was associated with bronchial hyperresponsiveness (BHR) (59) and asthma severity (57). The Gln-27 allele was also associated with high total serum IgE (60), BHR (61), and childhood asthma (62). The Gly-16 allele has been associated with a deficient bronchodilator response (58) and with a more severe asthma phenotype (55, 56). Paradoxically, neither the Gly-16 nor the Gln-27 alleles was more prevalent in patients with asthma who had died of their disease (57). To the extent that death is a marker of disease severity, these results suggest that variation in ADR function is not an important determinant of life-threatening asthma.

The IL-4 Gene

The interleukin 4 (IL-4) gene is also located within the 5q region and there is convincing biologic evidence that IL-4 is important in contributing to the elevated blood level of IgE that is characteristic of asthma and allergy. A polymorphism (IL-4 C589T) has been identified in a region of the gene that binds transcription factors and influences gene expression (65). The polymorphism may be associated with increased gene expression. A number of association studies have shown an increased prevalence of this polymorphism in individuals who have asthma or allergy (30, 65).

The CD14 Gene

Another candidate in the 5q region is the CD14 gene. CD14 is the major receptor that mediates the cellular response to endotoxin. A prevalent polymorphism has been identified in the CD14 gene and it has been shown to be associated with increased levels of IgE (69). It has been suggested that the link between CD14 and IgE levels is via modulation of the helper T-cell type 1/helper T-cell type 2 (Th1/Th2) phenotype. Binding of the CD14 receptor by endotoxin during infections in infancy may stimulate expression of Th1 cytokines steering the immune system away from the Th2 predominance that exists in utero and during the immediate neonatal period. If the CD14 polymorphism attenuates the strength of this immune modulation it could encourage persistence of a Th2 phenotype, especially in societies that have a low prevalence of bacterial infection (e.g., small nuclear families in affluent Western societies).

The  Chain of the High-Affinity IgE Receptor (FcRI) Gene

A candidate from the chromosome 11q13 region is the FcRI gene. Mutations in this gene could lead to increased signal transduction after allergen binds to IgE, and consequently to increased secretion of IL-4. One such mutation (Leu-181) was associated with atopy (70) and asthma (71, 72) in some populations but has not been detected in other populations. Another mutation in the FcRI gene causes an amino acid substitution (Glu237Gly) in the cytoplasmic tail of the protein. This mutation was associated with positive skin test response (73) and with childhood asthma (74). BHR but not asthma has been associated with a noncoding polymorphism in the FcRI gene (75).

The IL-4 Receptor  Gene

The IL-4 receptor  (IL-4R) gene is another potentially important candidate gene that is located in a linked region of chromosome 16q. One variant of the IL-4R gene (Gln576Arg) has been associated with increased signal transduction and high IgE levels, including the hyper-IgE syndrome (50). Another variant (Ile50Val) was associated with atopy and asthma in a Japanese population (51). The Ile-50 allele was associated with increased in vitro cell growth and IgE gene expression in B cell lines in response to IL-4. This gene is rich in polymorphisms and the difficulty will be in identifying the true function-altering polymorphism rather than sequence variants that are simply in linkage disequilibrium with the function-altering polymorphism.

The TNF- Gene

TNF- is a powerful proinflammatory cytokine. The TNF- gene is located on chromosome 6p within the MHC complex. An A G transition at position 308 in the promoter of the TNF- gene (TNF A308G) has been shown to be associated with increased TNF- secretion in vitro (76). The 308G allele has been associated with asthma in two studies (77, 78). However, the allele associated with asthma was not the same in both studies.

The ₁-Antitrypsin Gene

There are a number of studies that show that the ₁-antitrypsin gene variants that cause heterozygous deficiency states are associated with asthma (79). There is no evidence of linkage to the chromosomal region (14q32) containing the ₁-antitrypsin gene. However, there is biologic plausibility for deficient protease inhibitor activity contributing to asthma severity.

	WHAT IMPORTANT QUESTIONS REMAIN TO BE ANSWERED?

TOP INTRODUCTION WHAT IS KNOWN? WHAT IS PARTLY KNOWN? WHAT IMPORTANT QUESTIONS REMAIN... REFERENCES

There are several epidemiological issues that remain to be answered. For example, are there separate genetic contributions for increased IgE and BHR? Although there are some data to suggest that BHR can be inherited independently of an exaggerated IgE response, most of the evidence suggests that BHR is an acquired phenomenon caused by the structural and functional changes in the airway wall. Segregation analysis of BHR independent of atopy may help to answer this question. However, only when the function of asthma susceptibility genes is known will it be possible to determine whether they affect only IgE levels or also influence some component of bronchial responsiveness. In addition, is there a genetic component to so-called intrinsic asthma or is intrinsic asthma simply late- onset allergic asthma or recurrence of childhood asthma?

There are now four genome screens published for asthma and allergy phenotypes (23, 28, 37, 43). An important question that remains to be answered concerns which linkages are due to the presence of susceptibility genes and which are spurious. Replication of linkages can help to answer this question but replication remains a difficult task in complex diseases.

The next question concerns which genes are responsible for the linkages. In some cases candidate genes will be identified on the basis of their function. Although many investigators are focusing their efforts on known genes within the linked regions, it is entirely possible that many novel genes are harbored within these regions and variations in these genes could contribute to, as yet unrecognized, pathways in the pathogenesis of asthma and allergy. An important question, then, is the following: can we identify novel genes for asthma and allergies using the current methodologies? If a linked region contains no obvious candidates it will be extremely difficult to identify the causal gene. To the best of our knowledge no novel gene for a complex disease has ever been identified. Despite the difficulty, if novel genes can be identified and characterized it may lead to important new insights into the pathogenesis of asthma and allergy.

Once susceptibility genes are identified the next step is to determine the causal polymorphisms. This is often difficult because of the high frequency of polymorphisms in the human genome and because of linkage disequilibrium between their alleles. The identification of disease-causing polymorphisms is often impossible by genetic analysis alone and relies on proving that the polymorphism affects the function of a gene in a biologically plausible way.

Once disease-causing polymorphisms are identified it will be important to investigate their predictive value. Can screening tests be developed that would predict the likelihood of individuals developing atopy or asthma with a greater accuracy than presently can be achieved? Can the precision of prediction based on genetic screening improve on a good family history?

If at-risk individuals can be identified by genetic screening can they be targeted for preventive or therapeutic procedures that will ultimately influence disease prevalence, severity, or natural history? There have been a few genes that have already been investigated in the context of clinical management, e.g., the ₂-adrenergic receptor and 5-lipoxygenase (5-LO) genes. Although certain ₂-adrenergic receptor variants influence bronchodilator responsiveness and certain 5-lipoxygenase variants are associated with a variable response to 5-LO inhibitors in population studies, the power of their predictive value is probably not great enough to warrant genotypic tailoring of the pharmacotherapy of individuals with asthma.

Another important question concerns whether the enormous expense being committed by major pharmaceutical companies to finding asthma genes will lead to diagnostic or therapeutic innovation. A number of major pharmaceutical companies have taken the risk, and potentially they will be able to elucidate the function of novel genes in linked regions, identify whole new pathways of disease production, and develop specific effective inhibitory agents that will prevent or modify disease expression. However, it is unclear whether their enormous investment in gene discovery will ever be repaid at the level of stock dividends or patient benefit.

	Footnotes

Correspondence and requests for reprints should be addressed to Peter D. Paré, M.D., UBC Pulmonary Research Laboratory, St. Paul's Hospital, 1081 Burrard Street, Vancouver, BC, V6Z 1Y6 Canada.

	References

TOP INTRODUCTION WHAT IS KNOWN? WHAT IS PARTLY KNOWN? WHAT IMPORTANT QUESTIONS REMAIN... REFERENCES

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