The Genetics of Atopy and Airway Hyperresponsiveness

DIRKJE S. POSTMA, GERARD H. KOPPELMAN, and DEBORAH A. MEYERS

Department of Pulmonology, University Hospital Groningen, Groningen, The Netherlands; Department of Pulmonary Rehabilitation, Beatrixoord Rehabilitation Center, Haren, The Netherlands; and Department of Pediatrics, Center for Genetics of Asthma and Complex Diseases, University of Maryland, Baltimore, Maryland

	INTRODUCTION

TOP INTRODUCTION ATOPY HYPERRESPONSIVENESS CONCLUSION DISCUSSION REFERENCES

According to the available literature, there is a clear suggestion that atopy and airway hyperresponsiveness are genetically determined. Current knowledge suggests that many genes are involved in the clinical expression of these clinical entities. However, it must be established whether the genes for these two traits are acting completely independently of each other. Atopy by itself can be defined in several ways (see below) and atopy can express itself in different organs (e.g., skin, nose, and airways). Hence, it is questionable whether there exists one gene for atopy or whether there exist many genes that may interact, resulting in different disease expressions.

Twin studies have suggested that part of the genetic background for hay fever and asthma is similar (1, 2). Asthma and rhinitis coexist frequently, suggesting a common heritable origin. There are, however, also some arguments to suggest that some genes may be responsible for asthma, and others for atopy. A study in a London population showed that only 23% of patients with seasonal allergic rhinitis also experienced wheezing (3). Furthermore, Dold and coworkers (4) showed that having a relative with atopic dermatitis or rhinitis alone does not constitute a risk factor for children to develop asthma. But having a parent with asthma significantly increased the risk for development of asthma in the child. The study separately analyzed families with single allergic diseases of one parent and showed that only asthma, and not allergic rhinitis, is a predisposing factor for asthma in the offspring. Finally, children with two family members with an identical type of allergy had the highest risk of developing that specific type of allergy. This might suggest that there are more genes necessary for the expression of different allergies.

Another explanation for one genetic background of atopy with different clinical expressions, like asthma and rhinitis, might be that several different genes interact with each other to determine a certain phenotype (Figure 1). For instance, atopy and hyperresponsiveness are both associated with asthma, and it may be possible that the different genes responsible for either atopy or hyperresponsiveness act together in order to develop the full asthma phenotype. This is indirectly supported by the observation that rhinitis is associated with atopy, yet only a minor part of this population shows hyperresponsiveness or asthma. In this example, atopy is associated with a genetic predisposition and hence there must be at least two different genes for development of asthma (at least one for atopy and one for hyperresponsiveness). Using a principal component regression analysis, Lawrence and coworkers (5) and Wilkinson and coworkers (6) developed quantitative scores for "asthma" and "atopy" that appeared to be independent of each other. The heritability of the asthma score was 0.345, whereas the heritability of total serum IgE, the component that accounted for the majority of the atopy score, was 0.737. Using these integrated phenotypes, the asthma score in a multipoint test revealed an LOD score of 2.93 for a marker on chromosome 12q (D12S97) whereas this dropped to less than 1 for total IgE on the atopy score (6). This provides evidence for separate genes controlling asthma susceptibility and atopy, even though the latter has strong heritability.

View larger version (19K): [in this window] [in a new window]   Figure 1.   Possible interactions between genes for atopy in asthma and rhinitis.

Asthma is also present in nonatopic individuals, which also opens the way to hypothesize that the hyperresponsive gene or genes are the only ones mandatory for a clinical picture of asthma. Consequently, another option can be that genes for atopy only direct toward a milder course of the disease in patients with asthma. The latter has been suggested by longitudinal follow-up of patients with asthma (7). The decline in FEV₁ over time appears to be more severe in nonatopic patients with asthma than in patients with atopic asthma. Whatever will come out of the studies on the genetics of atopy and hyperresponsiveness in the near future, it is clear that genes for atopy and hyperresponsiveness are present in the genomic material of individuals with asthma (8). The intricate play of these genes with each other and with the environment may ultimately determine whether an individual develops asthma. Moreover, because 23% of children without any familial predisposition appear to develop atopy (4), it is extremely interesting to investigate these families in order to explore better the role of environmental factors in the development of atopy.

	ATOPY

TOP INTRODUCTION ATOPY HYPERRESPONSIVENESS CONCLUSION DISCUSSION REFERENCES

There is now compelling evidence that atopy is genetically determined to a large extent and that it expresses itself clinically, depending on environmental factors. Atopy can be defined as the response to exposure to minute amounts of allergens by the persistent production of high-affinity immunoglobulin E (IgE) antibodies. Atopy can be assessed by way of increased levels of total serum IgE, specific IgE to aeroallergens or food allergens, and skin test positivity to a battery of allergens. These three definitions of atopy do all have their age-related expression, in that IgE levels, specific IgE levels, and skin test positivity decline with age. Moreover, they are not always closely associated with clinical symptoms. As many as 25-30% of the total population develop a positive skin test. The prevalence is highest between 15 and 30 yr of age. Some individuals with positive skin tests have no symptoms, others have a few symptoms, and about 10-15% of the population will develop an atopic allergic disease. If both parents are atopic, there is about a 50% risk for the child to be atopic. If any parent or sibling is atopic, the risk is about 25%.

Most studies starting to investigate the genetic roots of atopy have set off to look into the origins of asthma as well. This is not surprising, as more than 80% of the asthmatic population has an atopic background. The distinction between atopic and nonatopic asthma is usually based on the presence or absence of skin test positivity to one or more aeroallergens. An extension to the background of atopy was the observation that total serum IgE was elevated in individuals with skin test positivity. Ishizaka and Johansson and their respective coworkers identified this protein as the main antibody against allergens, and associated it with the immediate immune response (9, 10). Some investigators have tried to dissociate atopic and nonatopic asthma by the level of IgE, yet this is not fully possible. Regardless of these criteria, atopic asthma appears to occur predominantly in young individuals, whereas nonatopic asthma is present at an older age. It remains to be established, however, given the diminishing immune response with aging, whether this is a true observation in cross-sectional studies or an artifact due to the specific age distribution of markers of atopic disease.

The relationship between skin test positivity, serum IgE levels, and asthma was assessed in many studies. Burrows and colleagues (11) made several interesting observations in a population study in Tucson, Arizona. Regardless of their atopic (skin test) status or their age group, the prevalence of asthma was closely related to the serum IgE level (standardized for age or sex) and no asthma was present in the 177 subjects with the lowest IgE levels for their age and sex. The odds ratio for asthma increased linearly with the serum IgE level after controlling for possible confounders and the degree of reactivity to skin tests. This observation challenges the concept that there are basic differences between so-called allergic and nonallergic forms of asthma. Moreover, it may suggest that total serum IgE and not skin test positivity is the predominant factor determining whether asthma is present or not. This is supported by the observation that cord blood IgE levels already predict whether a child will develop atopy (12).

In contrast to asthma, allergic rhinitis appeared to be associated primarily with skin test reactions to common aeroallergens, independent of the serum IgE level. The risk for rhinitis increased markedly with the degree of allergy skin test reactivity to the antigens applied in the study and serum IgE levels contributed little to the predictability of symptoms of rhinitis after the degree of atopy was taken into account. These observations indicate that when studying the genetics of atopy, it is necessary to consider which clinical expression of atopy is to be studied. So far, no available literature on the genetics of atopy and asthma takes into account this clinical consideration. Furthermore, most genetic studies have used a combination of markers for the assessment of atopy, for example, the presence of skin test positivity and/or radioallergosorbent assay (RAST) to common aeroallergens. This may hamper a validated conclusion on the genetic background of atopy. Finally, genetic studies must define the type of probands taken into consideration for analyses in familial studies or association studies of atopy. In light of the observations by Burrows and coworkers (11) and Dold and coworkers (4) it must be considered that the outcome of the genetic study on atopy will be different as well if probands with asthma and rhinitis are mixed with probands who have purely rhinitis or purely eczema.

Segregation Studies on Atopy

Segregation analysis of serum total IgE has suggested different models of inheritance. Using a single-locus approach, best fitting models were models for a major Mendelian gene, either codominant (13, 14), recessive (15), a mixed model of recessive inheritance (16), dominant (17), or, in two other studies, for polygenic inheritance (6, 18). Dizier and colleagues studied 234 Australian nuclear families (15) and found evidence of recessive inheritance of serum total IgE levels and significant residual familial correlations. However, these correlations were no longer significant when the presence of the specific immune response was accounted for in the analysis. This study therefore suggests that regulation of serum total IgE is independent of the regulation of allergen-specific IgE.

Xu and coworkers were the first to perform a two-locus approach to fit the serum total IgE data in 92 Dutch families ascertained through a proband with asthma (19). This resulted in a significantly better fit of the data than a one-locus model, thereby providing evidence of two unlinked loci regulating serum total IgE in these families. The first locus alone explained 50.6% of the variance of the level of serum total IgE, the second 19.0%. Considered jointly, the two loci account for 78.4% of the variability of serum total IgE levels in serum.

So far, no segregation analyses have been presented on skin test positivity or specific IgE levels to allergens as representative of atopy.

Taken together, segregation analyses of atopy, when expressed as total serum IgE, confirm its genetic background, but the mode of inheritance is still uncertain, as are the number of genes involved. Evidence of a major gene regulating serum total IgE was provided by studies in different countries, and one study suggested the inheritance of IgE to be different from that of specific IgE responses. Several explanations may be given for these contradictory results. A first explanation may be the definition of atopy, because it varies between studies. A second explanation may be the ascertainment of families for segregation studies. In families ascertained for asthma, estimates of frequencies of alleles regulating serum total IgE may be higher than in families sampled randomly from the general population. Finally, genetic heterogeneity may contribute to the various results. This means that different genes act in different populations toward the regulation of atopy. To date, this cannot be investigated because the exact localizations of these genes are still unknown.

Linkage Analysis of Atopy

In 1989, Cookson and coworkers were the first to report linkage of atopy on chromosome 11q (20). In this study, atopy was defined as either elevated serum total IgE raised allergen-specific IgE, or the presence of one or more positive skin prick tests. Seven families were studied, and most of the LOD score was accounted for by a single family using an autosomal dominant mode of inheritance. These authors replicated this finding in other samples, one of which was an Australian sample (21). In addition, other studies from The Netherlands, Germany, Japan, and Australia found evidence of linkage between an atopic phenotype and markers on chromosome 11q (24). Different expressions of atopy were used, either respiratory symptoms and elevated specific or serum total IgE levels, a clinical history of atopy and an elevated serum total IgE level, and a total serum IgE > 400 IU/ml; three or more positive intradermal skin tests > 9 mm or three or more positive RAST scores, respectively.

In an Australian study no linkage between chromosome 11q and atopy was found (27). However, airway hyperresponsiveness to methacholine appeared to be linked to 11q. Nevertheless, linkage of chromosome 11q to atopy and asthma is still controversial because of multiple failures to replicate this finding in several other populations (28).

In 1992, Cookson and colleagues suggested that maternal inheritance of atopy may have obscured linkage in other studies. Excess sharing of maternal, not paternal, alleles on chromosome 11q was shown in atopic children (36). Possible explanations for maternal inheritance of atopy are paternal imprinting or maternal modification of the developing immune response.

Chromosome 5q

Chromosome 5q31-q33 contains numerous candidate genes for atopy, such as a cluster of cytokine genes (interleukin 3 [IL-3], IL-4, IL-5, IL-9, IL-13, the  chain of IL-12) and the genes encoding the ₂-adrenergic receptor, the corticosteroid receptor, and the granulocyte-macrophage colony-stimulating factor. In 1994, linkage between serum total IgE levels and chromosome 5q was first reported by Marsh and colleagues in a U.S. Amish population (37). This finding was replicated by Meyers and coworkers in the same year in a study of Dutch families who where ascertained through a proband with asthma (38). As for many other regions on the chromosome, some studies have replicated these findings whereas others have not.

Chromosome 12q

Chromosome 12q is an interesting region for atopy, because of several candidate genes, such as interferon-, insulin-like growth factor I (IGF-I; promotes differentiation of both B and T lymphocytes), a mast cell growth factor, and the  subunit of nuclear factor Y (possibly upregulating transcription of both IL-4 and the HLA-D genes). Evidence for linkage and association was found to this chromosomal region for elevated total serum IgE (39, 40). An interesting finding is that the chromosomal regions on 12q implicated in these studies are not exactly the same. Further studies are needed to finely map this region and find out whether one or more regions on 12q are implicated in atopy.

Other Chromosomal Regions of Interest Detected by Genome-Wide Searches

To date, four genome-wide searches have been published, two providing results specifically on atopy (23, 41). Families were recruited in western Australia. The Netherlands, three ethnic groups from the United States, and from the Hutterites, a religious sect in South Dakota. Evidence of linkage to multiple chromosomal regions was reported in each study. In summary, evidence of linkage was found on chromosomes 1 (skin tests), 4 (IgE), 5 (IgE), 6 (IgE), 7 (IgE), 11 (skin tests, IgE), 12 (IgE), 13 ("atopy" and IgE), 16 (IgE), and 17 (IgE). Perhaps the most interesting regions for atopy (and asthma) are those reported by more than one group. These are chromosomes 4, 7, and 16. However, other genome-side screens have not fully evaluated all aspects of atopy and results may change when this has been performed.

Candidate Genes

There are several candidate genes for atopy; one on chromosome 11 is the  chain of the high-affinity IgE receptor. In 1994, Shirakawa and coworkers (44) reported that in a random British population sample an isoleucine (Ile)-to-leucine (Leu) change at position 181 in this protein was significantly associated with atopy if the Leu-181 variant was inherited maternally (45). Of the 60 families of allergic asthmatic probands under study, this variant was detected in 10 families. In addition, at position 183 a valine (Val)-to-leucine (Leu) change was found. The combination of Leu-181/Leu-183 was found in 4.5% of 1,004 members of 230 two-generation families in western Australia. When inherited maternally, the Leu-181/Leu-183 variant was associated with atopy (45). However, the Leu-181/Leu-183 variants were not detected in other populations, for example, in Italy and The Netherlands (33, 35). Other polymorphisms in this gene result in two restriction sites for the restriction enzyme RsaI, yet results are still conflicting (46).

The question remains whether the Ile-181 and Ile-183 variants in the gene that encodes the  chain of the high-affinity IgE receptor can account for the linkage reported by several groups, because it is detected in a subset of families or not detected at all in some populations. In addition, little is known about the altered function of one of these variants in relation to atopy. It is therefore plausible that other variants of this gene, such as the E237G variant, are more important in atopy.

Another candidate gene is the T cell receptor. In most individuals, this receptor is made up of  chains (gene at chromosome 14) and  chains (gene at chromosome 7). Around the  chain, increased sharing of alleles was found for the specific immune response in a U.K. and Australian population (49). Around the -chain gene, increased sharing of alleles was found for serum total IgE in a Japanese study (50). This study could not confirm the linkage to the region of the  chain of the T cell receptor gene. Further studies are needed to confirm these finding. The interleukin 4 receptor gene on chromosome 16 is an interesting candidate gene as well. Ober and colleagues (42) have reported strong linkage of the microsatellite D16S401, which is sited at 16p12.1, close to the gene encoding IL-4 receptor  chain. Hershey and coworkers and Deichmann and colleagues identified a polymorphism at amino acid 576 of the IL-4 receptor gene with high IgE and upregulation of the arginine-coding variant in a study of atopy (51, 52). In one study, only alleles inherited from the mother appeared to increase the risk in children (53). A second polymorphism at amino acid 50 was also shown to be associated with atopic asthma and upregulation of the gene expression (54).

	HYPERRESPONSIVENESS

TOP INTRODUCTION ATOPY HYPERRESPONSIVENESS CONCLUSION DISCUSSION REFERENCES

In a twin study, Hopp and colleagues reported that hyperresponsiveness to methacholine is under genetic control with a heritability of 66% (1). These same investigators demonstrated in a study of nonasthmatic parents of asthmatic individuals that hyperresponsiveness to methacholine may be inherited from one generation to the other independently of asthma (55). Segregation analysis indicated that although a familial component exists in the transmission of hyperresponsiveness to methacholine, this is not due to a single autosomal locus. In contrast, Longo and coworkers found evidence of dominant inheritance of hyperresponsiveness to carbachol (56). A further study in which a segregation analysis of hyperresponsiveness to histamine was performed also showed a "dominant model" to be the best fitting model (57). Holberg and coworkers (58) performed a segregation analysis of physician-diagnosed asthma in a Hispanic and white population in Arizona. Their findings were not conclusive, that is, there was evidence of an oligenic mode of inheritance with possibly a recessive component and an additional polygenic component. Although all data from segregation analyses suggest a genetic predisposition to hyperresponsiveness, the genetic regulation of hyperresponsiveness, the interaction with environmental stimuli, and the number of genes involved are not clear.

Linkage Studies on Airway Hyperresponsiveness

In general, more linkage studies have been performed on atopy than on hyperresponsiveness. Many investigations have not included hyperresponsiveness as a phenotype. Lympany and coworkers (28) and Amelung and coworkers (35) showed that there was no evidence of linkage between hyperresponsiveness and chromosome 11; however, Doull and colleagues and van Herwerden and coworkers (27) found positive linkage on airway hyperresponsiveness. Linkage with chromosome 5 has been shown in a Dutch population, in which IgE was linked to chromosome 5 as well (8). Furthermore, Kamitani found linkage to chromosome 5 (60). Daniels and coworkers found linkage to chromosome 5 as well in their genome-wide screen (23). Finally, Laitinen and coworkers found allelic association to chromosome 5 (61), and Mansur and coworkers did find a negative association (62).

Genome-Wide Search on Hyperresponsiveness

A genome-wide search in the aforementioned Dutch population suggested a linkage with chromosomes 1, 2, 3, and 5 (43). Among the Hutterites, linkage was found with chromosome 2, 3, 5, 9, 12, and 13. Daniels and coworkers found in the Australian population linkage of hyperresponsiveness with chromosomes 4 and 7. Thus, chromosomes 2, 3, and 5 are replications. Further data are not yet available, and more work is needed in order to elucidate the chromosomal regions for hyperresponsiveness.

Candidate Genes for Hyperresponsiveness: -Adrenergic Receptor

The gene encoding the ₂-adrenergic receptor is situated on chromosome 5q31. This receptor is a protein of 413 amino acids. In this gene, nine polymorphisms were identified, of which four lead to altered amino acid sequences at positions 16, 27, 34, and 164. In most studies on polymorphisms of the ₂-adrenergic receptor, none of these polymorphisms contribute to the risk of developing asthma (63). Moreover, current evidence suggests that the polymorphisms at positions 16 and 27 may play an important role in modifying the clinical severity of asthma. Amino acid 27 of the ₂-adrenergic receptor can either be a glutamine (Glu) or a glutamate (Glu). The Glu-27 variant was associated with elevated levels of serum total IgE in a study of 60 families with asthma. This variant was associated with more severe airway responsiveness compared with the Glu-27 variant as well (63, 66).

	CONCLUSION

TOP INTRODUCTION ATOPY HYPERRESPONSIVENESS CONCLUSION DISCUSSION REFERENCES

Data on the genetics of atopy are far more available than data on the genetics of hyperresponsiveness. The most intricate stage of genetics has now arrived, in that we will be able to look at the interaction between chromosomal regions and phenotypes of asthma. Atopy is an important aspect. It must be stressed that available data do suggest that atopy may be differently regulated in asthma than in rhinitis. This has important implications for understanding the pathophysiology of these two atopic entities. If, indeed, different genes are involved, this may ultimately lead to different intervention strategies for both atopic rhinitis and atopic asthma. Because both disease entities have a large bearing on patient quality of life and because asthma may in a severe stage of the disease constitute a life-threatening condition, it is clear that we are only taking the first steps currently to intervene adequately or prevent these diseases in the future. Further studies also need to unravel why some individuals with atopic rhinitis do have hyperresponsiveness and others do not have this phenotype. It must be studied whether this is due to genetic regulation and whether the presence of hyperresponsiveness in patients with rhinitis constitutes a risk factor for development of asthma on specific exposure. Finally, interaction of genes and environmental stimuli seems of utmost importance to develop atopy, asthma, and rhinitis. It must be determined which window in early life explains the occurrence of the disease in close interaction with one or more genes in the genome. This is an intriguing question, which will certainly lead to better understanding of the diseases and, it is hoped, to better treatment and intervention or prevention possibilities.

	DISCUSSION

TOP INTRODUCTION ATOPY HYPERRESPONSIVENESS CONCLUSION DISCUSSION REFERENCES

Holgate: I would like to illustrate another approach to study the genetics of asthma. Trait correlations and principal component analysis have been used to generate an IgE, RAST, and SPT cluster expressed as an atopy. This is another approach to integrate different traits into a single quantitative score. It could be useful to apply both this method and the one that Dr. Postma suggested. What we probably should be doing is, both the partial phenotype and the integrated one.

Postma: I agree. What I am warning about is that we all use different definitions of asthma different definitions of asthma and then come up with different locations. When we have made a particular analysis, we should replicate that in another population. We published an asthma algorithm and we would like to try that out in different populations as well.

Platts-Mills: Can you address a general issue, in which you are studying a disease that in some populations has increased in prevalence from 0.2% to 2% or from 2% to nearly 15%. In your presentation I don't see how the genetic analysis deals with that kind of change.

Postma: The recent increase of asthma, of course, cannot be explained genetically. This must be due to environmental factors or to environmental interactions with a set of genes.

Weiss: I support this. We have shown, for example, that there is an increased incidence of asthma in older women who have an increase in body mass index. Changes in body mass index in the Normative Aging Study predict changes in airway responsiveness. This suggests that the increase is a consequence of lifestyle changes, not genetics.

Quanjer: You said that replication of results is essential. If you have a sufficiently large population, and you split it in two, and you do the analysis in one half of the group, and in the other half of the group, then you want to come up with the same result, it would strengthen the idea that you have found a result.

Djukanovic: How do you explain differences in linkage found in different studies? Are these due to clear genetic differences or environmental factors? Can you elaborate on which environmental factors are being taken into account in the current genetic studies?

Martinez: We recently published a paper on a polymorphism we discovered in a gene called CD14, which is the main receptor for LPS. There is a polymorphism associated with IgE in our data. I am completely convinced that we are going to see that polymorphism, which is present in 50% of the chromosomes, in other words, 50% of the chromosomes are C and 50% are G in our population. If you go to the population in China, I am convinced that it is going to be totally unrelated to IgE, because the environment in China is completely different. In fact, I do hope that you will be able to study this. I think that is because it is a receptor for something that we are exposed to, it is a classical example of something that you can very easily study in terms of gene by environment interaction determining for example levels of IgE. At present, I believe that most of the differences that are found between populations have to do with differences in environment interacting with genes, rather than true genetic differences.

Weiss: I have not read the LPS paper yet, but we found in the Chinese population that the polymorphism of the  receptor, which is not independently associated with asthma in any population, there is a significant (with a odds ratio of 9) interaction between cigarette smoking and that particular polymorphism. This is in my mind the most significant finding in asthma genetics to date; no one has got an odds ratio of 9 for anything. And now Dr. Sterk at Bronchitis VI [Groningen, The Netherlands, 1998Ed.] made the point that this may not be an asthma gene, this may be a COPD susceptibility gene. Fine, I have no problem with that. If it identifies asthmatics who smoke, who are going to go on and get COPD, we made a big jump forward. Smoking is relatively easy to measure and people are doing that. But I think that all of these different techniques can be complementary in the sense that you can derive a hybrid design where you are using a combined linkage candidate gene type of approach, where you go to a specific are where there has been replication of linkage, pull out all the candidate genes, and do association studies.

	Footnotes

Correspondence and requests for reprints should be addressed to D. S. Postma, M.D., University Hospital Groningen, Department of Pulmonology, P.O. Box 30001, 9700 RB Groningen, The Netherlands. E-mail: d.s.postma{at}int.azg.nl

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