Interactions between genes and environment in the development
of asthma

Allergic diseases in general and asthma in particular have become an increasing problem for public health, especially in developed countries. Epidemiologic evidence suggests that the prevalence of asthma has increased significantly, especially among children (1, 2), and it is now the most frequent cause of chronic symptoms in the pediatric age (3). Some authorities questioned the validity of the first reports that suggested that the prevalence of asthma was increasing considerably in the population as a whole. The main argument was that the reported increases were due to a greater awareness among physicians and caregivers and among the population in general of the importance of asthma as a cause of chronic respiratory symptoms, especially among children (4). This was a plausible argument, because it is still true today that many children with asthma receive other diagnoses (wheezy bronchitis, spastic bronchitis, etc.). However, recent surveys that have included objective measures of risk factors for asthma, such as allergic sensitization and bronchial hyperresponsiveness (5), confirm that only a small proportion of the observed increases in the prevalence of asthma are due to a shift in diagnostic labeling. The same can be said for other diseases associated with IgE-mediated immune responses such as allergic rhinitis (6). There is widespread consensus today among the experts that these increases are real. Identifying the factors that have caused these increases and developing new preventive strategies that will address this epidemic are significant challenges for both the scientific community and public health authorities. The observed increases in the prevalence of asthma can-not be due to direct, qualitative, or quantitative changes in genetic susceptibility in the population as a whole. Genetic susceptibility is due to the presence of polymorphisms in genes that determine that certain individuals are at increased risk of developing those diseases. Several generations are needed for changes in the prev-alence of certain genetic variants to occur in the popu-lation in a way that will change genetic predisposition to conditions related to those variants. Since the changes in the prevalence of asthma and allergies have occurred in the span of not more than one or two generations, it can be concluded that these changes are due to modifications in the pattern of exposure to various environmental factors in large portions of the population. Nevertheless, the distribution of genetic variants in the population may have played a role in determining the recent changes in asthma prevalence. It is plausible to surmise that the environmental modifications that are causing the increases in asthma are more likely to exert their influences in individuals who have certain genetic backgrounds. The genetic variations (or combinations thereof) that predispose to the emerging cases of asthma surely were present in the population long before the current epidemics started. In the absence of certain environmental influences, these variations did not lead to the development of clinical illnesses in the past. In other words, complex diseases such as asthma and allergies are almost invariably the result of interactions between different sets of genes and environmental influences that, acting together with those genetic variations, make these complex diseases more likely. The above discussion has a very important corollary that needs to be taken into account in studying gene–environment interaction in the development of asthma. The environmental factors that are determining the increases in asthma prevalence may be different from those that determine the development of the same disease among individuals who would have had it even if these new environmental factors (whatever they may be) had not become more prevalent during the last decades. Moreover, the genetic factors that determine these more “endemic” forms of asthma and allergies are also likely to differ from those that determine the more “epidemic” forms. Christie et al. (7) have recently provided indirect evidence to support the contention that these new “epidemic” forms of asthma may have a different pathogenesis from that of “endemic” asthma. They found that the asthma risk associated with having at least one parent with the disease was significantly lower in their data than what had been reported in similar studies in the past. They speculated that the cases of asthma that are responsible for the increases in the prevalence of the disease may be occurring in individuals who would have been at low risk of developing the disease one or two generations earlier. The above arguments point to the complexity of the interactions that may determine asthma and allergies in different individuals. Whereas some genetic variants may increase the risk of asthma in individuals exposed to a very specific set of environmental determinants, other variants may determine the disease in other individuals who may have had a different environmental history. It is in this complex framework that one has to discuss and understand the potential role of different environmental exposures in determining the recent increases in asthma prevalence. Once it was established that these increases were real, the debate in the scientific community was centered on their causes. Given the complexities described above, it was natural to expect that no clear consensus would emerge from these discussions. Simply stated, it is most likely that more than one cause may explain the changes in prevalence observed during the last decades. The epidemiologic observations made many years ago that asthma is strongly correlated with the frequency of allergic sensitization to common aeroallergens suggested to some authors that exposure to these allergens could be an important risk factor for the inception of the disease (8). Moreover, a group of very influential researchers postulated that the recent increases in asthma prevalence could have been caused by an increase in the level of exposure to certain indoor aeroallergens (5). These authors reasoned that changes in the structure of modern homes had rendered them increasingly more impermeable to the outdoor environment, making the inhabitants of these homes significantly more exposed to indoor allergens. In addition, it was suggested that the use of certain materials for home construction and in furniture stimulated the growth of indoor allergen sources such as house-dust mites. Moreover, it was postulated that the modern tendency to keep cats and dogs inside homes could also increase the risk of sensitization to allergens produced by these pets. Since most of the epidemiologic studies of asthma have been performed in coastal areas, it was quite natural to conclude that allergens present in these areas were the “cause” of the disease in subjects who became sensitized to these allergens, and that it was thus the increased exposure to the allergens themselves that had caused the increases in asthma prevalence. This was a very influential idea, and it prompted several groups to design and conduct studies in which the main hypothesis was that, if levels of indoor allergens could be markedly decreased, sensitization to these allergens could be prevented and, consequently, asthma could also be prevented (9). Although not all the studies of this type were completed at the time of this writing, the results of those available do not confirm this hypothesis. Surveys in the Isle of Wight, England, for example, showed that children raised in environments with low exposure to allergens were less sensitized to these allergens by the age of 4 years than controls, but the prevalence of asthma at that age was not different in the two groups (10). This study has been criticized because not only were efforts made to decrease exposure to aeroallergens in the intervention group, but also measures were taken to stimulate breast-feeding and other actions that were also supposed to prevent the development of asthma. These extra measures, however, should have increased the differences between children in the intervention group and in the control group, but this was not observed. More recently, observational studies by Wahn and coworkers in Berlin, Germany, have contributed decisive new information regarding this issue. These authors measured the concentration of antigens of house-dust mites in the homes of children born and raised in that city, and, subsequently, determined the frequency with which enrolled children became sensitized to house-dust mites and developed asthma symptoms during the first 7 years of life (11). The results demonstrated that, much as in the Isle of Wight, there was a direct relation between exposure to house-dust mites and sensitization to their allergens. However, there was no relation between exposure to house-dust mites and prevalence of asthma by the age of 7 years. Not only did these results make it improbable that exposure to domestic allergens is a direct cause of asthma, but they also made implausible the hypothesis that the recent increases in asthma prevalence are due to an increase in allergen exposure. Moreover, recently published data suggest that there has not been a significant increase in indoor allergen concentrations during the last 30–40 years, in a time interval during which asthma prevalence has more than doubled (12). Finally, the observation that in inland arid regions, where indoor allergens such as those of house-dust mites are infrequent, asthma prevalence is not lower than in the coastal, more humid regions (13) has suggested that the relation between exposure to common allergens and asthma cannot be explained simply as a cause and effect association. It is interesting to stress here that in arid inland zones the allergens that have been most frequently associated with asthma are those of fungi, especially the genus Alternaria (14). In the arctic zones of Nordic countries such as Sweden, where, apparently, neither house-dust mites nor fungi are present to any large extent, the prevalence of asthma is still similar to that of the more temperate regions of those same countries (15). Up to 40% of school-aged asthmatic children are sensitized to common indoor aeroallergens (such as those of cats and dogs) in these areas, a prevalence that is significantly lower than that observed in regions where up to 80–90% of all asthmatic children are sensitized. Interestingly, in these arctic regions of Sweden, circulating IgE levels were significantly higher among skin-test-negative children with asthma than among skin-test-negative children without asthma (15). All this evidence suggests a different explanation for the increases in the prevalence of asthma. It has been proposed that childhood asthma is not caused by exposure or sensitization to any specific allergen (16). Nobody can deny that, in individuals who are sensitized to certain allergens, exposure to these allergens can trigger asthma symptoms. However, the fact that asthmatic individuals become sensitized to the allergens that their immune system is in contact with in the environment where these individuals were raised suggests that future asthmatics have an alteration in the immune response that is not limited to any specific antigen. Recent data on the characteristics of the immune response during the first years of life have led to new arguments in support of this hypothesis. Longitudinal studies have shown that the development of predominant IgE-mediated responses to local aeroallergens occurs early in life in future asthmatics (17). Moreover, infants who will become sensitized to these aeroallergens show important alterations in immune responsiveness during the first 12 months of life, long before specific IgE against these aeroallergens can be detected in the circulation. These alterations consist of a generalized impairment of cytokine responses to nonspecific stimuli by peripheral blood mononuclear cells (18). Although these alterations affect both cytokines of the T-helper 1 type (Th1) and those of the T-helper 2 type (Th2), it is mainly the former, and especially interferon-gamma (IFN-γ) responses, that are significantly decreased (19). As is well known, IFN-γ inhibits the production of IL-4 and IL-13 by Th2-type cells. These two interleukins are the only molecules capable of providing the signal to B cells to produce IgE. These data would suggest, therefore, that genetic and environmental factors interact in infants and young children to establish the patterns of immune responsiveness that predispose to the development of asthma. It is now well established that genetic determinants play an important role in the susceptibility to the development of asthma. Studies in identical twins have convincingly demonstrated that at least 50% of the susceptibility to asthma is determined by inherited predisposition (20). It has also been clearly established that no single gene or even a small number of genes exert a decisive influence in determining this susceptibility. Asthma is essentially a polygenic disease in which many genetic variants determine small changes in immune responses or in the manner in which the airway responds to the environment (21). As argued earlier, it is quite likely that different sets of genetic variants may interact with different environmental determinants to determine the risk of asthma in different individuals. This is the main source of difficulty when studying the genetic and environmental determinants of asthma: the recent changes in asthma prevalence are most likely due to many different environmental changes, each exerting its own small influence, and these changes may have been active at different ages and in different people. Moreover, environmental factors also interact among themselves and may determine a particular phenotype only if they are present in a certain context. This is what has been called context dependency in the determination of asthma risk (22). It is very difficult to measure simultaneously all the environmental influences that can interact to determine asthma risk, and particularly to measure them at the time in which they are active. It is thus very cumbersome (if possible at all) to design studies of risk factors for asthma that are based exclusively on laborious measurements of suspected environmental factors. The extreme complexity of the environmental determinants of a disease such as asthma has renewed hope that the study of the genetics of the disease may make an important contribution to our understanding of its pathogenesis. By definition, genetic factors are fixed for each individual; therefore, they can be measured with great reliability at any time during the life span. By anchoring studies of the role of environmental determinants of asthma on precise sets of genetic polymorphisms, it may be possible to determine which of these determinants are important in well-defined groups of subjects. We propose a general paradigm that may be useful to all those who are interested in elucidating what causes asthma and other complex diseases such as hypertension, myocardial infarction, diabetes, etc. This paradigm is based on the search for clues in two different and complementary areas. First, we need to use the in modern genetic genetic are now available that span the and these will to the presence of genetic variations with an increasing of Moreover, it is not even to which genes may be present in areas of the where the of genetic variants. There are several studies of this type in the in which different of asthma were of these studies have the presence of genes for asthma, that of genetic variants that explain a proportion of the susceptibility to the However, it is important to stress here that most of these studies have included a small number of with asthma, and this is particularly as we said earlier, studies of the of asthma had shown it to be a polygenic very of the disease have been and it quite likely that, these subjects with different forms of asthma were included the same that were supposed to be by the same disease may have included individuals asthma was determined by different sets of This would the results of any the levels of of most studies of asthma have been In of these a recent performed by and coworkers concluded that there is evidence that genetic variants associated with asthma and may be present in and in that same from the to the There is that we would significantly our understanding of the causes of asthma if we could the genetic polymorphisms responsible for these and if we could determine the alterations in the or in the by these that are by these for example, et al. were to several polymorphisms in the gene for in and showed these polymorphisms to be associated with an increased risk of having levels of IgE showed that these same polymorphisms were associated with an increased risk of asthma The IL-13 gene is in to genetic that showed evidence for with circulating levels of IgE in one of the first studies published et al. Several groups are now to determine the way in which the variants in the IL-13 gene influence the of IgE and bronchial especially that several studies in suggest that IL-13 can influence the of airway Although studies such as those described above may be very useful for our understanding of the pathogenesis of asthma and for the development of new it is that these studies will explain the increases in the prevalence of asthma or in the design of new preventive This is based on the fact that, on the one genetic variants associated with complex diseases are very common in the and it is very likely that they play a role in the complex that determine This is true for most common and it is thus that gene may be proposed in the future as a for the and of these diseases. the other no single gene is responsible for the of asthma, and it will thus be to study simultaneously genetic variants that increase asthma risk and environmental factors that interact with these variants to determine the asthmatic As explained earlier, the objective of this will be to specific environmental measures that could be on those subjects who are to these environmental factors and who have been by genetic Several studies published in recent years have environmental factors that to against the development of asthma. These studies may be the for new strategies that could be based on the paradigm described in the The relation between asthma and has been the of much discussion and debate during the last decades. It was for many years that could be one of the factors in the development of asthma. This was based on the that, many children who were with the respiratory developed have the or in some way the thus the conditions for the development of asthma. However, recent epidemiologic studies have to the relation between by and asthma These studies have shown that there is an increased risk of having asthma between the ages of and years in children who had in but this increased risk is of allergic sensitization and to decrease with during early Moreover, children who had lower of respiratory illnesses associated with were not more likely to become sensitized to local aeroallergens than their who did not have such illnesses of the relation between asthma and during the first years of life with studies performed in by et al. These studies the prevalence of asthma and in children born and raised in two zones of before the of the The results of these studies are well children from had a higher prevalence of but significantly less asthma, allergic and bronchial than children in studies performed in other countries of during the same these results There has been as to the possible causes of these However, one that is particularly important in the framework of this discussion is the of infants in the countries in These the great of in those countries to to the of their It is well that contact with other particularly in large is associated with a significant increase in the of respiratory illnesses More recent studies performed in countries have that children that are taken to during the first months of life do have a greater of lower respiratory illnesses during those first but they also have a significantly lower risk of having asthma and sensitization to allergens during the years decrease in the risk of having asthma and allergic sensitization has also been observed in children who have at home Although it is to surmise that, both in the of and in that of the presence of other children at the common factor was a greater exposure to the specific by which such exposure could prevent the development of allergies was not well very very source of information has been by the that, in different areas of and in children who in direct contact with have a significantly lower risk of allergic sensitization and asthma than children who in these same zones but without direct contact with More studies showed that one of the characteristics of children who in contact with and that them from those who did was a much higher exposure to a of the of is very in and it is a very of the of in indoor environments in areas et al. recently showed an relation between the level of indoor and the of sensitization to allergens during the first months of life in infants born and raised in These authors also showed that there was a direct relation between exposure to and the proportion of T-helper cells with reports of the results of studies on the prevalence of asthma in zones of other studies suggested that exposure to domestic during was associated with a decreased of allergic sensitization and asthma here there could be many for these it is interesting to stress that one of the factors that influences the level of indoor is the presence of at home These studies thus a that could explain some of the gene–environment interactions that are important at the of asthma. It is that is a of the production of by cells is a signal for the of the immune response the production of Studies in have shown that, if exposure to occurs before or exposure to an the IgE-mediated response that exposure to that allergen is very However, if exposure to occurs several exposure to the the is associated with a of the IgE-mediated This may explain exposure to increases bronchial in asthmatics and suggests that the response to exposure on the context in which the exposure as we explained earlier. The that exposure to during the first years of life can be an important factor against allergic sensitization and asthma a very paradigm for the type of gene–environment interaction studies that we suggested will be for our understanding of the pathogenesis of asthma. immune in have a structure that is to This system is centered on which is present both in and on the of and mononuclear immune cells in which genetic of has been become to to the point that these are to of that are associated with in postulated that, if exposure to is important as a factor against sensitization to allergens, a natural corollary would be that a genetic in the gene could have a role in the immune response search for polymorphisms was thus in the in very to the IL-13 gene and also to that have been shown to be to IgE levels to in the of the at from the was reported by et al. These authors showed that the of this was associated with a higher with lower IgE and with a number of to aeroallergens in subjects. least two other reports have these not all groups have been to do This should not be as we said earlier, the of environmental and genetic determinants of complex diseases on the context in which these diseases However, the of genetic variants in the system for a very for the design of studies in which of could be to prevent the development of asthma in because they have a certain genetic could be more to exposure to or to its Recent in our understanding of the environment interactions that determine susceptibility to asthma very clues to the asthma has increased during the last decades. They also the for the development of strategies for the of a disease that the of life and the of many and children all the This was by and and