Genetic and Perinatal Risk Factors for Asthma Onset and Severity: A Review and Theoretical Analysis

Received for publication July 24, 2002; accepted for publication January 3, 2003. Asthma is a major chronic disease, and several studies indicate that it is on the rise worldwide (1). A recent report (2) from the Centers for Disease Control and Prevention estimated that the prevalence of self-reported asthma in the United States rose 75 percent from 1980 to 1994, with 17.3 million asthmatics in 1998 (3). In 2000, asthma accounted for more than 11.2 million medical visits, including 1.8 million to emergency rooms (4, 5). Asthma is characterized by lung inflammation, reversible airflow obstruction, and enhanced airway responsiveness to a variety of environmental stimuli and is a phenotypically heterogeneous disorder with variable disease expression. Asthma has a considerably greater impact on Hispanics and African Americans than on Whites in the United States (2, 6–12). Compared with Whites, African-American children have higher (1.1–1.7 times) asthma prevalence rates (2, 13–18), 2–3.5 times the hospital admission rate for asthma (2, 19–23), and approximately 2–5 times the asthma mortality rate (2, 22, 24–26). Point prevalence asthma rates of 11.2 percent and cumulative prevalence rates (ever had asthma) of 20.1 percent are reported for Puerto Rican children, the highest for any ethnic group in the United States (12, 27). Asthma increasingly has been diagnosed in young children, starting in the 1970s (28) and continuing through the last two decades (29–31), but precise rates cannot be readily obtained because of the difficulty in diagnosing asthma in very young children (32). Wheezing is often used as a surrogate measure but is unreliable; in a Tucson, Arizona, cohort, by age 3 years, 19.9 percent of the children had at least one lower respiratory tract illness with wheeze but were no longer wheezing at age 6 years, 15.0 percent did not wheeze before age 3 years but did so at age 6 years, and 49.5 percent wheezed by age 6 years (33). Wheeze has been reported in the winter of the first year of life in 33 percent of infants (34) and to occur for 30 or more days in one third of infants who do wheeze (35). The difficulty in diagnosing childhood asthma has led to suggestions that the increase is in milder symptoms only and that some children may be treated inappropriately (29, 36). Despite a considerable literature on risk factors for asthma onset and severity in children, very little is known about possible intrauterine influences, particularly how these factors interact with the genotype to sensitize the fetus to allergen exposure in infancy. There have been several recent reviews of candidate genes, but they often have excluded consideration of those environmental risk factors likely to play a role in gene-environment interactions. In this review, we first discuss some of the major candidate genes currently thought to play a role in affecting susceptibility to allergen sensitization, inflammation and tissue damage, and asthma symptoms and bronchial hyperreactivity. We then consider perinatal risk factors, including intrauterine exposure and influence of the fetal environment. We summarize the literature regarding lactation and diet, early neonatal exposure, and environmental risk factors. Finally, we propose a model that describes the possible interplay of these factors in a plausible temporal sequence. Although environmental factors are clearly important determinants of asthma, numerous studies have revealed that asthma has a strong genetic component but does not follow monogenic patterns of inheritance (37–39). For a long time, asthma has been known to cluster in families, and family studies were the first to suggest that the disease was genetically inherited. More recent family studies found, for example, a 60 percent increased risk of atopy when both parents were affected (40), and the odds of asthma in a child increased from 3 when one parent was affected to 6 when both were (41). Maternal asthma appears to be more influential than paternal asthma (41, 42), particularly in children less than age 5 years (41). While family studies point to the likely importance of a genetic etiology, these studies do not definitively delineate genetic from environmental risks because of shared environments in families. Twin studies were among the earliest to demonstrate the importance of genetic factors in the etiology of asthma. One of these, conducted in Sweden (43), reported concordance rates for self-reported asthma of 19.0 percent in monozygotic and 4.8 percent in dizygotic twins. There have been many replications of this finding. Current twin studies confirm the importance of both genetic and environmental factors by comparing the concordance rates in monozygotic versus dizygotic twins from the same population, who are at increased risk of asthma because of parental atopy (44). In Finnish Twin Studies, 87 percent of the variation in susceptibility to asthma was owed to genetic factors in families with at least one asthmatic parent. Among families in which neither parent was asthmatic, the development of asthma was explained entirely by environmental risk factors (45, 46). Twin studies permit analysis of environmental risk factors, independent of genetic factors, without necessarily knowing the specific genes involved (47–50). The strategy for identifying candidate genes offers opportunities to further specify persons at increased risk for susceptibility to allergic sensitization (atopy), inflammation, bronchial hyperreactivity, and severity of asthma symptoms. Confirming the importance of candidate asthma genes will enable development of new diagnostic and therapeutic tools and of prevention and allergen avoidance strategies. Identification of candidate genes for asthma will also permit more precise elucidation of environmental risk factors operating at different stages of asthma development. Nonetheless, careful analysis and interpretation of these studies is required. Three explanations are possible for an association between a candidate gene and disease (51): 1) the candidate allele is the relevant mutation in the disease gene; 2) the allele is positioned very close to the disease gene (linkage disequilibrium); or 3) the association is due to confounding by the allele frequency being higher in population subgroups in which disease frequency is also higher (population admixture). Diseases with a complex genetic origin, such as asthma, also may be characterized by pleiotropy (the same genotype has different phenotypes), genetic heterogeneity (the same phenotype results from different polymorphisms), and incomplete penetrance (the same polymorphism does not always produce the same phenotype). Multiple regions of the human genome likely to contain susceptibility genes for asthma and associated phenotypes have been reported from candidate-gene approaches and genome-wide screening studies (52–54). For a candidate gene to potentially be important in the disease, a number of criteria must be met. First, the gene protein product must be relevant to the pathophysiology of the disease. Second, the gene must contain mutations within either the coding region or the regulatory regions controlling gene expression; these mutations need to be functionally relevant. Demonstration of functional relevance for a mutation is particularly important given the high rate of polymorphic variation within the human genome, estimated to be about 1 in 1,000 base pairs in coding DNA and about 1 in 500 base pairs in noncoding DNA. Third, functionally relevant mutations should demonstrate association and/or linkage with an appropriate phenotype. Finally, for a mutation to contribute to disease risk in a population, it must be relatively common: rare mutations may greatly increase the risk of developing asthma in individual families but are unlikely to be important in determining the population risk as a whole. However, it follows that the effects of common polymorphisms may be relatively small; if major deleterious consequences occurred in persons with a given polymorphism, it would soon be lost from the population. Genetic variants in the promoter region of the IL-4 gene (55) have been related to elevated immunoglobulin (Ig)E levels. The polymorphism at –589 involves a C→T substitution in the promoter region on chromosome 5q31, resulting in increased responsiveness to IL-4 (e.g., by enhanced IgE production). This locus has been associated with asthma diagnosis in some studies (56, 57). In an Australian population (n = 1,004), Walley and Cookson (57) reported positive associations between the IL-4 promoter polymorphism and specific IgE to dust mite and clinical symptoms of wheeze but could not duplicate these results in a smaller (n = 183) English population. Polymorphisms within the IL-13 gene are associated with high IgE levels and with the presence of asthma (58). IL4-Rα on chromosome 16 is a shared component of the receptor for both IL-4 and IL-13, and polymorphisms in this gene are also associated with asthma and atopy (59). It is of interest that different asthma-associated traits are associated with individual polymorphisms that affect splicing of IL4-Rα (60, 61), illustrating the complexity of mechanisms that may vary the actions of a single gene. Gene-gene interactions rarely have been studied, but recently an interaction between polymorphisms in IL4-Rα and IL-13 was reported to increase the risk of asthma fivefold (62). Innate immunity is becoming recognized as equally as important as specific immunity in the response to mucosal and skin injury. The innate immune system contains many molecules that recognize signals of infection, such as components of the bacterial wall and methylated bacterial DNA. molecules also the specific immune system and may IgE is a receptor for bacterial in the gene is associated with asthma, some of the for the This receptor may be of the mechanisms that the effects of childhood on asthma development. is an in increased in asthmatic and in from asthmatic The and and genes are within the human major complex on chromosome variation in the of of by or has been in association with polymorphism in the gene cluster and the locus Polymorphisms in the genes have been associated with the presence of asthma polymorphisms by the than the allergic The receptor for IgE is the of the response It is of one one and two The receptor is also in an The and the The is not for receptor but as an molecules are on the of in the skin and mucosal of the and and on The receptor IgE molecules and at the The presence of results in and of IgE The resulting of that of allergic and of gene resulting in of molecules such as and are to the and of allergic inflammation and may in also is on such as and in and The of the receptor for IgE as an approximately of the receptor response to within the has been associated with asthma bronchial and to be associated with disease. Genetic within and chromosome have been to IgE in the United States and strong of one or more in involved in IgE levels and bronchial The gene IL-4 is within this region and is a possible candidate for the reported genetic IL-4 influence responsiveness to and because genetic variants in IL-4 IL-4 gene these also may asthma In a of and African-American the presence of the IL-4 promoter allele was associated with in 1 of less than percent among In polymorphisms of the allele of the IL-4 receptor gene were associated with increased asthma, in infants with onset within years of age and asthma and airflow have been associated with polymorphisms in the IL-4 and IL-4 The IL-4 and IL-13 have a role in IgE IL-13 is related to and the two genes from of a single The for both an when greatly IgE IL-13 appears to affect asthmatic IgE candidate gene to chromosome is the receptor gene. of from asthma have that may be related to asthma common polymorphisms of this gene at 16 and and were with high in both asthmatic and from in with human airway in tissue that these two polymorphisms are involved in receptor A substitution of for at 16 in increased of In a substitution for at However, results from several clinical studies were in because these two polymorphisms were common and in linkage The polymorphism at 16 was reported to be associated with asthma asthma, and airway but not with or asthma the reported that was associated with lower airway in with asthma. The gene has recently been to be by lung and bronchial and it has been that polymorphisms may influence and to increased inflammation is to confirm the precise role of in asthma development. The greater influence of with paternal asthma and atopy on the development of asthma in a role of the perinatal environment. In this we first environmental risk factors the intrauterine which is often in studies that follow children from that influence asthma development through allergic sensitization of the fetus or through of the fetal are factors in the neonatal including and and the are Finally, we on environmental risk factors in early Despite a literature on risk factors for the development of asthma in children, is known about the role of intrauterine factors of the fetal that have been in asthma development in the in immune and and lung is one of the important risk factors for developing asthma, and asthmatics have immune The human immune response in and and early childhood are thought to be the influential with to to the perinatal The human fetus appears to produce but at relatively levels. 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A recent the fetal of were given the the stages of and the the through age years, children given the had the rate of of the group percent = children asthma, who were not by fetal is to the and development of the and/or to of lung early or may Maternal is to fetal and exposure may have effects Maternal also appears to increase the risk of asthma in the it has been to the risk from the effects of neonatal exposure that in exposure to without exposure to environmental the risk of a child asthma, exposure to environmental childhood was related to wheeze but not asthma In to a genetic asthma, a associated with respiratory and of the also may affect asthma development in by affecting fetal development. 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may increase IgE from the of is an important when the of lactation on atopy of both and avoidance of have a lower risk of but not asthma in the group one has been known to allergen avoidance with dust mite asthma and atopy were at 1 year of age the was at age years of the of avoidance gene-environment new should consider genetic susceptibility as an It recently was for several potentially confounding factors, who first in a were at increased risk of developing = percent The that infants in the were more likely to and exposure to This was conducted in a cohort, and the of is very different particularly with the greater of neonatal However, these infants to a of that may be important for sensitization to asthma or to asthma It also is known that the early of the immune system is on through in and that different This the that of in the neonatal may the development of asthma. children treated with have increased rates of asthma in early has been to increase risk of asthma at years = percent also about the of in the as as confounding by disease in studies will careful It has been that of and positive at as as who have an increased susceptibility to asthma with and are also at increased risk but of these factors are more common in those who have in the neonatal the independent effects of versus early have not been to they have been in the same in dust have been in the development and severity of asthma in dust mite and are among the important because of role in the development and of asthma. studies that allergen exposure in and children for wheeze and asthma have to a strong association with dust mite or allergen One that by asthma an interaction between exposure and genetic susceptibility least studies an association between in and respiratory symptoms. studies have reported that dust increased symptoms of wheeze in the first year of life and in allergen sensitization is common and may a from the of in the of is of interest for the This that children on had lower rates of asthma than did children from environments A recent publication that levels from the of children years in but not necessarily from were related to asthma and as as to by increased of exposure to and A particularly important in the of asthma, environmental is associated with a of and chronic effects The that the children of who or more had a percent increased risk of developing asthma and that percent of of asthma in the children of these could be to A recent reported that increased the risk of asthma, particularly in children with a of parental asthma, the importance of further the genotype of children human and suggest that particularly and may immune to and respiratory before the age of years have been associated with increased risk of asthma. of and exposure have been related to increased respiratory symptoms. Asthma development and severity are by a etiology that and environmental factors. of these risk factors may to intrauterine life by on these risk factors and a of the asthma the may to some on these single is likely to be for the increase in asthma onset and particularly the increase in It is due to new environmental factors, the gene is unlikely to have in the last environmental factors will influence phenotypes genetically to at stages in the development of disease. We have that asthma development may as early as the fetal and is infancy. The of the major of risk factors, this review, are in which has been from to the role of intrauterine and early neonatal It is likely that a complex interplay of these factors is for asthma development and Current that development of asthma polymorphisms in several genes in the same which will to complex and gene-environment interactions. interactions are likely to play at different stages early as the child to a variety of environmental complex interactions it to candidate genes to the role they play in asthma development and Although a number of susceptibility genes for asthma have been it is that the to be of shared of on a of affected persons from with a common is increasingly being used to candidate asthma genes with publication of the human genome, candidate asthma genes are likely to be at an The of candidate genes will of are the need for in publication in the for a candidate and a of effects when of criteria for known to will be are strong associations by population is the of the protein and response on or this complex of increasingly of new associations will be required. Although exposure to perinatal factors, and environmental risk factors the risk of asthma, only a of will asthma. We that susceptibility will vary on genetic and and of will permit more precise of environmental risk are in which both parents and the child be and the child from early through infancy. studies will enable analysis of the and interactions likely to influence asthma onset and model has in the interplay of the genotype with environmental factors, because it to the of clinical and In the the of is likely to be by studies of the responsiveness of with polymorphisms to a The model also the need for of among at risk of asthma and the importance of the complex of asthma etiology if more prevention are to be the genetic risk of may permit more allergen avoidance The model is also A polymorphism may influence the of asthma at more than one IL-13 polymorphisms have been to increase the risk of atopy and asthma the same time, environmental interactions are becoming more and also to environmental are at an enhanced risk of asthma. There are which are the of this review, in studies to and we are of conducted to for any disease. However, asthma is a disease for which such a complex of factors will be to of in asthma This was by and from the of The are particularly to for in the for to of of and 60 associations of and perinatal risk factors with asthma onset and severity in from 1 for and of and of of and of 3 The of United of