The prevalence of asthma has increased

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1 JOEM Volume 47, Number 12, December Asthma, Genes, and Air Pollution Robert J. McCunney, MD, MPH, MS Objective: The objective of this article is to evaluate genetic risks associated with the pulmonary response to air pollutants, including particulates and ozone. Methods: A comprehensive review of articles related to the genetics of asthma with particular attention to air pollution was conducted through a search of the National Library of Medicine s PubMed database. Results: Asthma, which affects over 15 million people in the United States, is characterized by inflammation leading to reversible airflow obstruction. Triggered by exposure to numerous occupational and environmental agents, asthma has long been considered to occur more frequently in families, with upwards of a 50% higher rate in the offspring of parents with asthma. Asthma genetic studies have used two major methods: mapping techniques that pinpoint gene loci and studies that identify genes and polymorphisms associated with various asthma mechanisms such as inflammatory mediators. The most consistently replicated chromosomal regions associated with asthma have been chromosomes 2q, 5q, 6p, 12q, and 13q. Because the formation of reactive oxygen species is a major aspect of the inflammatory process of asthma, genetic aberrations associated with antioxidants such as glutathione S-transferase (GST) may shed light on reasons why some people with asthma seem more at risk of exacerbations as a result of air pollution. People with a polymorphism at the GSTP 1 locus, which codes for GST, one of a family of pulmonary antioxidants, have higher rates of asthma. Children in Mexico City with the GSTM1 null genotype demonstrated significant ozone-related decrements in lung function. Animal studies support the key role of antioxidants in reducing the inflammatory response associated with exposure to diesel exhaust particles. Conclusions: Oxidative stress is a key mechanism underlying the toxic effects of exposure to some types of air pollution. Asthmatics with the null genotype for the antioxidant, GST, seem more at risk of the pulmonary effects of air pollution. (J Occup Environ Med. 2005;47: ) From the Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts. Address correspondence to: Robert J. McCunney, MD, MPH, MS, Department of Biological Engineering, Massachusetts Institute of Technology, 77 Massachusetts Avenue, , Cambridge, MA mccunney@mit.edu. Copyright by American College of Occupational and Environmental Medicine DOI: /01.jom bf The prevalence of asthma has increased worldwide over the past decades. 1 5 This potentially disabling and life-threatening condition affects nearly 15 million adults and 5 million children in the United States and accounts for approximately 5500 deaths per year. 6 9 Annually, treatment requires approximately 10 million office and 1.9 million emergency room visits, along with approximately 500,000 hospitalizations. The direct and indirect costs have been estimated to be as high as $12 billion in ,11 An asthmatic reaction, characterized primarily by varying degrees of shortness of breath and/or chest tightness, can be provoked by exposure to numerous organic, synthetic, and biologic agents. Air pollutants such as ozone, particulates, sulfur dioxide, oxides of nitrogen, volatile organic compounds, 12 diesel exhaust particles, 13 and polycyclic aromatic hydrocarbons (PAHs), among others, can cause shortness of breath and wheezing in some people. Numerous epidemiologic studies have shown associations between asthma and air pollutants, although the links have been inconsistent. Fine particulates and ozone have attracted the most attention as pollutants associated with asthma. The major health outcomes used in these studies have included mortality (primarily premature deaths) and morbidity such as hospital admissions, treatment and activity limitations. For many years, asthma has been recognized as occurring in greater frequency in certain families, observations that have suggested a genetic basis for the disease. In light of the advances associated with the Human Genome Project, investigators have

2 1286 Asthma, Genes, and Air Pollution McCunney attempted to pinpoint genetic aberrations associated with asthma risk. This effort, which has shown some promising results, has been hampered, however, by the complicated and not fully understood mechanisms of the disease. 14 Although gene gene and gene environmental interactions involved with asthma are complex and not fully delineated, preliminary results suggest that certain genes control distinct aspects of asthma. Both the isolation and characterization of genes associated with the respiratory responses associated with exposure to air pollutants have not been fully defined. Advances in human genetics promise intriguing areas of scientific inquiry regarding links among asthma, genetics, and air pollution. 15 Numerous questions surface with respect to asthma and air pollution, including are people who have asthma and certain genetic profiles more susceptible to air pollutants? If so, which agents are more capable of inducing an asthmatic response? Do particles, sulfur dioxide, ozone, or other agents pose more of a risk? What is the mechanism associated with pollution-associated asthmatic reactions? Is there a genetic basis of the mechanism? Can the more serious asthmatic reactions, like life-threatening anaphylaxis, be prevented through genetic testing? Answers to these questions may provide clues to prevention. In light of the increased prevalence of asthma, interest in its genetic links and the acknowledged effects of air pollution on asthma, research, and practical implications abound. This article presents an overview of asthma, highlights of genetic studies, and summarizes how people with certain genetic profiles can be adversely affected by exposure to air pollutants. Asthma Asthma is characterized by bronchial hyperresponsiveness, inflammation, and reversible airway obstruction 16 Genetic and environmental factors have long been considered to play a major role in both the onset and expression of symptoms of asthma. 17 In fact, according to some authors, air pollution remains one of the most underappreciated contributors to asthma exacerbations. 18 Risk factors include family history, obesity, and exposure to numerous environmental agents, including dust mites, pollutants, and environmental tobacco smoke, among others Viral infections are the most frequent triggers of asthma. 22 Recommended initial treatment for asthma is the proper use of inhaled steroid medications. 23 As a result of an increased risk of influenza complications among people with asthma, flu vaccination is also recommended. 24 Fortunately, deaths from asthma are relatively uncommon. 25 For some, asthma symptoms may remit over time. 26,27 A precise diagnosis of asthma, however, can be difficult. 28 A variety of investigations have noted inconsistencies in diagnosing asthma varying from under- to overdiagnosis. Chronic cough, for example, can be the result of asthma; however, the same symptom may result from gastroesophageal reflux disease (GERD), rhinosinusitis, and allergic disorders. Clearly, an accurate diagnosis is not only essential for precise prevalence surveys, but also for effective treatment and prevention. The American Thoracic Society has published criteria that include the presence of four of five clinical parameters as reflective of the disease. 29 In an attempt to assess the prevalence of asthma worldwide, an international working group published diagnostic guidelines; it also recommended the use of a designated questionnaire to ensure worldwide uniformity in diagnosis. 30 Common clinical criteria used in the diagnosis of asthma include symptoms (wheezing), physical findings (wheezing) on lung auscultation, and decrements in pulmonary function. The effects on lung function typically reflect an obstructive pattern, although during periods of wellness, lung function may be normal. Other useful clinical criteria include an improvement in forced expiratory volume in 1 second (FEV 1 ) after inhalation of a bronchodilator. A 10% improvement in FEV 1 postbronchodilator usually reflects reversible obstructive airways disease such as asthma. A methacholine challenge test can enhance diagnostic accuracy, especially among asymptomatic people. Peak flow meters have been used both by patients in monitoring their lung function, as well as in morbidity surveys. Advances in genetics have stimulated numerous efforts to determine genetic markers associated with the onset and severity of asthma. In evaluating the genetic basis of complex illnesses such as asthma, it is essential to understand the mechanism of the disease. Indeed, a thorough understanding of mechanisms may lead to not only isolation of genetic determinants, but also more effective pharmacologic treatment. 31 Although much needs to be learned about the pathophysiology of asthma, the major mechanism is reversible obstruction of the small airways, with airway inflammation being a predominant finding. 32,33 The inflammatory response of asthma involves numerous mediators, including eosinophils, mast cells, and CD 4 lymphocytes. One defining feature of asthma is the presence of many activated eosinophils. 34 Leukotrienes are also mediators of a variety of inflammatory conditions, including asthma. 35 T lymphocytes are essential features of airway inflammation. 26 Cytokines, mediators involved in the regulation of both inflammation and IgE synthesis, can be divided into various groups, including interferons, tumor necrosis factor, and interleukins, among others. Interleukin (IL) 4 has been proposed as essential for the development of airway inflammation, because it induces B cells to synthesize IgE antibodies, which play a major role in certain types of asthmatic reactions. 36 Interleukin 5 is a chemoattractant for eosinophils; its concentration in pe-

3 JOEM Volume 47, Number 12, December ripheral blood and airway secretions is closely correlated with the degree of hyperresponsiveness associated with asthma. In fact, the genetic regulation of the inflammatory response is likely to have a major effect in disease manifestation. Interleukin 13 is another central regulator of allergic inflammation; its genetic links have also been investigated in certain studies. 37,38 IL-13 appears to act through epithelial and smooth muscle cells, not through eosinophils or IgE-mediated events. 38 Glutathione S transferase (GSTs) enzymes play a major role in detoxifying xenobiotic compounds, including carcinogens and some agents associated with asthma. 39 GSTs interact with hydrophobic electriles that result from the metabolism of xenobiotics and from the activities of reactive oxygen species. (ROS) GSTs consist of five major classes, each of which has isoenzymes (alpha, mu, theta, pi, and chi). The mu class of GSTs is expressed primarily in the liver, brain, kidney, and lung. 40 Although the GSTM1 isoenzyme is found primarily in the liver, it also appears to regulate the expression of GSTM isoenzymes in the lung. The GSTM 1 null genotype has been associated with both lung cancer and asthma. 40 Discussion of specific studies of asthma and GSTM1 genotypes follows later in this report. Asthma and Air Pollution For well over 50 years, air pollution has been recognized as capable of precipitating acute respiratory illnesses such as asthma. 41 Various pollutants have been evaluated either in isolation or in combination regarding their potential to cause acute and chronic respiratory disease. 42 Ozone, oxides of nitrogen, sulfur dioxide, and particulates (especially those 2.5 m in diameter) can increase airway responsiveness, a central feature of asthma. Other agents, like diesel exhaust and PAHs, have also been shown to increase IgE synthesis. In an animal model, diesel exhaust particles also induced airway hyperresponsiveness, a central feature of asthma. Many studies have evaluated respiratory illness in relation to various types of particulate exposure. 43 Particles less than 10 m (PM10) have been the subject of most studies; however, within the past few years, greater attention has been directed to smaller particles, those less than 2.5 m in diameter. (PM2.5). 44,45 In animal inhalation studies, the smallersized particles, presumably as a result of a greater surface area, appear more damaging than larger inhaled particles. Increased childhood asthma has also been noted in many countries in association with exposure to environmental particulates, 46 including Northern Ireland, 47 South Korea, 48 and the United Kingdom, 49 among others. Results of epidemiology studies have been consistent across cultures and with the use of numerous health metrics. Increased rates of mortality and morbidity, including admissions, need for treatment, and activity limitations, have been demonstrated worldwide in relation to exposure to various types of air pollution. A major prospective study showed a 1% increase in admissions for lung disease with every 10- m increase in ambient concentration of PM The same authors later demonstrated a link between long-term exposure to fine particulates and lung cancer and cardiopulmonary mortality. 51 Most recently, the effect of ozone on asthma has been the subject of scientific investigations. New diagnoses of asthma have been associated with heavy exercise in areas with high concentrations of ozone. 52,53 Long-term exposure ( 15 years) has also been linked with the development of asthma in adult males. Children with asthma appear more susceptible to the effects of ozone-related air pollution. 54 In fact, exposure to ozone above Environmental Protective Agency (EPA) limits (80 ppb, 8-hour time-weighted average) has been shown to increase the risk of asthmatic symptoms, need for medication, and declines in lung function. Some authors have concluded that current standards may not be sufficiently protective of vulnerable populations such as children. 54 A 6-month perspective study in southern New England showed that asthmatic children on maintenance (preventive) medication were susceptible to levels of ozone below EPA standards. 55 Shortness of breath and the use of additional medication in children who were taking regular medication, but not in other asthmatic children, were noted. Despite the extensive literature on air pollution and respiratory disease, a relatively limited research base of studies has addressed the simultaneous effects of ozone and suspended particulates. According to some authors, air pollution is not a major risk factor for the development of asthma, although it may exacerbate asthma in individuals. 30,56 In an international study of the prevalence of asthma in 56 countries, asthma prevalence rates tended to be lower in regions such as China and Eastern Europe (geographic areas with some of the world s highest concentrations of ambient particulates and sulfur dioxide) in comparison to nations with lower pollution levels. 30 The most reliable method to evaluate the respiratory effects from exposure to air pollutants remains to be clarified. For example, what is the most appropriate health metric to assess the effect of air pollutants on asthma? Mortality data, admission records, and activity limitations have all been used to monitor the effects of air pollution on asthma. As reductions in levels of pollution continue, more subtle and sensitive health effect indicators may be necessary. In fact, periodic collection and analysis of certain health data, especially related to respiratory illnesses such as asthma, when evaluated in concert with air pollution data, can demonstrate both the effectiveness of control measures and areas in need of improvement.

4 1288 Asthma, Genes, and Air Pollution McCunney Asthma and Genetics Asthma is widely considered a polygenetic or multifactorial illness, in which family history is a consistent risk factor. 57,58 According to some authors, at least 50% of a person s susceptibility to asthma appears to be determined by inherited predisposition. 59 In fact, an asthma phenotype is present in upwards of 25% of the offspring of a parent who has asthma. 60 Genetic studies of asthma have focused primarily on genetic alterations associated with the major asthma phenotypes that correspond with the major physiological processes associated with asthma: bronchial hyperresponsiveness and inflammation, including inflammatory mediators such as eosinophiles, IgE, and antioxidants Progress in uncovering genetic links with asthma has been impeded, however, not only by asthma s convoluted mechanisms, but also because most common genetic variations uncovered in studies of complex diseases such as asthma cause relatively small changes in function. 65 Because clinical traits of asthma appear to be defined by distinct subsets of predisposing genes, it has been difficult to isolate one particular or two or more major genes that play a predominant role in asthma. In fact, no single gene or even a small number of genes appear to exert the major influence on asthma. In the face of these challenges, asthma genetic studies have used two major methods: 1) mapping techniques that pinpoint gene loci associated with various mechanisms of asthma, and 2) physiological studies associating genes and polymorphisms that may affect certain aspects of the disease process Positional cloning, also known as linkage, has recently been of value in uncovering findings related to insulindependent diabetes and Crohn disease. Recently, two novel genes related to asthma (PHF 11 and DPP 10) were identified with this technique. 71 Studies of genetic links to asthma have addressed hyperresponsiveness, atopy, IgE synthesis, and inflammatory mediators. Of the 20 chromosomal regions that have shown linkage to asthma, the most consistently replicated regions have been on chromosomes 2q, 5q, 6p, 12q, and 13q. 72 The most investigated location for atopy, a predisposing condition for both asthma and allergic rhinitis, has been the 5q region of the chromosome, which includes the genes for the cytokines IL-4, -5, -9, and ,74 IL-13, a product of the gene on chromosome 5q 31, has been repeatedly implicated in asthma/ genetic studies. As noted earlier, the interleukins play a major role in inflammation, an essential pathologic feature of asthma. Multiple genes of 5q may affect IgE synthesis. The 5q region has also been implicated with the beta-2 adrenergic receptor. In fact, a GLY 16 polymorphism has been associated with asthma severity because of its role in the beta-2 adrenergic receptor; sedentary asthmatic women with the GLY 16 polymorphism were over seven times more likely to be less responsive to asthma therapy. 75,76 IgE antibodies can affect the severity of some types of asthma. (IL-4) with immunomodulatory functions in upregulation of IgE production has been evaluated for a possible genetic role in asthma. Among 1120 German school children, SNPs in the IL-4 gene were associated with both the development of asthma and the regulation of serum IgE. 74 In a study of 460 pairs of siblings, a locus on the short arm of chromosome 20 was linked to bronchial hyperresponsiveness (BHR), a key feature of asthma. After investigators surveyed 135 polymorphisms of 23 genes, they identified ADAM-33 as having a link with asthma. 77 ADAMs, were first identified as cell surface proteins with two domains a disintegrin and metalloproteins hence the acronym ADAM. Although the role that ADAMs play in asthma is unclear, they have been implicated in airway reactivity and small airway remodeling, a physiological effect of chronic asthma. One author claimed an ADAM-33 polymorphism may accelerate proliferation of smooth muscle cells and fibroblasts, leading to bronchial hyperreactivity and subepithelial fibrosis. 78 In a study of six SNPs in a population of Puerto Rican and Mexican children, however, the ADAM 33 gene was not an important risk factor for asthma phenotypes. 79 One of the more recent concepts related to the genetics of asthma is the role played by glutathione-stransferases. 80 Since a 1981 report that first described a GSTM1 polymorphism, it has been postulated that a GSTM1 null polymorphism might be associated with susceptibility to certain diseases. 81 As noted earlier, inflammation leading to airway changes is a key phenotypical expression of asthma. Reactive oxygen species, which play a role in this inflammatory process, are metabolized by GSTs; these substances also detoxify xenobiotics The loci that encode these enzymes are located on at least 7 chromosomes. 84 Because many of the GST genes are polymorphic, interest has focused on whether certain allelic variants are associated with various phenotypical expressions of disease. Potential links between genetic deficiencies (primarily polymorphisms) in the expression of GST proteins have been investigated in a number of recent studies In an evaluation of over 200 people in Northern Europe, bronchial hyperresponsiveness, a key phenotype of asthma, was associated with a GSTP1 polymorphism. 86 The frequency of GSTP1 Val 105 /Val 105 was significantly lower in people with asthma than in controls. The authors reported that the presence of this genotype was associated with a sixfold lower risk of asthma. Other authors have come to similar conclusions. 87 Spiteri et al hypothesized that susceptibility to airborne irri-

5 JOEM Volume 47, Number 12, December tants was increased by deficiencies in the detoxification of inhaled irritants and ROS. Their case control studies indicated that polymorphisms at the GSTP1 locus on chromosome 11q13 might account for the variations in response to inhaled particles. The frequency of the GSTP1 Val/Val genotype was reduced in atopic individuals. 87 Strange et al have drawn similar conclusions that the GSTP 1 Val 105 /Val 105 was essentially protective against asthma. 84 Other investigators have addressed the role of genetic variations in the expression of GST enzymes with respect to nasal exposure to diesel particles. 85 In an established nasal provocation model, volunteers with either the GSTM1 null or the GSTP wild-type genotypes were evaluated. In this single-blind, randomized, placebo-controlled study, GTM1 null patients had a significantly larger increase in IgE and histamine in comparison to patients with a functional GSTM1 genotype. The authors concluded that GSTM1 and GSTP1 modify the effect of diesel exhaust particles on allergic inflammation. Animal studies support the key role of antioxidants (such as GSTs) in reducing the inflammatory response associated with diesel exhaust particles. 88 In an evaluation of 158 asthmatic children in Mexico City, those with the GSTM1 null genotype had significant ozone related decrements in lung function (FEF ). 89 Moreover, those children with the null genotype responded favorably to the antioxidant effects of vitamins C and E. Earlier work also suggested that the antioxidants vitamins C and E modulated the effect of ozone on the small airways of children with asthma. 90 The studies described here support the principle that oxidative stress is a key mechanism underlying the toxic effects of exposure to some types of air pollution. 91 GSTP1, expressed in the respiratory epithelium, is the dominant GST in the lung. As a result of the function of GSTs in detoxifying ROS, genetic variations in the expression of GSTs may account for the individual variability in how some people respond to inhaled particles. Occupational asthma, similar to air pollution-associated asthma, has undergone limited genetic studies. Most investigations have addressed human leukocyte antigen-associated polymorphisms. Results, however, have not been reproducible. One author has claimed: The best methodological approach needs to be determined and the results of genetic identification need to be confirmed in different samples. 92 Discussion Because asthma can result from gene/environmental interactions, considerable opportunities exist for pinpointing genes associated with various aspects of the illness. 93 Gene environmental interactions can be investigated with case control, cohort, and family-based genetic studies. Prospective studies of asthma in athletes, as well as studies of the effects of air pollution in children, can also help shed light on this complex disease. Benefits associated with the identification of genes associated with asthma include improved diagnosis, treatment, and prevention. In fact, pharmacogenetic studies are expected to improve therapy for acute asthma attacks and its prevention. A number of questions loom related to asthma and genetics, including are environmental influences associated with asthma more likely to affect people with certain genetic profiles? According to some authorities It will be necessary to study simultaneously genetic variants that increase asthma risk and environmental factors that interact with these variants. 94 Although diverse studies of the genetics of asthma have been performed, the clinical implications of the genes and genetic variations associated with asthma phenotypes remain unclear. 95,96 As a result, research priorities are numerous. According to the National Asthma Campaign in the United Kingdom, several thematic areas warrant attention, including the genetics of asthma and its environmental influences. 97 To enhance the value of asthma genetic studies, an improved characterization of asthma phenotypes would be helpful. A major challenge is to identify how genes that predispose to asthma interact with environmental factors to cause disease. Because one of the major mechanisms of asthma is hyperresponsiveness, genetic studies of this mechanism may prove valuable. In summary, an understanding of the genetic basis of the pulmonary response to air pollutants is likely to aid in treatment and prevention. Moreover, information gleaned in the environmental setting can also be valuable in assessing other exposurerelated causes of asthma. As mortality from asthma declines, greater attention can be focused on more subtle effects of asthma that result in illness and activity limitations. References 1. 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