What Causes Asthma? Is It Due to Genes, the Environment, Infection, or Some Combination of These?
In 1989, the cover of the journal Science had a picture of a child with a headline stating that the gene for cystic fibrosis had been isolated, and the medical future for people with this fatal genetic disease seemed much brighter.1 Discussions among those of us at the pulmonary and allergy meetings in the 1990s focused on isolating the gene or genes responsible for asthma. The identification of these specific genes would provide clinicians with the ability to accurately diagnose this common disease, provide investigators with the means to understand the mechanisms of its pathophysiology, and give pharmaceutical companies the building blocks to make new and more effective therapies. Almost 20 years later, the current conclusion from all the promising research is that the causes of asthma are a combination of multiple genetic variations interacting with numerous environmental triggers, which may be further modulated by infectious diseases in early childhood.2-4
This revelation does not diminish the brightness of the new information about asthma genetics, nor the importance for clinicians to be aware of and actively involved in pursuing knowledge about asthma genes. In the 21st century, there are commercial diagnostic gene laboratories that analyze distinct genes, and this diagnostic methodology will be available when a consensus for an asthma gene panel has been achieved.2
The methodology for the analysis of asthma genes has taken 2 broad investigative approaches to address the important contributing parameters that induce the asthmatic response. Thus, investigators and clinicians need to work together to collect genotypic, phenotypic, and diagnostic clinical information from each patient cohort. One approach for the genetic analysis of a population is to collect a sample cohort of patients diagnosed with asthma, such as an ethnic population or a group of pediatric patients, and to compare the sample groups’ genes with those from a control cohort of patients who do not have the clinical phenotype of asthma.1,2 Then, using comparative genomic hybridization and positional cloning, the investigators attempt to determine if specific genes are mutated, up-regulated, or deficient in the asthma cohort. Last, these genes are then sequenced, and the protein derived from the genetic sequence is isolated and then studied for its function within the lung. In this manner, the gene ADAM 33 coding for a bronchial smooth muscle protein was discovered in a selected asthmatic population.2
Another approach toward genetic analysis is to pick a pathway in the asthmatic cascade, such as the up-regulation of the immune response in asthmatic patients, and to study a candidate gene. Using a well-described asthma animal model, investigators hope to demonstrate that the candidate gene, which is either over-expressed or deficient in the animal model, will significantly disrupt the predictable asthmatic response in the animal model of interest. Then, these candidate genes can be targeted for study in a human asthmatic sample population. This was done for the PTGDR gene (prostaglandin D), which has an important role in T-cell chemotaxis.2
The analysis of one gene through bench science by a clinical investigator can provide the background knowledge for a pharmaceutical company to synthesize a drug to block or enhance the critical pathway. The dissemination and translation of this scientific knowledge to the public provides an additional challenge to us as clinicians. We must learn new genetic terms in order to address our families’ questions about asthma genes and the genetic basis of this disease. This process is actively unfolding in the cystic fibrosis community today as the genetic discoveries of the past decades are translated into targeted cystic fibrosis genotype-based therapies.1,2
While asthma genetic research continues to narrow the search among the pathways that are the most important in the pathophysiology of asthma pathology, there are 10 genes already identified as asthma genes (Table 6-1). Selective proteins coded by these genes include structural proteins in the respiratory epithelium, airway proteases, chemotactic mediators, and enzymatic granules released by activated immune cells.2 Thus, the current hypothesis suggests that while the asthma gene variations are present in the host, it is the exposure to environmental allergens and irritants and the infectious disease directives that propagate the asthmatic response of each patient over time.3,4
Multiple epidemiologic studies focusing on specific allergens and irritants demonstrate that the presence of dust-collecting clutter; high dust mite populations; environmental tobacco smoke exposure and smoking cigarettes; high pollen counts in humid summers; mold-infested homes, and homes along busy bus routes or highways that spew sulfides, nitrogen oxides, and particulate matter into the air significantly contributes to the genesis of asthma, induces asthma attacks, and impairs lung growth in pediatric patients.3-5
Prospective studies to analyze the effect of the environment on one mechanism of asthma, the induced immune response, are presented in the “Hygiene Hypothesis.” The environmental differences of the 2 populations in western versus eastern Germany provide a natural laboratory to select comparative pediatric populations and demonstrate differences in atopy, infectious events, and asthma symptoms as well as environmental measurements of air pollution, bacterial endotoxins, dust presence, and sibling contagions. The breadth of the experimental setting shows a deviation of the developing immune response from that of one fighting over systemic and respiratory infections to one that releases mediators that cause mucosal thickening and airway bronchoconstriction, the cardinal features of asthma.3
The “Hygiene Hypothesis” states that, in the socially cleaner, upscale environment of western Germany, there are more asthma-like symptoms because the T-helper cell 2 (Th2) immune cells are producing allergy-promoting cytokines. In contrast, in the lower socioeconomic environment of eastern Germany, in which there are crowded family houses and farm animals in close proximity, the immune response remains skewed toward the T-helper cell 1 (Th1) response, which releases mediators that fight off infection and downregulate nonessential immune responses, such as seen in atopic individuals and those with asthma (Table 6-2).3 These studies corroborate other American studies showing that children sent to daycare and those with many siblings tend to be sick as infants and young children but may be less likely to have asthma diagnosed at age 6 years.4 These studies did not look at the potential asthma gene panel, but they did take into account family history and allergic sensitization and found these to be important, albeit imperfect, predictors of the presence of asthma at age 6 years. However, back home in our asthma clinics, we do tell our patients and their parents that while most children will grow out of wheezing and asthma symptoms by age 6 years, they should try to avoid triggering allergens and irritants in the environment. In addition, we can use tools such as the “asthma predictive index” to try and predict who will and will not “outgrow” their asthma symptoms.5
Infants and young children are exposed to viral and bacterial infections continuously. Up to 90% of all 2-year-olds have been exposed to the respiratory syncytial virus (RSV). Infections can decrease airway function on pediatric pulmonary function tests and potentiate asthma-like symptoms in young children.5 This is particularly true of those with the genetic predisposition to atopy as measured by positive allergy tests. These infants and young children will most often develop recurrent respiratory symptoms consistent with asthma. The specific genes responsible for this predisposition, however, are not yet identified.4,5
It is clear that asthma, with its multiple pathophysiologic pathways and clinical phenotypes, results from a complex interplay of multiple genetic and environmental factors. The unavoidable viral and bacterial infections of childhood coupled with the genetic make-up of the individual child are critical. These are then further linked to critical environmental exposures to allergens or irritants. Together, this complex combination of stimuli and responses all combine to enhance respiratory symptoms and airway inflammation consistent with asthma. While the candidate genes that dominate these responses are being explored and will eventually be translated into specific therapies, those of us at the bedside are left with our clinical skills and intuition. We do not have a gene-based diagnostic kit, but the results of many large prospective epidemiological studies guide us in assessing risk and clinical parameters to assess the clinical severity. Thus, we all participate in a better understanding of childhood asthma.
1. Riordan JR, Rommens JM, Kerem B, et al. Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA. Science. 1989;245:1066-1073.
2. Cookson W, Moffitt M. Making sense of asthma genes. N Engl J Med. 2004;351:1794-1796.
3. Braun-Fahrlander C, Riedler J, Hera U, et al. Environmental exposure to endotoxin and its relation to asthma in school-age children. N Engl J Med. 2002;347:869-877.
4. Martinez FD, Wright AL, Taussig LM, Holberg CJ, Halonen M, Morgan WJ; Group Medical Associates. Asthma in the first six years of life. N Engl J Med. 1995;332:133-138.
5. Castro-Rodriguez JA, Holberg CJ, Wright AL, Martinez ED. A clinical index to define risk of asthma in young children with recurrent wheezing. Am J Respir Crit Care Med. 2000;162:1403-1406.