Asthma causes

Editor(s)-in-Chief: C. Michael Gibson, M.S., M.D. [mailto:mgibson@perfuse.org] Phone:617-632-7753; Philip Marcus, M.D., M.P.H. [mailto:pmarcus192@aol.com];

Overview
Asthma is caused by a complex interaction of environmental and genetic factors that researchers do not yet fully understand. These factors can also influence how severe a person’s asthma is and how well they respond to medication. As with other complex diseases, many environmental and genetic factors have been suggested as causes of asthma, but not all studies posing such claims have been verified by further studies. In addition, as researchers detangle the complex causes of asthma, it is becoming more evident that certain environmental and genetic factors may affect asthma only when combined.

Differential Diagnosis of Underlying Etiology
(By organ system)

Environmental

 * Many environmental risk factors have been associated with asthma development and morbidity in children, but a few stand out as well-replicated or that have a meta-analysis of several studies to support their direct association.
 * Environmental tobacco smoke, especially maternal cigarette smoking, is associated with high risk of asthma prevalence and asthma morbidity, wheeze, and respiratory infections.
 * Poor air quality, from traffic pollution or high ozone levels, has been repeatedly associated with increased asthma morbidity and has a suggested association with asthma development that needs further research.
 * Caesarean sections have been associated with asthma when compared with vaginal birth; a meta-analysis found a 20% increase in asthma prevalence in children delivered by Cesarean section compared to those who were not. It was proposed that this is due to modified bacterial exposure during Cesarean section compared with vaginal birth, which modifies the immune system (as described by the hygiene hypothesis).
 * Psychological stress, has long been suspected of being an asthma trigger, but only in recent decades has convincing scientific evidence substantiated this hypothesis. Rather than stress directly causing the asthma symptoms, it is thought that stress modulates the immune system to increase the magnitude of the airway inflammatory response to allergens and irritants.
 * Viral respiratory infections at an early age, along with siblings and day care exposure, may be protective against asthma, although there have been controversial results, and this protection may depend on genetic context.
 * Antibioticuse early in life has been linked to development of asthma in several examples; it is thought that antibiotics make one susceptible to development of asthma because they modify gut flora, and thus the immune system (as described by the hygiene hypothesis).
 * The hygiene hypothesis is an hypothesis about the cause of asthma and other allergic disease, and is supported by epidemiologic data for asthma. For example, asthma prevalence has been increasing in developed countries along with increased use of antibiotics, c-sections, and cleaning products.  All of these things may negatively affect exposure to beneficial bacteria and other immune system modulators that are important during development, and thus may cause increased risk for asthma and allergy.

Genetic Predisposition

 * Over 100 genes have been associated with asthma in at least one genetic association study. However, such studies must be repeated to ensure the findings are not due to chance. Through the end of 2005, 25 genes had been associated with asthma in six or more separate populations:


 * Glutathione S-transferase Mu 1 (GSTM1)
 * IL10
 * CTLA-4
 * SPINK5
 * LTC4S
 * lymphotoxin alpha (LTA)
 * GRPA
 * NOD1
 * CC16
 * GSTP1
 * STAT6
 * NOS1
 * CCL5
 * TBXA2R
 * TGFB1
 * IL4
 * IL13
 * CD14
 * ADRB2 (β-2 adrenergic receptor)
 * HLA-DRB1
 * HLA-DQB1
 * TNF
 * FCER1B
 * Interleukin-4 receptor (IL4R)
 * ADAM33


 * Many of these genes are related to the immune system or to modulating inflammation. However, even among this list of highly replicated genes associated with asthma, the results have not been consistent among all of the populations that have been tested.
 * This indicates that these genes are not associated with asthma under every condition, and that researchers need to do further investigation to figure out the complex interactions that cause asthma. One theory is that asthma is a collection of several diseases, and that genes might have a role in only subsets of asthma.
 * For example, one group of genetic differences (single nucleotide polymorphisms in 17q21) was associated with asthma that develops in childhood.

Gene-environment Interactions

 * Research suggests that some genetic variants may only cause asthma when they are combined with specific environmental exposures, and otherwise may not be risk factors for asthma.
 * The genetic trait, CD14 single nucleotide polymorphism (SNP) C-159T and exposure to endotoxin (a bacterial product) are a well-replicated example of a gene-environment interaction that is associated with asthma. Endotoxin exposure varies from person to person and can come from several environmental sources, including environmental tobacco smoke, dogs, and farms.  Researchers have found that risk for asthma changes based on a person’s genotype at CD14 C-159T and level of endotoxin exposure.