Asthma-2

Causes of Asthma

Asthma is caused by a complex interaction of environmental and genetic factors.

Researchers do not yet fully understand asthma.[6] These factors can also influence how severe a person’s asthma is and how well they respond to medication.[7] As with other complex diseases, many environmental and genetic factors have been suggested as causes of asthma, but not all of them have been replicated. In addition, as researchers detangle the complex causes of asthma, it is becoming more evident that certain environmental and genetic factors may only affect asthma when combined.

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 on the part of a child's caregiver has been associated with asthma, and is an area of active research. Stress can modify behaviors that affect asthma, like smoking, but research suggests that stress has other effects as well. There is growing evidence that stress may influence asthma and other diseases by influencing the immune system.

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. Antibiotic use 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.

The pool chlorine hypothesis is another hypothesis, based on several local and international studies published since 2003 by researchers in Belgium, in which long-term attendance at chlorinated swimming pools was found to correlate strongly with the probability of children having asthma. The suspected causal link, nitrogen trichloride, is directly associated with asthma in lifeguards and lung damage in recreational swimmers. This hypothesis overlaps epidemiologically with the hygiene hypothesis in that many cleaning agents contain high levels of chlorine.

Genetic

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:

GSTM1
IL10
CTLA4
SPINK5
LTC4S

LTA
GRPA
NOD1
CC16
GSTP

STAT6
NOS1
CCL5
TBXA2R
TGFB1

IL4
IL13
CD14
ADRB2 (β-2 adrenergic receptor)
HLA-DRB1

HLA-DQB1
TNF
FCER1B
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.

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.

CD14-endotoxin interaction based on CD14 SNP C-159T Endotoxin levels     CC genotype     TT genotype

High exposure     Low risk     High risk

Low exposure     High risk     Low risk

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