Asthma is a heterogeneous disease that is characterized by reversible airway obstruction and airway inflammation. It is among the most common chronic diseases, affecting more than 300 million people worldwide9
. Similar to other immune-mediated diseases, the prevalence of asthma is highest among developed countries and has risen significantly over the past few decades10
, especially in countries transitioning to a western lifestyle9
, attesting to the importance of environmental modifiers of disease risk.
Epidemiologic studies of asthma have revealed numerous associations between exposures and subsequent risk for asthma. The sheer number of validated risk factors for asthma, many of which are often known and measurable, have placed asthma at the forefront of studies on GEIs and some of the best and most replicated examples of such interactions have come from this field (see, for examples, recent reviews on this topic11
). Moreover, these studies have established that timing of exposure in the lifecycle is a critical variable in determining risk (), and that risks differ for childhood-onset and adult-onset asthma.
Figure 1 Risk and Protection Factors Influence Asthma Risk Throughout the Lifecycle. Epidemiologic studies of asthma have established numerous risk and protection factors that exert their effects at specific stages of the lifecycle. The relationship of some investigated (more ...)
The prenatal environment is the first exposure that establishes lifelong risks for asthma in the fetus. During this period, maternal smoking is a significant risk for subsequent asthma15
. Maternal asthma is among the most significant and consistent risk factors, and a greater risk factor than paternal asthma, for childhood asthma18
, thereby suggesting that the in utero
environment differs between asthmatic and non-asthmatic mothers and contributes to subsequent risk of asthma in the fetus. Sex, which is established at conception, has opposite effects on asthma risk in the pre- and post-puberty periods, whereby many more boys receive a diagnosis of asthma by the age of 6 but diagnoses in girls predominate after puberty (reviewed in reference21
). Moreover, asthma resolves in many boys with early-onset asthma so that by adulthood there are significantly more women than men with asthma. Sex may exert its effects on risk prenatally or throughout life by modifying responses to other environmental risk factors, or it may directly affect risk by differentially modifying gene expression (discussed in detail in reference 21
During the first year of life, and in some cases prenatally, a number of exposures have been associated with protection from asthma in childhood. For example, exposure to large animals among European farmers22
, having a dog in the home26
, attending daycare29
, or drinking unprocessed cow’s milk32
has been associated with protection against asthma in childhood, and gives support to the ‘Hygiene Hypothesis’ (Box 1
) as an explanation for the rising prevalence of asthma risk in westernized countries34
. In contrast, some ‘exposures’ during the first three years of life are associated with higher risk for asthma. These include allergic sensitization and the presence of wheezing illnesses with respiratory viral infections, particularly those due to rhinovirus or respiratory syncytial virus35
. Whether these conditions themselves alter the risk profile of the child or are merely early manifestations of asthma in genetically susceptible children is not known, but their associations with the subsequent development of asthma by age 6 is undisputed.
The Hygiene Hypothesis
The Hygiene Hypothesis is an evolving concept. The hypothesis was initially formulated to explain the protective effect of having older siblings on risk of hay fever and eczema34
and later extended to explain the marked increase in the prevalence of allergies observed in western societies over the last few decades. Reduced exposure to infections in early childhood not only due to smaller family sizes, but also to improved living standards and higher personal hygiene, has been proposed to result in increased risk of developing allergic diseases. This theory was then integrated with the then dominant Th1/Th2 paradigm and further suggested that the hygienic environments associated with western lifestyles deprive the immune system of stimuli required to boost Th1 responses in early childhood, leading to a surge in the prevalence of Th2-mediated allergic disease105
. When it became clear that both Th2-mediated allergic disorders and Th1-mediated autoimmune diseases are on the rise in the western world10
, the hygiene hypothesis was further updated with a regulatory twist. According to its most recent version, immuno-regulatory mechanisms are activated by interactions between the innate immune system and the microbial environment, particularly when these interactions occur in utero
and/or in early life106
. These mechanisms balance and fine tune both Th1 and Th2 responses, but are currently compromised by a decrease in, and possibly by qualitative alterations of, the microbial burden the immune system encounters in western societies108
. This hypothesis awaits further integration with our still incomplete understanding of the role that genetic variation plays in shaping immune responses to environmental stimuli109
Beyond infancy, additional exposures are important in establishing risk for asthma, including obesity or high body mass index (BMI)39
, occupational exposures42
, and air pollution44
. These risks are likely increasing the penetrance of asthma in genetically susceptible individuals, but it is noteworthy that the risk alleles associated with occupational asthma47
, for example, are often at loci that have not been implicated in asthma in non-exposed individuals. Moreover, it is likely that childhood- and adult-onset asthma (i.e., age of onset of asthma) have only partially overlapping genetic etiologies2
Demonstrating that a particular exposure is associated with risk for or protection from a disease does not necessarily imply that GEIs are at play, but the fact that not all exposed individuals develop the disease suggests that genetic variation between individuals may be important. To establish a GEI one must show that specific genotypes have different responses to the same ‘exposure’ by demonstrating that the effects of ‘exposure’ (for example, the development of or protection from a disease) vary between individuals with different genotypes. GEIs can show different patterns of associations, which are described below for asthma and in for other phenotypes and diseases. The different patterns of GEIs are illustrated in .
Examples of recent (2009–2010) reports of GEIs for behavioral, gene expression, and disease phenotypes.
Figure 2 Types of GEIs. The yellow line in each panel corresponds to risk in exposed individuals; the red line corresponds to risk in non-exposed individuals. Examples from this review that illustrate each type of interaction are shown below the panels. It is (more ...)