Gene–Environment Interactions—What Can These Tell Us about the Relationship between Asthma and Allergy?

Asthma is a common condition, which is associated with atopy and allergic conditions including hay fever, eczema, and food allergies. Asthma and atopy are both complex conditions where genetic and environmental factors are implicated in causation. Interactions between genetic and environmental factors, likely via epigenetic mechanisms, are widely thought to be important in determining the risk for developing asthma and atopy. The nature of the relationship between asthma and atopy is unclear and the answer to the question “does atopy cause asthma?” remains unknown. This review explores the relationship between asthma and atopy from a gene–environment interaction perspective and tackles the question “are similar gene–environment interactions present for asthma and atopy?” The main finding is that gene–environment interactions are described for asthma and atopy in children but these interactions are seldom sought for both asthma and atopy in the same population. In the few instances where a gene–environment interaction is related to both asthma and atopy, there is no consistent evidence that similar interactions are common to asthma and atopy. Many plausible gene–environment interactions for asthma and atopy are yet to be explored. Overall, from the gene–environment interaction perspective, there is absence of evidence to better understand the complex relationship between asthma and atopy.

where approximately ten genes each make a modest contribution to risk [(5), p. 68-74]. There are several environmental exposures, which are associated with childhood asthma and these include exposure to second hand smoke (SHS), inhaled chemicals, mold, ambient air pollutants, some deficiencies in maternal diet, and respiratory viruses (6). Recent work suggests that the relationship between environmental exposures and asthma may change over time; for example, the relationship between SHS and asthma has become slightly stronger over time, perhaps as children become more susceptible (7). Many non-communicable diseases, such as asthma, have both a genetic predisposition and environmental triggers. The gene-environment relationship is nicely captured in the phrase "genetics loads the gun and the environment pulls the trigger. " Atopy, defined here as production of Immunoglobulin E specific to a common environmental exposure, is a highly prevalent phenomenon in modern children. Some children who are atopic have no symptoms [(8), p. 580-587] and the prevalence of childhood atopy is hard to detect due to it being clinically silent in some individuals, but is likely to be in excess of 30% in Western populations. The prevalence of atopic conditions such as eczema and hay fever is more easily identified due to the presence of symptoms and is close to 30% in many populations despite the use of self-reported diagnosis captured often by different definitions [(9), p. 733-743; (10), p. e008446]. Twin studies of eczema [(11), p. 535-539] and hay fever [(12), p. 2177-2182] suggest that hereditary factors explain up to 80% of causation of these atopic conditions.
The nature of the relationship between asthma and atopy is unclear. While many children with asthma are also atopic and have eczema, hay fever, or food allergies, there are many more children with atopy than with asthma [(9), p. 733-743; (10), p e008446]. In the largest community study of asthma and atopy in the UK, approximately 50% of 6 year olds with asthma (as evidenced by wheeze) were atopic (as evidenced by skin prick positivity) [(13), p. 974-980], i.e., many young children with asthma symptoms are not atopic. The "atopic march, " where at a population level, the prevalences of food allergy, eczema, asthma, and hay fever peak at increasing ages [(14), p. 99-106], has been cited as evidence to support a causal relationship between atopy and asthma but at an individual level, this "march" is very rarely seen [(15), p. e1001748]. While it is possible that atopy may lie on a causal pathway toward asthma, the reverse may also be true (i.e., asthma may lead to the development of atopy) and a third possibility remains that asthma and atopy are independently caused by some other process. The present review is one in a series, which explores the nature of the relationship between asthma and atopy from a number of perspectives. The focus of this review is to review the relationship between asthma and atopy from the gene-environment perspective. Specifically, the hypothesis tested here is: the same gene-environment interactions are associated with both asthma and atopy.
To test this hypothesis, a 2007 review of gene-environment interactions for asthma [(16), p. 1032-1035] was summarized and the literature published after 2007 describing geneenvironment interactions for asthma was reviewed. The literature describing gene-environment interactions for atopy and atopic conditions was also summarized. This was not an exhaustive or systematic review, instead, the aim was to identify a number of gene-environment interactions for asthma and for atopy and determine whether there were any common interactions. Papers were included, which described gene-environment interactions for severity of asthma and atopy. Epigenetic mechanisms are covered elsewhere in this series and the interested reader is referred there.

MeTHODOLOGiCAL iSSUeS FOR GeNe-eNviRONMeNT iNTeRACTiONS
The study of gene-environment interactions for asthma and atopy in childhood is challenging for a number of reasons, which are discussed more fully elsewhere [(17), p. 1229-1240]. The reader should be aware of the following issues before considering the evidence: 1. Definitions of asthma and atopy differs between studies, which makes comparison challenging. For asthma, definitions include self-reported symptoms, current, or "ever" doctor diagnosed asthma and also objective measurements of respiratory physiology, e.g., FEV1. For atopy, definitions might include self-reported current or "ever" eczema, hay fever, and food allergy symptoms, and objective measures such as skin prick reactivity and total IgE. 2. Measuring environmental exposures is a challenge and many different methodologies might be applied to the same exposure. Often, exposure is by subjective report, which is known to be potentially unreliable, e.g., exposure to tobacco smoke. 3. Studies require a large sample size to avoid false positive finding and also to detect small effect sizes. Many studies are underpowered. Publication bias means that relatively small studies where associations are seen are published whereas similar sized studies where no associations are seen are not accepted (or even submitted) for publication. 4. Studies require replication in more than one population to be considered generalizable. 5. How are genetic factor(s) of interest selected and related to which environmental exposure(s)? Searching for plausible interactions between candidate genes and environmental exposures can be justified based on current knowledge but this confines research to what is already known. 6. New analytical approaches are required, which can consider large numbers of single-nucleotide polymorphisms (SNPs) and environmental exposures, often which are measured at different ages in the same individual.

GeNe-eNviRONMeNT iNTeRACTiONS FOR ASTHMA
The 2007 non-systematic review of gene-environment interactions for asthma [(16), p. 1032-1035] found that the majority of the literature had been published since 2000 and was focused in two areas: first, interactions between oxidant exposures (primarily SHS) and variants in genes coding for antioxidant defenses [especially the family of antioxidant enzymes collectively called glutathione-S transferase (GST)]; and second, interactions between exposures to bacteria or bacterial products and variants in genes coding for components of the adaptive and innate immune system (e.g., CD14). See Figure 1.
Since 2007, interactions between oxidant exposures and variants in GST continue to be described, Table 1. Two papers reported on associations between variants coding for the antioxidant protein glutathione S-transferase P1 (GSTP1) and SHS exposure [(18), p. 125; (19), p. 226-232] and neither found an association although one [(18), p. 125] was able to describe increased risk for asthma among those exposed to SHS and low dietary vitamin E, who also were genetically predisposed to oxidant stress. Two other studies related SNPs in the gene coding for GSTP1 and exposure to dampness [(20), p. e30694] and air pollution [(21), p. e52715]; one study described complicated genegene and gene-environment interactions for dampness (but not several other exposures) and asthma [(20), p. e30694] while the second described a small increased risk for asthma among those genetically predisposed to oxidant stress and exposed to nitrogen dioxide (NO2) [(21), p. e52715]. In addition to variants in genes coding for GST, a study from Hungary also observed a twofold increase in asthma risk for children with rare SNPs, which might reduce host antioxidant defenses but only on exposure to high ambient NO2 concentrations [(22), p. [25][26][27][28][29][30][31][32][33].
Exposure to products of tobacco smoke is a well-known risk factor for childhood asthma (6) and interaction with genetic variants, which reduce GST have already been discussed, but interactions with variants in other genes might also be important. The ORMDL3 gene is associated with asthma in many populations and is found in the 17q21 region, so not surprisingly, geneenvironment interactions have been sought between this area of the genome and exposure to products of tobacco smoke.
Two papers [(24), p. 1985-1994; (23), p. 94-97] examined the relationship between many SNPs in the 17q21 region and SHS exposure. One paper found evidence of an interaction between mutant variants and early exposure to SHS and early onset asthma in young adults [(24), p. 1985-1994]. The second paper found no evidence between a single SNP and antenatal exposure to products of tobacco smoke but the mutant variant was associated with a modest increase in risk for early wheeze in association with exposure to pets [(23), p. 94-97]. A third study, from Mexico, reported an unexpected interaction between SNPs in the gene coding for tumor necrosis factor and increased smoking among non-asthmatic children [(26), p. 616-622]. A fourth paper described an interaction between maternal smoking and genetic variant in the IL-1 receptor antagonist for childhood asthma [(25), p. 502-508]. Smoking is an exposure, which is often under reported and which is confounded by many variables including lifestyle and domestic environment, so although not infrequently implicated in gene-environment interactions for asthma, the nature of the relationship cannot be assumed to be causal.
Genetic interactions with house dust mite (HDM) have been sought in two studies [(28), p. 885-92.e2; (27), p. 229-237]; both studies described associations between increased HDM exposure and variants in genes coding for factors associated with the inflammatory response and increased risk for asthma or for respiratory physiological changes associated with asthma. One of these studies was not able to replicate findings in all the populations studied [(28), p. 885-92.e2]. The final exposure considered in gene-environment interactions for asthma in this review is exposure to a farming environment. A study of five populations [(29), p. 138; Jan-144] was not able to replicate interaction between farm exposure and a number of candidate genes for asthma. Not reported 5 SNPs tested were associated with lung function and among those exposed to 10 µg/g HDM, homozygous for the rare genotype for 3 of these SNPs were associated with reduced FVC or increased PC40 among those exposed to higher HDM concentrations compared to children homozygous for the wild type  were associated with lower IgE concentrations for those exposed to pets and higher for those not exposed to pets. No association with asthma and wheeze SNPs were associated with rhinitis (rs1800896), eczema (rs227306), or elevated IgE (rs324015) among those "exposed" to Western environment. Magnitude of effect not stated  Compared to the literature describing gene-environment interactions for eczema, considered for atopy per se is rather sparse. While an interaction between CD14 variants and pets for IgE or eczema is plausible, this need replication in other populations.

CONCLUSiON
Gene-environment interactions were the "new kids on the block" during the first 10 years of this century, and during this time, there were many publications and regular review articles. Since 2010, there has been a notable reduction in the number of published original research articles and reviews of gene-environment interactions for asthma and atopy (or eczema to be more precise). The shift of focus away from gene-environment interactions may be partly explained by disappointment in the relatively few interactions described and their apparently small effect size. Technological developments may also have shifted scientific thinking and gene-environment-wide interaction studies (GEWIS) may be the So what is the evidence that there are common gene-environment interactions for asthma and atopy? One paper describing gene-environment interactions for asthma identified in the earlier review [(16), p. 1032-1035] described an interaction between a variant coding for toll-like receptor 2 (rs 4696480) and living on a farm for both asthma and atopy [(30), p. 1117-1124], but this could not be replicated in other populations subsequently [(29), p. 138; Jan-144]. The present review did identify three studies where a relationship between the same gene-environment interaction was sought for both asthma and atopy but no common interaction was found [(24), p. 1985-1994; (26), p. 616-622; (37), p. 621-630]. There is, therefore, absence of evidence to robustly answer the question "are the same gene-environment interactions associated with both asthma and atopy?" but there is some evidence of absence that the same gene-environment are not related to asthma and atopy.
Studying the relationship between asthma and atopy is not easy due to issues, which include definitions and the coexistence of the two conditions in many individuals in Western populations. The association between asthma and atopy (as evidenced by eczema) may change over time for a population (7), which adds to the challenge in better understanding the nature of the relationship. A paper that is based on epidemiology studies, and which will be frequently cited in this series of reviews, suggests that perhaps as much as 50% of asthma may be attributable to atopy [(41), p. 268-272]. In some countries, many children with asthma are nonatopic [(42), p. 409-416], so the relationship between asthma and atopy is apparently irrelevant for some individuals.
Ultimately, gene-environment interactions are likely to be important to the development of both asthma and atopy but, at this time, do not give a useful insight into the nature of the relationship between asthma and atopy. Other perspectives, for example, intervention studies, may be more helpful in understanding the inter-relationship between asthma and atopy. Some interventions are linked to reduced eczema in preschool children but not asthma [ (43)

AUTHOR CONTRibUTiONS
The author confirms being the sole contributor of this work and approved it for publication.

FUNDiNG
No funding was required for this manuscript.