gene by environment interactions in the development of asthma

Gene by environment interactions in the development of asthma

F. D. MARTINEZ

Respiratory Sciences Center, The University of Arizona Health Sciences Center, Tucson, Arizona, USA

Summary

Present knowledge suggests that asthma is a heterogeneous condition. Different genetic back-grounds may or may not express themselves as asthma-like symptoms, depending on both the natureand the timing of exposures in the individual. Although particular attention has been paid toenvironmental factors that may increase the risk of asthma, it is equally important to understand`protective' exposures that may have decreased during the last decades and may thus explain thereported increases in asthma prevalence. Among these `protective' factors are certain infections andthe role they may have in the inception of allergics and asthma, particularly when they occur atcritical times in the development of the immune system.

In considering the interactions between genetic suscept-ibility and environmental factors in determining theasthma phenotype, two related but different aspects areof relevance. There is convincing evidence that, inestablished asthmatics, factors such as viral infections[1], aeroallergen exposures [2], cold air and weatherchanges [3], among others, can trigger acute exacerba-tions of the disease. The mechanisms by which theseexposures interact with the `asthmatic' immune systemor with the `asthmatic' airway to determine acutesymptoms will not be the main focus of this work.Our main interest is to determine the factors thatinteract with susceptibility genes for asthma, at a time inwhich the asthma phenotype has not yet been estab-lished. In other words, we are interested in thoseexposures that may influence the incidence of asthma.

Inheritability of asthma

The role of genetic influences, relative to those of theenvironment, in the determination of any complex,chronic condition is difficult to ascertain. Theoretically,twin studies provide the best insight regarding theseissues. Since monozygotic (MZ) twins share 100% of thegenetic information transmitted from each parentwhereas dizygotic (DZ) twins share only 50% of thissame information, concordance for asthma in large setsof MZ and DZ twins can be used to assess the role of

genetic factors in determining asthma above and beyondshared environmental backgrounds.

In the case of asthma, twin studies have shown thatbetween 35 and 75% of the susceptibility to asthma isexplained by genetic influences [4±6]. However, twinstudies are not devoid of potential biases. Asthma doesnot have a clear cut and widely accepted definition, andthis is likely due to the wide range of phenotypicexpressions of asthma and asthma-like syndromes in thepopulation. It is possible that minor recurrent wheezing,for example, may be labelled as asthma in an MZ twinof an established asthmatic more often than in the caseof a DZ twin of an established asthmatic. In addition,comparisons of MZ twins and DZ twins are based onthe assumption that both sets of twins share roughly thesame environmental exposures and thus differ only intheir genetic background. It is likely, however, that dueto social and cultural pressures, MZ twins may sharemore of their environment than DZ twins particularlyduring early life. These two sources of bias would spuriouslyincrease the calculated heritability index of asthma.

It is clear from the above considerations that, in theabsence of an accurate knowledge of the aetiology ofasthma, the role of environmental factors can only bedetermine indirectly. The recent increases in asthmaprevalence, which seem to be occurring in manydifferent countries and locales [7], also provide strongevidence in favour of a role of exposures in determiningasthma incidence. In this case, changes in the geneticcomposition of large populations are very unlikely tooccur in such a brief period of time. A further argument

Clinical and Experimental Allergy, 1998, Volume 28, Supplement 5, pages 21±25

AhedBhedChedDhedRefmarkerFigmarkerTablemarkerRef endRef start

# 1998 Blackwell Science Ltd 21

Correspondence: Dr F. D. Martinez, Respiratory Sciences Center, The

University of Arizona Health Sciences Center, Tucson, AZ 85724, USA.

Paper 23 Disc

in favour of a very important role of environmentalfactors in determining asthma incidence is provided bycomparisons of prevalence of asthma and asthma-likesymptoms in populations of similar genetic backgroundswho have either lived in [8] or migrated to [9] localeswith markedly different environmental conditions.These studies raise the issue of what proportion of thepopulation is susceptible to developing asthma symp-toms and, as a corollary, what proportion of thepopulation will not develop asthma-like symptoms evenin the most adverse conditions. Several longitudinalstudies have now shown that, although a core of 5±12%of general population samples (and this `core' preva-lence varies depending on the methods used and thelocales under study) has chronic established disease, atleast three times as many subjects have mild andsporadic asthma-like symptoms sometime during theirlifetime. Who these subjects are is also a function of age.Some subjects only wheeze mildly at an early age duringviral infections, and their symptoms remit sponta-neously with growth [10]. At the other extreme of theage spectrum, elderly subjects may develop asthma-likesymptoms in the absence of exposure to tobacco smokewithout any recall of similar symptoms occurring everbefore in their lives. Finally, a proportion of subjectsdevelop asthma symptoms for the first time after beingexposed to organic and inorganic inhaled chemicals inthe workplace, and some authors believe that themechanism of inheritance of this form of asthma maybe different to that of other forms [11].

The data to support the hypothesis that theseapparently very different expressions of asthma areattributable to different genetic backgrounds are notavailable. Moreover, studies of the familial segregationof asthma have suggested that asthma is inherited eitheras a polygenic condition [12] or with an oligogenicpattern (i.e. a small number of genes having an effectthat goes beyond that of the polygenic background) [13].Taken as a whole, therefore, the evidence presentlyavailable strongly suggests that genetic and environ-mental influences play different relevant roles indifferent subjects. At one extreme, asthma may be the(inevitable) result of the expression of a large number ofsusceptibility genes in a small minority of subjects. Atthe other extreme, asthma may be the (fortuitous) resultof a very specific exposure that results in the expressionof asthma under very specific circumstances. For themajority of subjects, however, asthma appears to be theresult of the interaction between susceptibility genes andnon-specific exposures that are likely to affect either allsubjects or a large majority of subjects in a givenpopulation. This latter mechanism is the most interest-ing one from the point of view of public health, and the

knowledge we have accumulated during the last decadeswill be briefly summarized below.

Allergen exposures and the incidence of asthma

There is little doubt that asthma is associated with anincreased risk of sensitization to certain aeroallergens[14]. It is thus not surprising that exposure to theseaeroallergens has been proposed as a causative factor indetermining asthma [15]. The possibility that genes thatincrease susceptibility to becoming sensitized to theseaeroallergens could interact with early exposure to theseaeroallergens is particularly attractive because it offers amodel for the primary prevention of the disease. Ifexposures to specific aeroallergens can be reduced to aminimum during susceptible periods, the theory goes,the development of asthma could be prevented or atleast postponed [15].

The most widely and persistently studied suchenvironmental factor has been the house-dust mite. Thisugly-looking creature has lingered in the lives of asthmaresearchers for the last 20 or 30 years and has evenominously appeared in the background of scary picturespublished in such prestigious journals as Time Maga-zine. The idea that exposure to house-dust mites couldcause asthma seems to be supported by a widely quotedstudy that suggested that the degree of exposure tohouse-dust mites during the first 2 years of life wasassociated with the likelihood of developing asthma upto age 11 years [16]. The basic tennet behind thisparticular model of asthma causation is that asthmamay behave in general population samples in a mannersimilar to the model suggested by occupational asthma.If there is a specific genetic susceptibility that determinessensitization to specific aeroallergens such as house-dustmites, then avoidance of exposure to these same miteswill inevitably decrease asthma incidence and asthmasymptoms. Trials of rigorous avoidance of house-dustmite exposure are now under way to test this hypothesis.

The main weakness of this rather simplistic approachis that it has not been possible to prove that, within agiven country, subjects exposed to markedly differentlevels of house-dust mite have significantly differentprevalence rates of asthma. In Australia, for example,rates of asthma are slightly higher in the desert interiorwith respect to the coastal regions, but exposure tohouse-dust mites are several times higher in the latterthan in the former [17]. In the USA it has been shownthat in the south-west region of the country, wheresubjects are exposed to significantly lower doses ofhouse-dust mite antigen than in the coastal regions,prevalence of asthma is not lower than that observed inother parts of the country [18]. Both in the Australian

# 1998 Blackwell Science Ltd, Clinical and Experimental Allergy, 28, Supplement 5, 21±25

22 F. D. Martinez

Paper 23 Disc

inland and in the desert south-west of the USA, itappears that Alternaria is the main aeroallergenassociated with asthma, at least as measured by theproportion of asthmatics who are sensitive to this localantigen. In the inner cities of the USA, recent evidencesuggests that sensitization to cockroach antigens isstrongly associated with prevalence and severity ofasthma [19]. Thus, unless one believes that personswho are genetically predisposed to becoming sensitizedto specific antigens decide to live where those antigensare present, the data suggest that sensitization to certainspecific antigens is not the cause but the consequence ofthe process leading to asthma. In other words, personswho are predisposed to asthma become sensitized to thoseaeroallergens that the immune system `sees' through theairway defence system very early during that process.Subsequent exposure to these aeroallergens can certainlymake the process worse, but cannot be considered thefactor that triggers the incidence of the disease. In thisframework, the increased concordance for sensitizationto certain aeroallergens such as house-dust mite amongasthmatic subjects would not be the consequence of acommon genetic predisposition to becoming sensitizedto this antigen, but more likely the result of a sharedpredisposition to reacting with an IgE-mediated responseto substantially similar exposures during early life.

The beginnings of asthma and the timing of allergicsensitization

Strong support for this hypothesis is provided by theelegant studies by Peat et al. on early and late sensitizationand its relationship to asthma [20]. If sensitization tocertain aeroallergens is a causative factor in theinception of asthma, one would expect that the age atwhich sensitization occurs would not have a strongbearing with respect to the likelihood of developing thedisease. In other words, subjects who become sensitizedlate in life would have similar odds of developingasthma as those who become sensitized early in life. Peatet al. [20] showed that children who developedsensitization to aeroallergens (especially house-dustmites) after the age of 8 years old were not more likelyto become asthmatics or to have significant bronchialhyperresponsiveness than those who became sensitizedbefore that age. Moreover, we have shown that subjectswho develop wheezing lower respiratory illnesses duringthe first 3 years of life and who will still be wheezing bythe age of 6 years already have high levels of IgE at amean age of 9 months [10]. All the available evidencesuggests that at that age these subjects either do notproduce IgE against the aeroallergens they will becomesensitized to later in life, or if they do produce IgE, the

levels are so low that they are undetectable by skin testor by the most sensitive assays for specific IgE in serum[21]. It is thus likely that, for the bulk of asthma cases inthe population, an alteration of immune responsivenessmay be present very early in life that predisposes to thedevelopment of IgE mediated reactions in the airway.This appears to be a global pattern of responsiveness,and would thus involve only peripherally a geneticpredisposition to becoming sensitized to specific aero-allergens. This hypothesis does not certainly exclude thepossibility that in certain subjects and given specificpatterns of exposure, exposure to specific inhaled sub-stances may trigger allergic sensitization and the develop-ment of asthma-like symptoms. An example of this patternwould be many forms of occupational asthma. However,the fact that so many subjects can become sensitized, giventhe right exposure patterns, to environmental antigens is notcompatible with the paradigm of a genetically predisposedpopulation to which this pattern of responsiveness isrestricted. In other words, the paradigm of asthma as aresult of the interaction between enhancing environmentalfactors and a population of subjects that is geneticallypredisposed to IgE-mediated immunity is not compatiblewith the epidemiological evidence available today.

A new paradigm: environmental `protective' factors

Epidemiology has been historically much more comfor-table with the classical paradigm of disease causationfirst proposed by Pasteur and Koch. In this paradigm,disease is the result of a `negative' environmental factorsuch as infection that interacts with a genetic back-ground that enhances the expression of the environ-mental factor. There is little doubt that this paradigmhas been extremely successful in developing publichealth policies that have significantly improved morbid-ity and mortality, particularly in developed countries. Itis thus not surprising that many investigators have triedto apply the same general paradigm to complex diseasessuch as asthma. This has resulted in a very expensivesearch for environmental `enhancers' of the expressionof asthma. The observation that asthma seems to bemarkedly less prevalent in environments and areas ofthe world where many of these suspected enhancers (i.e.poverty, exposure to particulates, malnutrition, highrates of infection, etc.) are highly prevalent, suggeststhat this traditional paradigm may not be valid for complexdiseases. An alternative hypothetical scenario explainingthe present epidemiological evidence is badly needed.

Holt et al. [22] have proposed that IgE-mediatedreactions should not be considered as `abnormal', but asone (of several) developmental pathways that can befollowed by the immune system in early life. Based on


Environmental interactions in asthma development 23

Paper 23 Disc

data by Ridge and coworkers [23], Holt et al. havespecifically proposed that this Th2-like pattern is in factthe default alternative present at birth. The developmentof a normal, Th1-like reactivity would thus be the resultof interactions between the immune system and envir-onmental factors (mainly infections) which would `deviate'the immune system towards the Th1-like pattern ofreactivity. In the case of viral infections, their influencecould be explicated through the development of inter-feron gamma-producing CD8+ reactivity during earlylife. In the case of bacterial infections, on the otherhand, the interaction between bacterial products andmacrophages, especially dendritic cells in the airway,would allow the maturation of these antigen presentingcells (APCs), with enhanced production of IL-12 at thetime of antigen presentation. Both interferon-g (IFN-g)and IL-12 are strong signals for naive T-helper cells todevelop into the Th1-like phenotype [22]. In this context,the development of a Th2-like pattern of response wouldoccur in the absence of certain `protective' factors, andboth viral and bacterial infections could be consideredexamples of this type of `protective' influences.

In the context of this paradigm, the presence of geneticvariants that can enhance this protective mechanism mayprove crucial in determining susceptibility to asthma. Forexample, Holt et al. have proposed that exposure tolipopolysaccharide (LPS) at the time of the first encounterswithaeroallergens in theairwaycouldbeapotentprotectivefactor for the development of allergies to inhaled antigens.It is tempting to speculate that genetic alterations in thesignalling pathways that allow LPS and other bacterialproducts to enhance IL-12 production by APCs couldenhance the expression of allergies in early life. Similarly,subjects genetically predisposed to either increased IFN-gproduction or increased responsiveness to IFN-g duringviral infections in early life could also develop strongerprotective mechanisms against the predominance of Th2-like responses in early life. The inverse scenario could bepostulated for subjects who either produce significantamounts of IL-4, or are more responsive (because ofalterations in receptor mechanisms) to IL-4 stimuli [24].

Conclusions

It is unlikely that a single scenario explains the pattern ofresponsiveness to environmental factors present in adisease such as asthma. The phenotypic expression ofasthma is likely to be the final common pathway of manydifferent pathogenic mechanisms. It is thus crucial toconsider a new way of understanding the development ofcomplex diseases that takes into account both enhancingand protective environmental factors. These environ-mental factors interact with a genetic background that is

not `black or white'. More likely, genetic predispositionfor asthma is a spectrum of genotypes going from themost highly predisposed to the most highly protective.

Acknowledgement

This work was funded by grants RO1 (HL-56177) anda Research Development Award for Minority Fac-ulty (HL-031540) from the National Heart Lung andBlood Institutes.

References

1 Johnson SL, Pattenmore PK, Sanderson G et al. Therelationship between upper respiratory infections andhospital admission for asthma: a time-trend analysis. Am

J Respir Crit Care Med 1996; 154:654±60.2 O'Hollaren MT, Yunginger JW, Offord KP et al. Exposure

to an aeroallergen as a possible precipitating factor in

respiratory arrest in young patients with asthma. N Engl JMed 1991; 324:359±63.

3 Jamason PF, Kalkstein LS, Gergen PJ. A synoptic

evaluation of asthma hospital admission in New YorkCity. Am J Respir Crit Care Med 1997; 156:1781±8.

4 Harris JR, Magnus P, Samuelsen SO et al. No evidence foreffects of family environment on asthma. A retrospective

study of Norwegian twins. Am J Respir Crit Care Med1997; 156:43±9.

5 Duffy DL, Martin NG, Battistutta D et al. Genetics of

asthma and hay fever in Australian twins. Am Rev RespirDis 1990; 142:1351±8.

6 Nieminen MM, Kaprio J, Koskenvuo M. A population-

based study of bronchial asthma in adult twin pairs. Chest1991; 100:70±5.

7 Woolcock AJ, Peat JK. Evidence for the increase in asthmaworldwide. In: The Rising Trends in Asthma. Wiley & Sons,

Chichester. Ciba Foundation Symposium 206. 1997; 122±139.8 von Mutius E, Martinez FD, Fritzsch C et al. Prevalence of

asthma and atopy in two areas of West and East Germany.

Am J Respir Crit Care Med 1994; 149:358±64.9 Leung R, Ho P, Lam CW et al. Sensitization to inhaled

allergens as a risk factor for asthma and allergic diseases in

Chinese population. J Allergy Clin Immunol 1997; 99:594±9.10 Martinez FD, Wright AL, Taussig LM et al. Asthma and

wheezing in the first years of life. N Engl J Med 1995;

332:133±8.11 Cullinan P, Taylor N. Inferences from occupational asthma.

In: The Rising Trends in Asthma. Wiley and Sons, Chichester.Ciba Foundation Symposium 206. 1997; 160±172.

12 Holberg CJ, Elston RC, Halonen M et al. Segregationanalysis of physician-diagnosed asthma in Hispanic andnon-Hispanic White families. Am J Respir Crit Care Med

1996; 154:144±50.13 Jenkins MA, Hopper JL, Giles GG. Regressive logistic

modeling of familial aggregation for asthma in 7,394

population-based nuclear families. Genet Epidemiol 1997;14:317±32.


24 F. D. Martinez

Paper 23 Disc

14 Sears MR, Herbison GP, Holdaway MD et al. The relative

risks of sensitivity to grass pollen, house dust mite and catdander in the development of childhood asthma. Clin ExpAllergy 1989; 19:419±24.

15 Peat JK. Prevention of asthma. Eur Respir J 1996; 9:1545±55.16 Sporik R, Holgate ST, Platts-Mills TAE et al. Exposure to

house dust mite allergen (Der p 1) and the development ofasthma in childhood: a prospective study. N Engl J Med

1990; 323:502±7.17 Peat JK, Woolcock AJ. Sensitivity to common allergens:

relation to respiratory symptoms and bronchial hyperre-

sponsiveness in children from three different climatic areasof Australia. Clin Exp Allergy 1991; 21:573±81.

18 Halonen M, Stern D, Wright AL et al. Alternaria as a major

allergen for asthma in children raised in a desert environ-ment. Am J Respir Crit Care Med 1997; 155:1356±61.

19 Rosenstreich DL, Eggleston P, Kattan M et al. The role ofcockroach allergy and exposure to cockroach allergen in

causing morbidity among inner-city children with asthma.N Engl J Med 1997; 336:1356±63.

20 Peat JK, Salome CM, Woolcock AJ. Longitudinal changes

in atopy during a 4-year period: relation to bronchialhyperresponsiveness and respiratory symptoms in a popu-lation sample of Australian schoolchildren. J Allergy Clin

Immunol 1990; 85:65±74.21 Duff AL, Pomeranz ES, Gelber LE et al. Risk factors for

acute wheezing in infants and children: viruses, passivesmoke, and IgE antibodies to inhalant allergens. Pediatrics

1993; 92:535±40.22 Holt PG, Sly PD, Bjorksten B. Atopic versus infectious

diseases in childhood: a question of balance? Ped Allergy

Immunol 1997; 8:53±8.23 Ridge JP, Fuchs EJ, Matzinger P. Neonatal tolerance

revisited: turning on newborn T cells with dendritic cells.

Science 1996; 271:1723±6.24 Hershey GK, FriedrichMF, Esswein LA et al. The association

of atopy with a gain-of-function mutation in the alpha subunitof the interleukin-4 receptor. N Engl J Med 1997; 337:1720±5.


Environmental interactions in asthma development 25

Paper 23 Disc

gene by environment interactions in the development of asthma

Documents