Genetics of Asthma: What Do We Need To Know?

Peter LeSoue f, MD, FRCP (UK), FRACP*

Summary. Establishing the contribution of genetics to the acquisition of asthma is likely to beessential in allowing fundamental questions regarding asthma etiology to be answered. Sometopics that could be addressed include determination of different types of asthma, individualswho have the potential to become asthmatics, and the effect of environmental factors to causeasthma in genetically susceptible individuals. Epidemiological and immunological evidence hasshown that there is an increased prevalence of asthma within families, and twin studies haveshown greater concordance for asthma in monozygotic than dizygotic twins. Similar findingshave been reported for IgE and IgE-related parameters. These observations strongly suggest agenetic component to asthma, but the strength of this influence has been difficult to ascertaindue to the inevitable sharing of environment and genes in family studies. Recent work hasfocused on determining genes involved in asthma. Several genome searches have now beencompleted and regions in 16 of the 22 autosomal chromosomes have been associated withvarious asthma-related phenotypic factors, including total and specific IgE production, airwayhyperresponsiveness, and symptoms of asthma. Polymorphisms associated with changes inphenotype have been described for several genes, including the genes for interleukin-4, tumornecrosis factor-a, the b-chain of the high-affinity receptor for IgE, and the b2-adrenoreceptor.These findings indicate that the molecular genetics of asthma is highly complex and that muchmore work will be needed to allow the genetic susceptibility of asthma to be defined at themolecular level. Pediatr. Pulmonol. 1997; Supplement 15:3–8. © 1997 Wiley-Liss, Inc.

Key words: asthma; genetics; genome searches; candidate gene; association studies.

WHY STUDY GENETICS?

Asthma may best be considered as a loosely definedsyndrome characterized by respiratory symptoms, airwaynarrowing and inflammation; however, this definition en-compasses a wide group of conditions and diseases. Thefailure of previous research to establish a clear definitionof asthma points toward the likelihood that asthma con-sists of a large group of diseases with similar symptoms.Whether or not particular clinical patterns of respiratorydisease should be considered as asthma still remains tobe determined. For example, should viral-inducedwheeze in infants be considered as asthma or a separatecondition?1

Previous work has provided a great deal of importantinformation. Investigations into the etiology of asthmahave established associations between familial and envi-ronmental factors and the risk of development of asthma,whereas other studies have revealed many aspects of thecellular and molecular basis of airway inflammation. Un-fortunately, this information has done little to increasethe understanding of individual susceptibility to asthmaor provide answers to fundamentally important questionsrelated to asthma etiology. Further progress in this fieldmay come from knowledge of the molecular genetic ba-sis of susceptibility to airway narrowing.2,3 Such knowl-edge should help answer basic questions regardingasthma, for example, the following.

1. How Many Different Varieties of AsthmaAre There?

Even though there is a very high prevalence of asthma,it has not, so far, been possible to separate it into differentvarieties. Problems with the subdivision of asthma existat several levels. The first problem is at the level ofdefinition or diagnosis: much has been written on thissubject, and clearly, no universal definition of asthmaexists. This means that there are patients with respiratorysymptoms who fit one definition of asthma but not an-other. Another problem is separating patients who fit ageneral definition of asthma into different subgroups. Forexample, in children with similar symptoms, atopy mayor may not be present, and asthma symptoms may or maynot be present in children with similar evidence ofatopy.4 In addition, some patients have minor evidence ofatopy, and whether they are classified as ‘‘atopic’’ or notis open for debate. For the purposes of this article, a‘‘variety’’ is taken to mean a common molecular genetic

*Correspondence to: Dr. Peter LeSoue¨f, University of WesternAustralia, Department of Paediatrics, Children’s Hospital MedicalCentre, GPO Box D184, Perth, Australia 6001. E-mail: peterles@paed.uwa.edu.au

University of Western Australia, Department of Paediatrics, Chil-dren’s Hospital Medical Centre, Perth, Australia.

Pediatric Pulmonology, Supplement 15:3–8 (1997)

© 1997 Wiley-Liss, Inc.

susceptibility. This definition in itself may eventuallyprove to be too simplistic, because there may be multiple‘‘asthma genes’’ with many combinations of these genescontributing variably to susceptibility.

The question arises as to the importance of separatingasthmatic patients into different types. First, it wouldallow different causes to be determined for each type. Bygrouping subjects with similar genetic factors into thesame study, the chance of finding common patterns ofenvironmental interaction would be enhanced. Second, itwould allow more precise definitions to be developed.This would improve the power of epidemiological stud-ies to identify risk factors and aid clinicians in reachinga diagnosis in difficult cases. Third, it would allowasthma therapies to be targeted toward patients fitting aparticular group. Current trials of new therapies forasthma are generally aimed at asthmatics fitting a broaddefinition of the condition. Response to treatment may bepresent in some types of asthma but not others. Fourth, itwould improve the understanding of the natural historyof asthma and may explain why asthma subsides in somepatients but not others. Finally, it may allow more accu-rate predictions to be made as to those persons mostlikely to develop asthma and facilitate successful preven-tative programs.

2. How Many Individuals Have the Potential toBecome Asthmatic?

From present knowledge, there is no way of determin-ing whether all individuals are susceptible to developingasthma, or if asthma can only develop in certain indi-viduals. An accurate description of the molecular geneticpredisposition toward asthma should help answer thisquestion.

3. How Do Environmental Factors Cause Asthmain Genetically Susceptible Individuals?

To date, extensive epidemiological studies have notbeen able to answer this question. However, understand-ing the susceptibility to asthma at the molecular levelshould allow advances to be made. Theoretically, theexplanation of how genetic and environmental interac-tions cause airway disease could begin at the level of the

interaction between a person’s molecules (abnormalitiesin protein structure or level produced by an altered DNAsequence) and molecules in the environment.

EPIDEMIOLOGICAL ANDIMMUNOLOGICAL EVIDENCE

Epidemiological Evidence

For many years asthma has been known to run infamilies,5 but the strength of the genetic influence hasbeen difficult to ascertain because of the inevitable shar-ing of environment and genes in family studies. Studiesof twins have shown a greater concordance for asthma inmonozygotic than dizygotic twins.6–8 Similar findings intwins have been reported for IgE and IgE-related param-eters9 and for airway responsiveness.10 These twin studydata strongly support a genetic component in asthma, butthey also show a strong environmental effect becausethere are high levels of discordance in the monozygotictwin studies.

Gender is also associated with differences in asthmaprevalence, with males having a greater prevalence thanfemales during early childhood;11 however, this differ-ence is not seen in the second decade of life.12 Respira-tory illness13 and atopy14 are more prevalent in male thanfemale infants. Airway size is a possible reason for thisgender difference, because respiratory function is lowerin male compared with female infants,15 but there is nodifference in respiratory function between male and fe-male adolescents.16 In addition, ethnic background maybe important because the prevalence of asthma variesconsiderably worldwide, but the relative balance of genesand environment is unknown. Airway responsivenessmay be an independent genetic factor, because a recentstudy found that the level of airway responsiveness at 1month of age was not related to any other risk factor forasthma, but did predict airway responsiveness, lung func-tion, asthma, and atopy at 6 years of age.17

Immunological Evidence

The studies on IgE and related measures in twins notedabove5,9 act as excellent evidence for immunological fac-tors having a genetic component. Animal models of IgEinheritance also showed clear evidence of genetic in-volvement, with some rodent studies showing autosomal-dominant, and others autosomal-recessive, inheritance.18

Segregation analyses of IgE responses in humans19

showed either autosomal-dominant20 or -recessive20,21

inheritance, but many families did not show a clear Men-delian pattern. Umbilical cord IgE levels are morestrongly associated with a maternal than a paternal his-tory of atopy.14,22 This could be caused by a direct ma-ternal effect on the intrauterine environment, or by ge-

Abbreviations

FcER1-b High-affinity IgE receptorIgE Immunoglobulin EIL InterleukinNIH National Institutes of HealthSSCP Single-stranded conformational polymorphismTCR T-cell receptorTNF-a Tumor necrosis factor-a

4 LeSouëf

nomic imprinting.23 Associations between umbilical cordIgE levels and outcome have proved to be inconsistent,but the longest follow-up study found that raised umbili-cal cord IgE levels were associated with a fivefold in-crease in asthma at 11 years of age.24

MOLECULAR EVIDENCE

Finding Genes

Over the past few years, research has focused on de-tecting genetic variations that predispose to asthma.Three basic types of study have been undertaken: ge-nome searches, candidate gene, and association studies.

1. Genome searches

Genome searches are used to detect genes when thereis no information about the location of a gene involved.The entire human genome can be scanned using from 150to 400 DNA markers. Approximately 1000 subjects areneeded from nuclear families for such studies. Familiesare often selected with a bias toward asthma, and thismay allow a smaller population to be screened. Eachsubject studied undergoes a full phenotypic assessment,including historical details, respiratory function, airwayresponsiveness and IgE-related parameters. Either link-age analysis or sib-pair analysis can be used to locateregions of the genome involved.25,26 However, theseDNA regions are still relatively long, and other complexand expensive techniques that involve gene mapping arerequired to find the actual gene.

2. Candidate Gene

The candidate gene approach is used when a particulargene is thought to be involved and the gene’s DNA se-quence is known. For example, some of the possiblecandidate genes associated with the inflammatory path-way after airway antigen challenge are illustrated in Fig-ure 1. The simplest way to detect DNA variations in aparticular gene is to compare a group of subjects whohave a clear asthma phenotype with a similar-sized ‘‘nor-mal’’ group.27 Several different molecular techniques areused to screen the appropriate gene to find DNA varia-tions, including the SSCP technique,28 the heteroduplexmethod, chemical and enzyme mismatch cleavage, anddirect sequencing.29 Of these approaches, SSCP is cur-rently the most used, but it can only screen relativelyshort DNA lengths (150–200 base pairs) and detect 70–80% of variations.29 However, when used in combinationwith one of the other techniques, almost 100% of varia-tions can be detected.29

3. Association Studies

Association studies are going to be increasingly usedin the future. As polymorphisms that are associated withphenotypic changes are identified, they can be used inlarge population studies to help define genotype/phenotype relationships. The most useful information islikely to come from studies with extensive longitudinaldata extending from early childhood into adulthood.Eventually, the effect of combinations of polymorphismsin different genes will be examined. If a large number ofrelatively common functional polymorphisms are discov-ered, the genotype/phenotype associations may be verycomplex.

Molecular Genetic Data Currently Available1. Data from Genome Searches

Several genome screening studies have now beencompleted and regions in at least 16 of the 22 autosomalchromosomes have been associated with various asthma-related phenotypic factors, including total and specificIgE, airway hyperresponsiveness, asthma diagnosis, andsymptoms of asthma. Initial publications noted linkagefor atopy or bronchial responsiveness with markers onchromosomes 5, 11, and 14.30–34The first publication ofan extensive genome search recently reported linkage ofvarious asthma parameters for markers on chromosomes4, 6, 7, 11, 13, and 16 (Table 1).35 Further preliminaryinformation has been presented orally at major interna-

Fig. 1. Candidate genes that are possibly involved in airwayhyperresponsiveness after allergen challenge. APC, antigen-presenting cell; Eos, eosinophil; FcER1- b, high-affinity IgE re-ceptor; IFN- g, interferon- g; IL-4, interleukin-4; IL-5, interleukin-5; TCR, T-cell receptor; TNF- a, tumor necrosis factor- a.

Genetics of Asthma 5

tional meetings. For example, results from the large NIHstudy were presented at the Annual Scientific Meeting ofthe American Thoracic Society, in New Orleans, in Mayof 1996. From various components of that study, statis-tically significant linkages were reported for various pa-rameters for chromosomes 1, 2, 6, 7, 10, 12, 13, 17, 18,20, and 21. Although, these NIH results did not includethe markers involved and are very preliminary and notfully confirmed, these results, and the other publishedwork, do point to the likelihood of a very large number ofgenes being involved in causing asthma.

From these results, one can see that linkage is notobtained for the same chromosomal markers by the vari-ous research groups studying different populations. Thus,the question arises, if different genes are shown to belinked to asthma in different populations, does this meanthat the populations have different genotypes? Intuitivelythis would be suspected to be so, but does not have to bethe case. Another explanation is that two populationscould have similar genotypes, and that environmentaldifferences between the two populations could producedifferent phenotypes. Further work is needed before itwill be possible to determine the relative influences ofgenes and environment in a given population.

2. Specific Molecular Genetic Findings

Specific molecular genetic polymorphisms that are as-sociated with changes in phenotype have been describedfor several genes, and some of these are outlined in Table2 and in the text below.

a. Chromosome 5 linkage.The cytokine cluster regionon chromosome 5 is of special interest with regard toatopy and asthma because it contains genes that regulateIgE production. Linkage between markers in this regionand atopy has been reported by several cohorts inEurope, North America, and Australia.31–33,36,37Link-age between the cytokine cluster region and bronchialhyperresponsiveness has been reported in a cohort inHolland.31

b. Chromosome 5, IL-4 gene.A polymorphism hasbeen described in the promoter region (−589 C to T) ofthe IL-4 gene.38 Associations between this mutation andeither asthma or IgE levels have been reported by severalgroups, and Rossenwasser and colleagues have demon-strated that the mutation is associated with changes inIL-4-mediated activity using protein binding and trans-fection experiments in vitro.38 The IL-4 gene is one ofthe strongest candidate genes for causing atopy, becauseIL-4 is the most important cytokine in the control of IgEproduction.39 Location of the mutation in the promoter ofthis gene is in agreement with an up-regulation of IgEresponses.

c. Chromosome 5,b2-adrenoreceptor gene.The genefor the b2-adrenoreceptor has been systematically se-quenced for common mutations associated with asthmaand found to contain four functional mutations. One ofthese, Arg16→Gly, might account for steroid responsive-ness of asthmatics.27 Another mutation, Glu 27 (79 G toC), was associated with reduced airway responsivenessin asthmatics.40 Because these mutations are generallypresent in the same proportion for both asthmatics andnonasthmatics, they are not a likely cause of asthma, butonce asthma is present, they do appear to exert an effecton the severity of asthma.27,40

d. Chromosome 6, HLA genes.Some of the inter-individual differences in reactivity to common allergensoriginates from differences in the individuals’ HLA classII genes. Molecular techniques have been used recentlyto demonstrate an association between particular HLAloci and skin reactivity to environmental allergens.41

e. Chromosome 6, TNF-a gene.The gene for TNF-ais located within the class III region of the human MHCclose to the HLA-B locus. TNF-a has a central role as amediator of the inflammatory response, and has an im-portant role in regulating the immune response.42,43 Re-cent evidence suggests that it may play a pivotal role inthe pathogenesis of asthma.43 Polymorphisms within theTNF-a promoter region have been noted (one of thesebeing −308 G to A).43 An association has been reportedbetween another polymorphism (Nco1) and asthma incohorts from England and from Busselton, Australia.44

f. Chromosome 11 linkage.Linkage between markersin the region of 11q13 and both atopy and bronchialhyperresponsiveness have now been reported by severalgroups.30,45,46However, several other groups have failedto detect linkage in this region.47

g. Chromosome 11, FcER1-b. The gene for theb-chain of the FcER1-b lies within this region. Involve-ment of an FcER1 gene in causing atopy and asthma isbiologically plausible, because this receptor is the mainreceptor responsible for IgE activation of mast cells.Polymorphisms in this gene have been described.48 Oneof these, Leu181–183, was associated with elevated spe-cific IgE of the Busselton population,49 although the im-

TABLE 1—Summary of Positive Results from a GenomeSearch for Quantitative Trait Loci Underlying Asthma 1

Chromosome

TotalserumIgE

Skintest

Eosinophilcount

Airwayresponse to

mechacholine

‘Atopy’(skin test,

RAST,total IgE)

4 +6 + + +7 + + +

11 + +13 +16 + +

1Adapted from Ref. 35.

6 LeSouëf

portance of this mutation remains in doubt. Anotherpolymorphism that has been detected in the gene isE233G, and this results in a change from glutamic acid toglycine at residue 233.50 E233G has been found to beassociated with increases both in skin responses and inbronchial hyperresponsiveness of the Busselton popula-tion, where it occurs in 5.3% of the population.50

h. Chromosome 14 linkage and TCR gene mutation.The alpha/delta region of TCR genes are also candidatesfor causing atopy and asthma. Linkage has been shownbetween DNA markers for the alpha/delta region of chro-mosome 14q11 and both total and specific IgE responsesto house-dust mite and grass.34 A biallelic polymorphismin the Va8.1 gene of the TCR locus has recently beenshown to be associated with increased IgE responses toDer p1 in the Busselton cohort.44

CONCLUSION

Extensive epidemiological studies have made littleprogress in determining individual susceptibility toasthma. Molecular genetic studies of asthma offer theprospect of defining susceptibility at a genetic level andallowing more precise studies on the etiology of asthma.Current findings suggest that many genes are involved inasthma susceptibility, and that the genetic nature ofasthma will be very complex.

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TABLE 2—Genetic Polymorphisms Associated with Asthma Phenotype

Gene Chromosome Polymorphism Phenotype

Interleukin-4 promotor 5 −589 C to T IgE increaseHigh-affinity IgE receptor 11 237 G to A HyperresponsivenessT-cell receptor 14 Va8.1 Increased IgE response to Der p1b2-adrenoceptor 5 Arg 16 to Gly Steroid responsiveness in asthma

5 79 G to ATNF-a promotor 6 −308 G to A Asthma pathogenesis

Genetics of Asthma 7

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