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(Chest. 2002;121:7S-13S.)
© 2002 American College of Chest Physicians

Asthma Genetics*

William Osmond Charles Cookson, MA, DPhil, MD

* From the Department of Human Genetics, University of Oxford, Oxford, UK.

Correspondence to: William Osmond Charles Cookson, MA, DPhil, MD, Wellcome Trust Centre for Human Genetics, Roosevelt Dr, Headington, Oxford OX3 7BN, UK; e-mail: wocc{at}well.ox.ac.uk


   Abstract
TOP
 Abstract
Genome Screens
 Chromosome 5
 Chromosome 6
 Chromosome 11q
 Chromosome 12
 Chromosome 13q14
 Sharing of Loci With...
 Mendelian Disorders
 Conclusion
 References
 
Asthma is the most common chronic childhood disease in developed nations and is a complex disease that has high social and economic costs. Asthma and its associated intermediate phenotypes are under a substantial degree of genetic control. Identifying the genes underlying asthma offers a means of better understanding its pathogenesis, with the promise of improving preventive strategies, diagnostic tools, and therapies. A number of chromosomal regions containing genes influencing asthma and atopy have been identified consistently by different groups, and a role for several candidate genes has been established.

Asthma has become an epidemic, affecting 155 million individuals in the world. One child in seven in the United Kingdom wheezes,1 and similar numbers suffer from the related disorder of eczema (atopic dermatitis).2 3 Asthma is due to a combination of strong genetic and environmental factors. It has risen in prevalence over the past 30 years in all Westernized societies,4 perhaps as a result of the loss of childhood infections.5 6 7

Many candidate gene and positional cloning studies of asthma have now been carried out. Although the number of candidate gene studies in asthma is growing rapidly, many contain small numbers of subjects and give equivocal results that do not subsequently replicate. This review will, therefore, concentrate on regions identified consistently through genetic linkage, because these by and large represent the strongest genetic effects, and candidates studied within these regions will be discussed in detail.


   Genome Screens
TOP
 Abstract
 Genome Screens
Chromosome 5
 Chromosome 6
 Chromosome 11q
 Chromosome 12
 Chromosome 13q14
 Sharing of Loci With...
 Mendelian Disorders
 Conclusion
 References
 
The first genome-wide screen for linkages to quantitative traits underlying asthma identified significant evidence for linkage on chromosomes 4q, 6 (near the major histocompatibility complex [MHC]), 7, 11q (containing Fc{epsilon}RI-ß), 13q and 16. A replication sample of families in the same study confirmed linkage to chromosomes 4, 11, 13, and 16.8 A two-stage screen in Hutterite families from the United States found suggestive evidence for linkage and replication for loci on chromosome 5q, 12q, 19q, and 21q.9 A screen in German families identified suggestive evidence for linkage to asthma on chromosomes 2q (near the interleukin-1 cluster), 6p (near the MHC), 9, and 12q.10 A genome screen for responsiveness to the house dust mite (HDM) allergen found suggestive linkages to chromosomes 2q, 6p (near the MHC), and 13q, as well as chromosome 8p.11 A genome screen in American families from three racial groups found a weak linkage to broad regions that might match other studies on chromosomes 2q, 5q, 6p, 12q, 13q, and 14q.12 A two-stage genome screen in French families found replicated linkages on chromosomes 1p, 12q, and 17q.13

Thus, the loci most consistently and robustly identified by these screens are on chromosomes 5, 6, 12, and 13.


   Chromosome 5
TOP
 Abstract
 Genome Screens
 Chromosome 5
Chromosome 6
 Chromosome 11q
 Chromosome 12
 Chromosome 13q14
 Sharing of Loci With...
 Mendelian Disorders
 Conclusion
 References
 
Chromosome 5q31 has been studied by many groups following an original observation of genetic linkage to total serum IgE concentrations in extended Amish pedigrees14 and the confirmation of linkage to the same region.15 The region also has been linked to eosinophil levels16 and to schistosomiasis resistance.17 The region contains several genes that modulate atopic responses, including interleukin (IL)-4, IL-13, IL-5, CD14, and granulocyte macrophage-colony-stimulating factor.

Humans (and different strains of mice) seem to exhibit a constitutional preference for either cellular or humoral immune responses,5 18 which are associated with distinct cytokine profiles in T-helper cells (Ths). The profiles are classified as Th-1 or Th-2 responses, respectively. Th-2 responses are characterized by high levels of secretion of IL-4, IL-13, and IL-5, and are associated with atopy.

A number of polymorphisms have been identified in IL-13 and are convincingly associated with a variation in IgE levels in large population samples.19 IL-13 enhances bronchial mucus secretion and up-regulates IgE production.20 It is in close proximity to IL-4 and is highly homologous to that gene. Polymorphisms within IL-4 have been less securely related to IgE levels or atopic disease than IL-13.21 22 Functionally important polymorphisms within the IL-4 receptor {alpha} gene (on chromosome 16) are associated with atopy and asthma,23 24 although positive findings are not universal.25

CD14 is found on the surface of monocytes and macrophages, as well as in a soluble form. CD14 acts as a high-affinity ligand for bacterial lipopolysaccharide (LPS) [endotoxin], and initiates the nonspecific innate immune response to bacterial infection. A polymorphism upstream of the transcription start site for CD14 is associated with high levels of soluble CD14 and low levels of IgE.26 The prevalence of asthma correlates inversely with a rural lifestyle and high ambient levels of LPS, so it has been suggested that the CD14 interaction with LPS may be protective against allergic disease.26

The level of variation in IgE associated with any of the chromosome-5 polymorphisms is of the order of 1% or 2%, and the polymorphisms so far identified cannot be considered to have major influences on the allergic process. Genetic linkage maps of the region suggest the presence of a least two genes influencing atopy.27 Localizations within the region have been imprecise, and the overall impression is that of a weak linkage to a number of adjoining loci.

However, the coincidence of nonhomologous cytokine genes within a limited interval suggests that the region is involved in the coordinate regulation of cytokine responses. Sequence comparison between human and mouse of 1 megabase of the proximal cluster, including interleukins 4, 13, and 5, found 90 noncoding highly conserved sequences.28 Fifteen of these elements were found to be present in other mammals.28 The characterization of the largest element in yeast artificial chromosome transgenic mice revealed it to be a coordinate regulator of IL-4, IL-13, and IL-5.29 This work, therefore, has begun to unpick at a structural level the mechanisms for T-cell commitment to a particular cytokine profile. It also has identified a high level of conservation of controlling elements of gene expression between species. It will be of interest to see whether this level of conservation is observed in other genomic regions.


   Chromosome 6
TOP
 Abstract
 Genome Screens
 Chromosome 5
 Chromosome 6
Chromosome 11q
 Chromosome 12
 Chromosome 13q14
 Sharing of Loci With...
 Mendelian Disorders
 Conclusion
 References
 
The MHC region on chromosome 6 has shown consistent linkage to asthma-associated phenotypes in several studies8 9 10 11 12 and may be considered to be a major locus influencing allergic diseases.

The MHC contains many molecules involved in innate and specific immunity. At the same time, the asthma phenotype is complex, containing inflammatory and allergic components. An investigation of the effects of the MHC on asthma and its related phenotypes, therefore, poses a methodological and statistical challenge.

The class II genes of the MHC have recognized influences on the ability to respond to particular allergens.30 31 32 33 34 35 Asthma and bronchial hyperresponsiveness are associated primarily with an allergy to the HDM and to a lesser degree with allergy to cat dander and molds,36 37 so that genetic control of specific IgE responses is of relevance to clinical disease. The T-cell receptor (TCR) genes, on chromosomes 7q and 14q, are also important potential genetic modifiers of the specific IgE response. Genetic linkage and allelic association have been reported between specific IgE responses and the TCR {alpha}/{delta} locus on chromosome 14q.38 39

The class I genes of the MHC may have important effects on atopic responses, but these have not yet been adequately investigated. Similarly, the class III complement genes contain polymorphisms that may be of relevance to inflammatory or immune diseases, but which have not yet been tested in asthmatic subjects.

Nonclassical MHC genes also may have an impact on asthma through nonallergic pathways, and a polymorphism in the control elements of inflammatory cytokines and their receptors is an important mechanism for flexibility in the immunoregulatory machinery.40 Tumor necrosis factor (TNF) is a potent proinflammatory cytokine that is found in excess in asthmatic airways. A polymorphism in the TNF complex is associated with variation on the expression of TNF-{alpha} and with the presence of asthma.41 42 43 These results emphasize the inflammatory nature of the asthmatic response, as distinct from its allergic basis.


   Chromosome 11Q
TOP
 Abstract
 Genome Screens
 Chromosome 5
 Chromosome 6
 Chromosome 11q
Chromosome 12
 Chromosome 13q14
 Sharing of Loci With...
 Mendelian Disorders
 Conclusion
 References
 
The linkage of atopy to a VNTR (ie, variable number of tandem repeats) polymorphism on chromosome 11q13 was first reported in 198944 and was at first disputed.45 The ß-chain of the high-affinity receptor for IgE (Fc{epsilon}RI-ß) was subsequently localized to the region. The Fc{epsilon}RI receptor acts as the allergic trigger on mast cells and other types of cells, and is central to the allergic response.46 The ß-chain is not essential for Fc{epsilon}RI function, but it both stabilizes the surface expression of the receptor and acts as an amplifying element within it.47 Any variation in the level of the ß-chain expression may therefore modify receptor function.

A polymorphism in Fc{epsilon}RI-ß has been related to atopy,48 asthma,49 bronchial hyperresponsiveness,50 51 and severe atopic dermatitis.52 A polymorphism within the gene also has been associated with levels of IgE in heavily parasitized Australian aborigines, implying a protective role for the gene in helminth infestation.53

Although coding changes have been identified within Fc{epsilon}RI-ß,54 55 they are conservative and do not seem to alter gene function.56 The Ile181Leu polymorphisms identified by Shirakawa et al54 have not been found in several other studies57 58 59 but have been found in association with asthma in Kuwaiti Arabs60 and black South Africans.61 The difficulty in their identification nevertheless suggests that they are artifactual or in homologous sequences out of the Fc{epsilon}RI-ß gene. The structural variation that causes the effect of this gene on patients with asthma, therefore, has not yet been identified.

The genetic linkage and association of atopy to the locus both have been typified by a strong maternal effect,52 62 63 with preferential linkage and the transmission of maternal alleles to affected children. Maternal effects are well-recognized in allergic disorders, and asthma, eczema, elevated serum IgE concentrations, and skin prick test positivity in children all have been accompanied by an increased prevalence of asthma or atopy in mothers.64 The preferential transmission of or linkage to alleles from either the maternal or paternal sides also has been observed for other loci influencing allergic disease, including those identified on chromosomes 13 and 16.8

Parent-of-origin effects have been noted in other immunologic disorders, including type I diabetes,65 rheumatoid arthritis,66 inflammatory bowel disease,67 and selective IgA deficiency.68 Parent-of-origin linkages also have been observed in the same diseases, so that the preferential linkage of paternal alleles is seen from the insulin locus and type I diabetes,69 and HLA alleles for selective IgA deficiency.68 These findings suggest a common underlying mechanism for parent-of-origin effects in immune disorders. The monoallelic expression of cytokines and cell-signaling molecules is recognized70 71 72 and mediated by methylation,73 providing a potential mechanism for these effects.


   Chromosome 12
TOP
 Abstract
 Genome Screens
 Chromosome 5
 Chromosome 6
 Chromosome 11q
 Chromosome 12
Chromosome 13q14
 Sharing of Loci With...
 Mendelian Disorders
 Conclusion
 References
 
The initial demonstration of the genetic linkage of asthma to chromosome 12q74 was followed by single-locus confirmatory studies75 76 and by several general genome screens.9 10 12 13 In addition, a genome screen in a mouse model of asthma found a linkage to bronchial hyperresponsiveness on mouse chromosome 10 in the region of syntenic homology to human chromosome 12q.77 The facility with which many groups have identified a linkage to this region suggests that it is a true major atopy locus. Interferon-{gamma} does not seem to be responsible for the linkage. High-density mapping of the region has been begun,78 and it is likely that positional cloning of the gene will be possible.


   Chromosome 13Q14
TOP
 Abstract
 Genome Screens
 Chromosome 5
 Chromosome 6
 Chromosome 11q
 Chromosome 12
 Chromosome 13q14
Sharing of Loci With...
 Mendelian Disorders
 Conclusion
 References
 
A linkage of the total serum IgE to the esterase D protein polymorphism on chromosome 13q14 was reported in 1985.79 The linkage of chromosome 13q to atopy was confirmed by a genome-wide scan8 and by a single-locus study of Japanese families.80 The same study identified potential linkage disequilibrium (LD) between disease and D13S153.80 A two-stage screen in Hutterite families from the United States found a linkage of asthma to chromosome 13q21.39 in the first-stage families but not in the second-stage families. A linkage of chromosome 13q14 to HDM allergy in children with asthma also has been observed,81 as has a linkage to children with atopic dermatitis.82

These results suggest that chromosome 13q14 also contains a major atopy locus. The same chromosomal region has been shown to be linked to total serum IgA concentrations.83 Low levels of serum IgA occur much more frequently in atopic children than in healthy children,84 and salivary IgA deficiency is more common in infants with atopic parents.85 Ig production is known to be under the control of many genes (reviewed by Corrigan86 ), none of which have been mapped to chromosome 13q14. The gene of interest may encode a regulatory component of the humoral immune system but, alternatively, might influence both IgA levels and atopic status by influencing the mucosal handling of allergens.


   Sharing of Loci With Other Disorders
TOP
 Abstract
 Genome Screens
 Chromosome 5
 Chromosome 6
 Chromosome 11q
 Chromosome 12
 Chromosome 13q14
 Sharing of Loci With...
Mendelian Disorders
 Conclusion
 References
 
Genetic studies of other disorders also may have an impact on asthma and atopy. Crohn’s disease and ulcerative colitis are inflammatory bowel diseases of unknown etiology that show familial clustering.87 88 89 Genome-wide screens have implicated loci on chromosomes 3, 7, 12, and 16.90 91 92 The regions on chromosomes 7 and 12 may coincide with the asthma and atopy loci on the same chromosomes. Polymorphism in the IL-1 cluster on chromosome 2 also has been shown to influence the severity of the disease.93 94 A genome-wide screen in families with rheumatoid arthritis similarly has shown linkage near the asthma locus on chromosome 2 and the TCR-{alpha} locus on chromosome 14.95 Linkage to type I diabetes is found near Fc{epsilon}RI-ß on chromosome 11q13.96 These findings suggest that important genes or gene families may be common to several inflammatory and immune disorders.


   Mendelian Disorders
TOP
 Abstract
 Genome Screens
 Chromosome 5
 Chromosome 6
 Chromosome 11q
 Chromosome 12
 Chromosome 13q14
 Sharing of Loci With...
 Mendelian Disorders
Conclusion
 References
 
Asthma, eczema, and allergic diseases are associated with a number of mendelian disorders. The identification of genes causing such disorders is much easier than the positional cloning of complex disease genes. These mendelian disorders may therefore be extremely helpful in identifying genes influencing asthma and allergy. They include Netherton’s syndrome,97 98 Job syndrome (also known as hyper-IgE syndrome or Buckley’s syndrome),99 thymic hypoplasia (DiGeorge syndrome), cellular deficiency with Igs (Nezelof syndrome),100 selective IgA deficiency, and Wiskott-Aldrich syndrome.

Netherton’s syndrome is a rare recessive disease in which children are born with a severe ichthyotic dermatosis.97 Severe symptomatic atopy is a universal accompaniment of the disease.98 The gene for Netherton’s syndrome has recently been located distal to the chromosome 5 cytokine cluster,101 and the gene underlying the disorder has been identified as SPINK5.102 SPINK5 codes a multidomain serine protease inhibitor LEKTI, which is expressed in the epithelium, mucosa, and thymus.103 Common coding polymorphisms have been identified in the gene by our group, and these show associations with atopy, asthma, and eczema in children without Netherton’s syndrome. These findings therefore define a new pathway for allergic disorders.

Other mendelian disorders localize to regions that may be relevant to common allergic diseases. Selective IgA deficiency has been localized to the MHC.68 Hypereosinophilia syndrome has been localized to the distal part of the chromosome 5 cytokine cluster,104 and it is of interest that acquired hypereosinophilia is associated consistently with translocations on chromosome 5q35.105 106 Hyper-IgE syndrome has been linked to the distal arm of chromosome 4q.107 A small chromosomal deletion in one child with the disease may have limited this localization to a 20-megabase interval.107 A linkage of the total serum IgE to this region has been seen in at least one genome scan (http://www.well.ox.ac.uk/asthma/public/GenomeScan/index.html),8 suggesting that this locus also may have an affect on the normal regulation of IgE levels.


   Conclusion
TOP
 Abstract
 Genome Screens
 Chromosome 5
 Chromosome 6
 Chromosome 11q
 Chromosome 12
 Chromosome 13q14
 Sharing of Loci With...
 Mendelian Disorders
 Conclusion
References
 
The positional cloning of the genes underlying asthma and allergic disorders is becoming increasingly tractable. Agreed-on regions of strong genetic linkage have emerged, some of which coincide with linkages to single-gene disorders or to other immunologic diseases. The completion of the human genomic sequence and the availability of the deep public expressed sequence tag databases mean that laborious physical mapping of these loci may not be necessary. The key element in gene discovery will be the identification of robust patterns of LD between markers and disease. LD mapping of at least one atopy locus has shown that LD is irregularly distributed,108 and the challenge is to develop statistical as well as genotyping methods to handle dense local single-nucleotide polymorphism maps.


   Footnotes
 
Abbreviations: HDM = house dust mite; IL = interleukin; LD = linkage disequilibrium; LPS = lipopolysaccharide; MHC =major histocompatibility complex; TCR = T-cell receptor; Th = T-helper cell; TNF = tumor necrosis factor


   References
TOP
 Abstract
 Genome Screens
 Chromosome 5
 Chromosome 6
 Chromosome 11q
 Chromosome 12
 Chromosome 13q14
 Sharing of Loci With...
 Mendelian Disorders
 Conclusion
 References
 

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