(Chest. 2004;126:105S-110S.)
© 2004
American College of Chest Physicians
Genetics of Asthma and COPD*
Similar Results for Different Phenotypes
Deborah A. Meyers, PhD;
Michael J. Larj, PhD, FCCP and
Leslie Lange, PhD
* From the Center for Human Genomics, Wake Forest University School of Medicine, Winston-Salem, NC.
Correspondence to: Deborah A. Meyers, PhD, Center for Human Genomics, Wake Forest University School of Medicine, Medical Center Blvd, Winston-Salem, NC 27157
 |
Abstract
|
|---|
Asthma and COPD are common respiratory diseases that are caused by the interaction of genetic susceptibility with environmental factors. Environmental influences are important in both diseases, and although there are differences in genetic susceptibilities, there are also similarities. Three examples of interest for both asthma and COPD patients are discussed. The first is the results of family studies, which have shown evidence for susceptibility loci for both asthma-related and COPD-related phenotypes in the same chromosomal region. Second, evidence for a gene-environment interaction with passive smoking for asthma patients compared with individual smoking for COPD patients will be covered. The third is an example of one candidate gene (interleukin-13), in which similar results have been observed for both asthma and COPD.
Key Words: asthma • COPD • FEV1 • FVC
|
Introduction
|
|---|
Asthma and COPD are common respiratory diseases that are caused by the interaction of genetic susceptibility with environmental factors.12 The individual risk of developing asthma or other atopic diseases is defined by the complex interaction of these hereditary factors and environmental stimuli. Asthma and COPD are distinct because airway obstruction in asthma patients is largely reversible, while COPD has a more pronounced fixed deficit.23 COPD is strongly influenced by environment. An example is cigarette smoking, but not all individuals with a significant smoking history develop this disease, suggesting genetic susceptibility. Environmental influences are also important in the development of asthma, and include exposure to environmental pollutants such as cigarette smoke, allergens both within and outside the home, and respiratory infections, especially viral infections.4567
Research of late has examined genetic susceptibilities that are common to the two entities. The following three examples of interest for both asthma and COPD patients from different areas of genetics will be discussed: (1) results of family studies showing evidence for susceptibility loci for both asthma-related and COPD-related phenotypes in the same chromosomal region; (2) results from gene-environment analyses showing evidence for a gene-environment interaction between passive smoking and asthma compared with the known relationship between smoking and COPD; and (3) the results of several studies on a single candidate gene showing evidence for a significant association with both asthma and COPD (Table 1
).
|
Genome-Wide Screens for Both Asthma-Related and COPD-Related Phenotypes Showing Linkage to Chromosome 2q
|
|---|
Genome-wide screens are routinely performed to identify chromosomal regions that are likely to contain genes related to the phenotype of interest. After characterizing families for the disease or trait of interest, these screens are performed by genotyping family members for highly informative DNA markers. Cosegregation of the disease or trait with DNA markers from a given chromosomal region indicates the presence of a disease-related gene. A genome-wide screen of families,8 which was ascertained through a proband with COPD for the related phenotype FEV1/ FVC ratio, has shown evidence for linkage to chromosome 2q. A genome-wide screen in Dutch asthma families9 has shown evidence for linkage to the same region for the asthma-related and allergy-related phenotype of total serum IgE levels.
A genome-wide screen has been performed in families of patients with early onset COPD.8 Seventytwo probands with early onset COPD were collected with an FEV1 of < 40% predicted and a mean age of < 53 years. First-degree and older second-degree relatives were studied, and a subsequent mean pedigree size of 8.1 individuals was attained. Three hundred seventy-eight DNA markers were genotyped in 607 subjects.8 The number of pack-years of individual smoking was included as a covariate in the analyses. In the initial genome-wide scan, significant evidence for the linkage for the FEV1/FVC ratio was demonstrated on chromosome 2q, with a logarithm of the odds (LOD) of 4.12 at 222 centimorgans in these COPD families. The LOD score represents the odds in favor of linkage between a given DNA marker and the phenotype of interest. An LOD score of 3.3 is considered to be significant for a genome-wide screen. The heritability estimate was 35.3%. Significant covariates included age and the number of pack-years of smoking.
A genome-wide screen for asthma-related phenotypes was performed in a Dutch asthma family population. Two hundred subjects with asthma who were originally studied between 1962 and 1975 were restudied for asthma-related and allergy-associated phenotypes approximately 25 years later. In addition, the same phenotypic characterization was performed on their spouses, children, and grandchildren over age 6, resulting in data on 200 families with 538 subjects.9 Families were used in linkage studies, while probands and their spouses, used as case patients and control subjects, were appropriate for association studies (see the interleukin [IL]-13 example later in this article). From this family study cohort,9 a genome-wide search for genes regulating total serum IgE levels was performed. Evidence for linkage to chromosome 2q was seen for the regulation of total serum IgE levels in this asthma family study in the same region as that seen for FEV1/FVC ratio in the early onset COPD family study that was performed by Silverman and colleagues.8 Total serum IgE levels have been previously shown101112 to correlate with asthma and bronchial hyperresponsiveness. In addition, in this population, there was a significant correlation between log total serum IgE levels and FEV1/FVC ratio (r = 0.33; p < 0.001).
The findings from these two studies suggest that polymorphisms in at least one gene on chromosome 2q are important in determining the degree of obstructive lung disease, as measured by the FEV1/FVC ratio, in which a decrease in ratio is a finding that is characteristic of both COPD and asthma. In addition, either the same gene or an additional linked gene is important in the regulation of total serum IgE levels, a measure that is associated with both the asthmatic and atopic phenotype.
|
Gene-Environment Interaction for Asthma Susceptibility
|
|---|
Genome-Wide Screen and Passive Smoking Exposure
Evidence also exists for gene-environment interactions for asthma susceptibility and for COPD. Cigarette smoking is the major environmental determinant of COPD. However, not all smokers develop COPD, suggesting the importance of other factors including genetic susceptibility.
Early environmental factors are important in asthma, although they are difficult to quantify. Several studies131415 have demonstrated that prenatal or early childhood exposure to cigarette smoke has a detrimental effect on lung function and increases the risk of respiratory diseases such as asthma. There are now two studies showing evidence for a geneenvironment interaction for asthma susceptibility and passive exposure to cigarette smoke.
The Collaborative Study on the Genetics of Asthma16 ascertained families through the identification of two siblings with asthma. Family members completed a comprehensive respiratory questionnaire, had spirometry performed both before and after bronchodilator administration, and, additionally, underwent a methacholine challenge. Total serum IgE levels were measured, and skin-prick testing was performed for multiple antigens. Further analysis of the Collaborative Study on the Genetics of Asthma cohort, using a history of exposure to passive smoking, was performed on 144 white families. The probands (ie, siblings with asthma) all had a < 5-pack-year history of smoking, but in 51 of the 144 families these siblings had passive smoke exposure that was related to parental cigarette smoking. Several areas of linkage were strengthened or refined when passive smoking history was included in the genome-wide linkage analysis. Three regions with nominal evidence for linkage were identified. When stratified on the basis of smoke exposure, each showed a significant increase from the baseline LOD score. For chromosome 1p, the LOD score in the exposed group (51 families) increased to 1.29 from an LOD score of 0.54 using all 144 families. The LOD score for the unexposed families was zero. The linkage peak in the exposed group also appeared narrower than the peak found in all asthmatic patients in this region. For chromosome 5q, the initial LOD score was 0.34 in the total sample, but this increased to 1.23 in the exposed group (p = 0.05). This region also had an LOD score of zero at this position in the unexposed families.17 Although the evidence for linkage in the total sample was relatively weak, the evidence increased when analysis was performed for a genotype-environment interaction (ie, passive tobacco smoke exposure).
More definitive results were seen in the second study of the same Dutch families described previously.18 In the 200 Dutch families, the families were identified through a parent with asthma who had originally been identified 25 to 30 years before. Although the probands were selected for not having a significant history of smoking when first studied, approximately half of the probands (98 probands) did have a history of smoking, resulting in exposing their children to passive tobacco smoke in the prenatal period and/or as infants and young children. A genome-wide screen analysis showed evidence for susceptibility loci for the development of bronchial hyperresponsiveness in several chromosomal regions, with the strongest evidence for chromosome 5q, a region also seen in other studies. For chromosome 5q, the LOD score was 2.8 in the entire sample but increased to 3.7 in the tobacco-exposed families.18 The LOD score was 0.2 in unexposed families. Thus, a strong gene-environment effect for passive smoke exposure was again observed.
Exposure to passive smoking may represent an environmental factor that can be used in family studies where it is usually very difficult to obtain detailed information on specific environmental exposures occurring in early childhood before an individual develops bronchial hyperresponsiveness and asthma. The incorporation of environmental tobacco exposure into the linkage analysis enhanced the evidence for linkage in regions that harbor susceptibility genes interacting with environmental factors, such as exposure to tobacco smoke, and subsequently confer increased risk for asthma or COPD (Fig 1
). Taking into account known environmental risk factors might also help to identify more homogeneous subgroups to help clarify the multiple independent genetic pathways for the development of asthma or COPD.
View larger version (11K):
[in this window]
[in a new window]
[Download PPT slide]
|
Figure 1. Changes in LOD score on chromosome 5q in separate genome-wide screens for asthma-related phenotypes, stratified on the basis of passive tobacco smoke exposure. Data from Colilla et al17 and Meyers et al.18
|
|
|
Candidate Gene Association Studies for IL-13 in Populations Ascertained for Different Pulmonary Phenotypes
|
|---|
Another approach to determining genetic susceptibility to common diseases is to identify candidate genes based on their function and/or chromosomal location (from the results of genome-wide screens in families), and to study these genes in populations of case patients who have the disease in question as well as appropriate unaffected control subjects. This approach has led to the evaluation of common candidate genes for COPD and asthma, and several common polymorphisms in candidate genes have been analyzed for both diseases. Examples are the candidate gene association studies that have been performed for the promoter polymorphism –1111 in the IL-13 gene (Fig 2
) in populations identified as having either asthma or COPD. This polymorphism has been found to be associated with asthma in two separate Dutch populations and with COPD in a Dutch population.
Numerous genetic studies192021 have mapped an asthma or atopy susceptibility gene to a region on chromosome 5q31-q33 in several populations. This region contains a cluster of proinflammatory cytokines that are important in immune regulation, including IL-13 and IL-4. These cytokines are produced by T helper cells and are capable of inducing isotype class switching of B cells to produce IgE. Therefore, it is possible that polymorphisms in the IL-13 gene contribute to the complex regulation of atopy, asthma, and COPD phenotypes.2223 In allergic asthma patients, van der Pouw Kraan and colleagues24 found a significant difference in the frequency of the T allele for case patients and control subjects in a promoter polymorphism (–1055) in the IL-13 gene. By assuming the Hardy-Weinberg equilibrium, the frequency of the T allele was calculated as 28.2% in case patients and 14.9% in control subjects. A comparison of the frequencies of the genotypes resulted in a p value of 0.02 (Table 2
). This assessment was performed in 101 allergic asthmatic patients and 107 nonatopic control subjects.24 This same polymorphism was evaluated in the Dutch asthma family study by Howard and associates.25 The case patient and control subject frequencies for an IL-13 polymorphism (–1111) were very similar (Table 2) and were significantly different between case patients and control subjects (p = 0.02). One hundred seventy-one asthmatic adults and 120 control subjects were studied.25
Evidence for the association of the IL-13 polymorphism (–1111) also has been seen in COPD patients. In a further study by van der Pouw Kraan et al,26 case patient and control subject frequencies for the IL-13 polymorphism (–1111) in COPD showed a frequency of the T allele of 26.5% in case patients and of 14.6% in control subjects (p < 0.01) [Table 2]. This was observed in 151 COPD patients and 99 control subjects (frequency in 78 smoking control subjects, 16.0%).26
Case patient and control subject frequencies for an IL-13 polymorphism (–1111) have shown similar frequencies for the T allele in two asthma studies and in one COPD study. However, there were relatively small sample sizes in each study, and larger, statistically more powerful studies may not show this difference.27 Similar data by Ohar and coworkers28 evaluating the IL-13 polymorphism (–1111) in COPD patients showed a similar frequency of the T allele in the case patients but a much different frequency in the control subjects. The frequency of the T allele was 23.9% in COPD patients and 20.0% in control subjects (difference not significant). This evaluation was performed in 205 individuals with COPD and in 408 control subjects with > 20 pack-years of smoking (frequency in all control subjects, 22.0%; 942 control subjects). However, these results for the IL-13 gene demonstrate the approach of evaluating candidate genes for both asthma and COPD, and observing similar allele frequencies in patients with either disease.
|
Summary
|
|---|
Asthma and COPD are common pulmonary diseases having both different and similar clinical features.29 Genetic studies have provided evidence for multiple-susceptibility loci for each disease. As shown in the examples described above, some of these loci may be the same for both diseases. Genome-wide screen analyses have shown similar results in at least one chromosomal region for both diseases as well as evidence for gene-environment interactions (eg, active smoking in COPD patients, and passive smoking in asthma) [Fig 1]. In addition, there are candidate genes such as IL-13 that have been studied in patients with each disease with similar results (Table 1). Future genetic studies of both diseases should be designed to further investigate these differences and similarities.
|
Footnotes
|
|---|
Abbreviations: IL = interleukin; LOD = logarithm of the odds
|
References
|
|---|
- Howard, TD, Meyers, DA, Bleecker, ER (2003) Mapping susceptibility genes for allergic diseases. Chest 123,363S-368S[Abstract/Free Full Text]
- Pauwels, RA, Buist, AS, Calverley, PMA, et al Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: NHLBI/WHO Global Initiative for Chronic Obstructive Lung Disease (GOLD) workshop summary. Am J Respir Crit Care Med 2001;163,1256-1276[Free Full Text]
- National Institutes of Health, National Heart, Lung, and Blood Institute. National Asthma Education and Prevention Program Expert Panel Report: guidelines for diagnosis and management of asthma; update on selected topics. 2002 National Institutes of Health. Bethesda, MD: NIH Publication No. 02–5075
- Wang, Z, Chen, C, Niu, T, et al Association of asthma with ß2-adrenergic receptor gene polymorphism and cigarette smoking. Am J Respir Crit Care Med 2001;163,1404-1409[Abstract/Free Full Text]
- Holgate, ST Genetic and environmental interaction in allergy and asthma. J Allergy Clin Immunol 1999;104,1139-1146[CrossRef][ISI][Medline]
- Weiss, ST, Tager, IB, Muñoz, A, et al The relationship of respiratory infections in early childhood to the occurrence of increased levels of bronchial responsiveness and atopy. Am Rev Respir Dis 1985;131,573-578[ISI][Medline]
- Busse, WW, Lemanske, RF, Jr, Dick, EC The relationship of viral respiratory infections and asthma. Chest 1992;101(suppl),385S-388S
- Silverman, EK, Palmer, LJ, Mosley, JD, et al Genomewide linkage analysis of quantitative spirometric phenotypes in severe early-onset chronic obstructive pulmonary disease. Am J Hum Genet 2002;70,1229-1239[CrossRef][ISI][Medline]
- Xu, J, Postma, DS, Howard, TD, et al Major genes regulating total serum immunoglobulin E levels in families with asthma. Am J Hum Genet 2000;67,1163-1173[ISI][Medline]
- Burrows, B, Martinez, FD, Cline, MG, et al The relationship between parental and children’s serum IgE and asthma. Am J Respir Crit Care Med 1995;152,1497-1500[Abstract]
- Sherrill, DL, Lebowitz, MD, Halonen, M, et al Longitudinal evaluation of the association between pulmonary function and total serum IgE. Am J Respir Crit Care Med 1995;152,98-102[Abstract]
- Sears, MR, Burrows, B, Flannery, EM, et al Relation between airway responsiveness and serum IgE in children with asthma and in apparently normal children. N Engl J Med 1991;325,1067-1071[Abstract]
- Li, YF, Gilliland, FD, Berhane, K, et al Effects of in utero and environmental tobacco smoke exposure on lung function in boys and girls with and without asthma. Am J Respir Crit Care Med 2000;162,2097-2104[Abstract/Free Full Text]
- Mannino, DM, Moorman, JE, Kingsley, B, et al Health effects related to environmental tobacco smoke exposure in children in the United States: data from the Third National Health and Nutrition Examination Survey. Arch Pediatr Adolesc Med 2001;155,36-41[Abstract/Free Full Text]
- Lanphear, BP, Aligne, CA, Auinger, P, et al Residential exposures associated with asthma in US children. Pediatrics 2001;107,505-511[Abstract/Free Full Text]
- Xu, J, Meyers, DA, Ober, C, et al Genomewide screen and identification of gene-gene interactions for asthma-susceptibility loci in three U. S. populations: collaborative study on the genetics of asthma Am J Hum Genet 2001;68,1437-1446[CrossRef][ISI][Medline]
- Colilla, S, Nicolae, D, Pluzhnikov, A, et al Evidence for gene-environment interactions in a linkage study of asthma and smoking exposure. J Allergy Clin Immunol 2003;111,840-846[CrossRef][ISI][Medline]
- Meyers, DA, Bleecker, ER, Jonepier, J, et al Genetic susceptibility to asthma and exposure to passive smoking. Eur Respir J 2003;22,296S
- Meyers, DA, Postma, DS, Panhuysen, CI, et al Evidence for a locus regulating total serum IgE levels mapping to chromosome 5. Genomics 1994;23,464-470[CrossRef][ISI][Medline]
- Collaborative Study of the Genetics of Asthma (CSGA). A genome-wide search for asthma susceptibility loci in ethnically diverse populations. Nat Genet 1997;15,389-397[CrossRef][ISI][Medline]
- Ober, C, Cox, NJ, Abney, M, et al Genome-wide search for asthma susceptibility loci in a founder population: the Collaborative Study on the Genetics of Asthma. Hum Mol Genet 1998;7,1393-1398[Abstract/Free Full Text]
- Grunig, G, Warnock, M, Wakil, AE, et al Requirement for IL-13 independently of IL-4 in experimental asthma. Science 1998;282,2261-2263[Abstract/Free Full Text]
- Zhu, Z, Homer, RJ, Wang, Z, et al Pulmonary expression of interleukin-13 causes inflammation, mucus hypersecretion, subepithelial fibrosis, physiologic abnormalities, and eotaxin production. J Clin Invest 1999;103,779-788[ISI][Medline]
- van der Pouw Kraan, TCTM, van Veen, A, Boeije, LC, et al An IL-13 promoter polymorphism associated with increased risk of allergic asthma. Genes Immun 1999;1,61-65[CrossRef][ISI][Medline]
- Howard, TD, Whittaker, PA, Zaiman, AL, et al Identification and association of polymorphisms in the interleukin-13 gene with asthma and atopy in a Dutch population. Am J Respir Cell Mol Biol 2001;25,377-384[Abstract/Free Full Text]
- van der Pouw Kraan, TC, Kucukaycan, M, Bakker, AM, et al Chronic obstructive pulmonary disease is associated with the –1055 IL-13 promoter polymorphism. Genes Immun 2002;3,436-439[CrossRef][ISI][Medline]
- Keavney, B, McKenzie, C, Parish, S, et al Large-scale test of hypothesised associations between the angiotensin-converting-enzyme insertion/deletion polymorphism and myocardial infarction in about 5000 cases and 6000 controls: the International Studies of Infarct Survival (ISIS) Collaborators. Lancet 2000;355,434-442[ISI][Medline]
- Ohar, JA, Bleecker, ER, Howard, TD, et al IL-13 polymorphism: predisposition towards COPD and asbestos-induced diseases [abstract]. Eur Respir J 2001;18,P3588
- Larj MJ, Bleecker ER. Therapeutic implications of the Dutch hypothesis: corticosteroids in asthma and COPD. Chest 2004 (in press)
This article has been cited by other articles:
|
|
|
|
 
M. J. Holtzman, J. T. Battaile, and A. C. Patel
Immunogenetic Programs for Viral Induction of Mucous Cell Metaplasia
Am. J. Respir. Cell Mol. Biol.,
July 1, 2006;
35(1):
29 - 39.
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. J. Holtzman, J. W. Tyner, E. Y. Kim, M. S. Lo, A. C. Patel, L. P. Shornick, E. Agapov, and Y. Zhang
Acute and Chronic Airway Responses to Viral Infection: Implications for Asthma and Chronic Obstructive Pulmonary Disease
Proceedings of the ATS,
August 1, 2005;
2(2):
132 - 140.
[Abstract]
[Full Text]
[PDF]
|
|
|
TOP
Abstract
Introduction
