- Email: [email protected]
IL12B promoter polymorphism and asthma
CORRESPONDENCE
Sir—Grant Morahan and colleagues1 admit that there is no plausible biological explanation for their chance finding of an association between severity of asthma and heterozygosity for the IL12B promoter polymorphism. Furthermore, interpretation of the functional data used to lend support to this association is probably confounded by dose of corticosteroid. Since individuals who were heterozygous for the IL12B promoter polymorphism had more severe asthma than those who were homozygous, the heterozygotes may have been taking a higher average dose of inhaled corticosteroid or may have received systemic corticosteroids more recently than the homozygotes. However, Morahan and co-workers do not present data about asthma therapy for study participants. R Dekruyff and colleagues2 report that corticosteroids inhibit lymphocyte production of interleukin 12 in vitro.2 A systemic effect of corticosteroids would, therefore, account for the reduced production of interleukin 12 by mononuclear cells from the heterozygote group. Andrew Sanford and Peter Paré3 discuss why promoter heterozygosity should affect production of interleukin 12. Without an answer to this question or any substantive functional data, any true relation between asthma and the IL12B promoter polymorphism remains speculative. Simon P Hart MRC Centre for Inflammation Research, Medical School, Edinburgh EH8 9AG, UK (e-mail: [email protected]) 1
2
3
Morahan G, Huang D, Wu M, et al. Association of IL12B promoter polymorphism with severity of atopic and non-atopic asthma in children. Lancet 2002; 360: 455–59. Dekruyff RH, Fang Y, Umetsu DT. Corticosteroids enhance the capacity of macrophages to induce Th2 cytokine synthesis in CD4+ lymphocytes by inhibiting IL-12 production. J Immunol 1998; 160: 2231–37. Sandford A, Paré P. Homing in on the asthma gene. Lancet 2002; 360: 422–23.
Authors’ reply Sir—John Warren draws a distinction between a Mendelian trait—ie, a qualitative phenotype determined by alleles in a single gene—and a quantitative phenotype with a continuous, possibly normal, distribution in the population. He points out that an example of the former would be cystic fibrosis and an example of the latter would be bronchial responsiveness. Warren contends that asthma is merely a cut-off point in the normal distribution of bronchial responsiveness. However, asthma cannot be
equated with bronchial hyperresponsiveness. Asthma is a clinical diagnosis based on a constellation of historical (symptoms) and physiological features, of which bronchial hyper-responsiveness is one component. Asthma can occur in the absence of bronchial hyper-responsiveness and vice versa. Nevertheless, as Warren observes, the complex nature of asthma means that, unlike in single-gene disorders, clear-cut identification of affected individuals is difficult. Warren points out that the genetic component of a trait that exhibits continuous variation is probably composed of many genes. Therefore, an individual’s susceptibility to asthma is likely to be predicted from the sum total of the risk alleles present in that individual. We agree with this assessment; like all complex genetic diseases, multiple genes may interact with environmental factors to produce the phenotype. Warren also suggests that it is logical to predict not only genes associated with for asthma but also those that afford a protective effect. But care is needed to distinguish genes from alleles. Some genes may be associated with an increased risk of asthma—for example, tumour necrosis factor or interleukin 4—and others may have a protective effect—for example, interleukins 10 and 12. However, alleles in each of these genes could either increase risk or be protective. Thus, an allele in the tumour necrosis factor gene that resulted in decreased expression of this pro-asthma gene would be protective against asthma, whereas an allele that resulted in lower interleukin-10 activity would increase susceptibility to asthma. Individuals who are unusually hyporesponsive could be regarded as having an excess of protective alleles or a dearth of risk alleles, but these are really two sides of the same coin. Warren questions the value of searching for asthma genes and asks if we are any further on from knowledge derived from the spirometer. We believe that there are at least four reasons for searching for asthma genes. Firstly, studies of families with members who have asthma could pinpoint genes, hitherto unknown, that have a role in the pathogenesis of asthma—for example, the metalloprotease ADAM33.1 Such work may lead to a better understanding of the aetiology of asthma and, perhaps, reveal new therapeutic targets. A second reason in favour of genetic studies is the possibility of identifying genes that affect an individual’s response to asthma medication, as was shown by J Drazen and co-workers2 for
THE LANCET • Vol 360 • December 21/28, 2002 • www.thelancet.com
the 5-lipoxygenase gene. This knowledge may allow for the development of individualised treatment protocols that would provide more effective therapy—Drazen and colleagues2 identified individuals who did not respond to an inhibitor of 5lipoxygenase. Another reason to search for asthma genes is that knowledge of an individual’s genetic predisposition to asthma would increase the power of basic science studies and clinical trials. If variations in genetic susceptibility could be eliminated, or adjusted for, more effective investigation of environmental risk factors or the efficacy of a treatment would be possible. Finally, individuals who have a high risk of developing asthma could be identified and targeted for environmental interventions to reduce the risk or severity of disease, if such interventions can be identified. Although few of these benefits have come to pass, we believe that the potential is there to improve patients’ care in the future. *Andrew Sandford, Peter Paré McDonald Research Laboratories/iCAPTURE Center, St Paul’s Hospital, Vancouver, BC V6Z 1Y6, Canada (e-mail: [email protected]) 1
2
Van Eerdewegh P, Little RD, Dupuis J, et al. Association of the ADAM33 gene with asthma and bronchial hyperresponsiveness. Nature 2002; 10: 10. Drazen JM, Yandava CN, Dube L, et al. Pharmacogenetic association between ALOX5 promoter genotype and the response to anti-asthma treatment. Nat Genet 1999; 22: 168–70.
TARGET follow-up study Sir—The results of the 6-month followup of the TARGET study (Aug 3, p 355)1 show no difference in events between the tirofiban and abciximab groups, whereas the 1-month results showed a significant advantage in favour However, David of abciximab.2 Moliterno and colleagues do not elaborate on the difference in events between US and non-US patients, such as described in figure 3.1 More detailed information, available online,3 shows a difference in events between the tirofiban and abciximab groups in non-US patients (11·6% vs 8·4%, respectively) but not in US patients (15·6% vs 15·7%, respectively). Moreover, in the non-US group, there is a significant difference in myocardial infarction between tirofiban and abciximab after 6 months (7·6% vs 3·6%, respectively; p=0·01). Additionally, the relative number of events in the US is almost twice the amount found in the non-US abciximab group.
2085
For personal use. Only reproduce with permission from The Lancet Publishing Group.
Sir—Grant Morahan and colleagues1 admit that there is no plausible biological explanation for their chance finding of an association between severity of asthma and heterozygosity for the IL12B promoter polymorphism. Furthermore, interpretation of the functional data used to lend support to this association is probably confounded by dose of corticosteroid. Since individuals who were heterozygous for the IL12B promoter polymorphism had more severe asthma than those who were homozygous, the heterozygotes may have been taking a higher average dose of inhaled corticosteroid or may have received systemic corticosteroids more recently than the homozygotes. However, Morahan and co-workers do not present data about asthma therapy for study participants. R Dekruyff and colleagues2 report that corticosteroids inhibit lymphocyte production of interleukin 12 in vitro.2 A systemic effect of corticosteroids would, therefore, account for the reduced production of interleukin 12 by mononuclear cells from the heterozygote group. Andrew Sanford and Peter Paré3 discuss why promoter heterozygosity should affect production of interleukin 12. Without an answer to this question or any substantive functional data, any true relation between asthma and the IL12B promoter polymorphism remains speculative. Simon P Hart MRC Centre for Inflammation Research, Medical School, Edinburgh EH8 9AG, UK (e-mail: [email protected]) 1
2
3
Morahan G, Huang D, Wu M, et al. Association of IL12B promoter polymorphism with severity of atopic and non-atopic asthma in children. Lancet 2002; 360: 455–59. Dekruyff RH, Fang Y, Umetsu DT. Corticosteroids enhance the capacity of macrophages to induce Th2 cytokine synthesis in CD4+ lymphocytes by inhibiting IL-12 production. J Immunol 1998; 160: 2231–37. Sandford A, Paré P. Homing in on the asthma gene. Lancet 2002; 360: 422–23.
Authors’ reply Sir—John Warren draws a distinction between a Mendelian trait—ie, a qualitative phenotype determined by alleles in a single gene—and a quantitative phenotype with a continuous, possibly normal, distribution in the population. He points out that an example of the former would be cystic fibrosis and an example of the latter would be bronchial responsiveness. Warren contends that asthma is merely a cut-off point in the normal distribution of bronchial responsiveness. However, asthma cannot be
equated with bronchial hyperresponsiveness. Asthma is a clinical diagnosis based on a constellation of historical (symptoms) and physiological features, of which bronchial hyper-responsiveness is one component. Asthma can occur in the absence of bronchial hyper-responsiveness and vice versa. Nevertheless, as Warren observes, the complex nature of asthma means that, unlike in single-gene disorders, clear-cut identification of affected individuals is difficult. Warren points out that the genetic component of a trait that exhibits continuous variation is probably composed of many genes. Therefore, an individual’s susceptibility to asthma is likely to be predicted from the sum total of the risk alleles present in that individual. We agree with this assessment; like all complex genetic diseases, multiple genes may interact with environmental factors to produce the phenotype. Warren also suggests that it is logical to predict not only genes associated with for asthma but also those that afford a protective effect. But care is needed to distinguish genes from alleles. Some genes may be associated with an increased risk of asthma—for example, tumour necrosis factor or interleukin 4—and others may have a protective effect—for example, interleukins 10 and 12. However, alleles in each of these genes could either increase risk or be protective. Thus, an allele in the tumour necrosis factor gene that resulted in decreased expression of this pro-asthma gene would be protective against asthma, whereas an allele that resulted in lower interleukin-10 activity would increase susceptibility to asthma. Individuals who are unusually hyporesponsive could be regarded as having an excess of protective alleles or a dearth of risk alleles, but these are really two sides of the same coin. Warren questions the value of searching for asthma genes and asks if we are any further on from knowledge derived from the spirometer. We believe that there are at least four reasons for searching for asthma genes. Firstly, studies of families with members who have asthma could pinpoint genes, hitherto unknown, that have a role in the pathogenesis of asthma—for example, the metalloprotease ADAM33.1 Such work may lead to a better understanding of the aetiology of asthma and, perhaps, reveal new therapeutic targets. A second reason in favour of genetic studies is the possibility of identifying genes that affect an individual’s response to asthma medication, as was shown by J Drazen and co-workers2 for
THE LANCET • Vol 360 • December 21/28, 2002 • www.thelancet.com
the 5-lipoxygenase gene. This knowledge may allow for the development of individualised treatment protocols that would provide more effective therapy—Drazen and colleagues2 identified individuals who did not respond to an inhibitor of 5lipoxygenase. Another reason to search for asthma genes is that knowledge of an individual’s genetic predisposition to asthma would increase the power of basic science studies and clinical trials. If variations in genetic susceptibility could be eliminated, or adjusted for, more effective investigation of environmental risk factors or the efficacy of a treatment would be possible. Finally, individuals who have a high risk of developing asthma could be identified and targeted for environmental interventions to reduce the risk or severity of disease, if such interventions can be identified. Although few of these benefits have come to pass, we believe that the potential is there to improve patients’ care in the future. *Andrew Sandford, Peter Paré McDonald Research Laboratories/iCAPTURE Center, St Paul’s Hospital, Vancouver, BC V6Z 1Y6, Canada (e-mail: [email protected]) 1
2
Van Eerdewegh P, Little RD, Dupuis J, et al. Association of the ADAM33 gene with asthma and bronchial hyperresponsiveness. Nature 2002; 10: 10. Drazen JM, Yandava CN, Dube L, et al. Pharmacogenetic association between ALOX5 promoter genotype and the response to anti-asthma treatment. Nat Genet 1999; 22: 168–70.
TARGET follow-up study Sir—The results of the 6-month followup of the TARGET study (Aug 3, p 355)1 show no difference in events between the tirofiban and abciximab groups, whereas the 1-month results showed a significant advantage in favour However, David of abciximab.2 Moliterno and colleagues do not elaborate on the difference in events between US and non-US patients, such as described in figure 3.1 More detailed information, available online,3 shows a difference in events between the tirofiban and abciximab groups in non-US patients (11·6% vs 8·4%, respectively) but not in US patients (15·6% vs 15·7%, respectively). Moreover, in the non-US group, there is a significant difference in myocardial infarction between tirofiban and abciximab after 6 months (7·6% vs 3·6%, respectively; p=0·01). Additionally, the relative number of events in the US is almost twice the amount found in the non-US abciximab group.
2085
For personal use. Only reproduce with permission from The Lancet Publishing Group.