Comment
with treatment response. Low VEGF-D concentrations were associated with lack of disease progression in a proportion of patients given placebo, and poor response to sirolimus in those receiving the drug. Young and colleagues’ findings lead to several important questions. First, although VEGF-D seems to be a reliable marker of disease severity and response in about 75% of patients, concentrations are not increased in other patients. Could the 25% of patients with normal VEGF-D concentrations have a different molecular subtype of lymphangioleiomyomatosis that is not caused by TSC2 mutations and mTORC1 activation?12 Second, in patients with raised VEGF-D concentrations, determination of whether VEGF-D can serve as an acute marker of therapeutic response is important. Young and coworkers reported that 6 month VEGF-D concentrations did not correlate with 12 month FEV1 response to sirolimus, suggesting that VEGF-D will not serve this purpose. However, further study is highly worthwhile since an acute marker of response would be very useful in assessments of the benefits of novel treatments. Finally, is VEGF-D produced directly by LAM cells, and could VEGF-D not only be a biomarker but also a direct contributor to pathogenesis by causing lung parenchymal destruction through MMP enhancement? Although not likely in my view, in this case VEGF-D might become not only a biomarker but also a therapeutic target in lymphangioleiomyomatosis.
David Kwiatkowski Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA [email protected] I declare that I have no conflicts of interest. 1 2
3
4
5
6
7 8 9
10
11
12
McCormack FX. Lymphangioleiomyomatosis: a clinical update. Chest 2008; 133: 507–16. Hayashi T, Fleming MV, Stetler-Stevenson WG, et al. Immunohistochemical study of matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) in pulmonary lymphangioleiomyomatosis (LAM). Hum Pathol 1997; 28: 1071–78. Hayashi T, Kumasaka T, Mitani K, et al. Prevalence of uterine and adnexal involvement in pulmonary lymphangioleiomyomatosis: a clinicopathologic study of 10 patients. Am J Surg Pathol 2011; 35: 1776–85. Kumasaka T, Seyama K, Mitani K, et al. Lymphangiogenesis-mediated shedding of LAM cell clusters as a mechanism for dissemination in lymphangioleiomyomatosis. Am J Surg Pathol 2005; 29: 1356–66. Carsillo T, Astrinidis A, Henske EP. Mutations in the tuberous sclerosis complex gene TSC2 are a cause of sporadic pulmonary lymphangioleiomyomatosis. Proc Natl Acad Sci USA 2000; 97: 6085–90. Cudzilo CJ, Szczesniak RD, Brody AS, et al. Lymphangioleiomyomatosis screening in women with tuberous sclerosis. Chest 2013; published online March 28. DOI:10.1378/chest.12-2813. Henske EP, McCormack FX. Lymphangioleiomyomatosis—a wolf in sheep’s clothing. J Clin Invest 2012; 122: 3807–16. McCormack FX, Inoue Y, Moss J, et al. Efficacy and safety of sirolimus in lymphangioleiomyomatosis. N Engl J Med 2011; 364: 1595–606. Seyama K, Kumasaka T, Souma S, et al. Vascular endothelial growth factor-D is increased in serum of patients with lymphangioleiomyomatosis. Lymphat Res Biol 2006; 4: 143–52. Young LR, Vandyke R, Gulleman PM, et al. Serum vascular endothelial growth factor-D prospectively distinguishes lymphangioleiomyomatosis from other diseases. Chest 2010; 138: 674–81. Young LR, Lee H-S, Inoue Y, et al, for the MILES Trial Group. Serum VEGF-D concentration as a biomarker of lymphangioleiomyomatosis severity and treatment response: a prospective analysis of the Multicenter International Lymphangioleiomyomatosis Efficacy of Sirolimus (MILES) trial. Lancet Respir Med 2013; published online June 12. http://dx.doi.org/10.1016/S2213-2600(13)70090-0. Badri KR, Gao L, Hyjek E, et al. Exonic mutations of TSC2/TSC1 are common but not seen in all sporadic pulmonary lymphangioleiomyomatosis. Am J Respir Crit Care Med 2013; 187: 663–65.
The hunt for genes associated with the onset, progression, and course of asthma has been ongoing for several decades. Fuelled by the observation that asthma runs in families, many attempts using either hypothesis-driven or hypothesis-free approaches to decipher the disease’s genetic code have been made. Hypotheses about potential underlying mechanisms of asthma have been tested in candidate gene studies,1 in which the frequencies of single nucleotide polymorphisms (SNPs) in a particular gene were compared between patients with asthma and those without, although sample sizes were often very small. By contrast, hypothesis-free approaches aim to discover novel asthma genes.2 This approach has www.thelancet.com/respiratory Vol 1 August 2013
been boosted by the advent of increasingly affordable high-throughput techniques to genotype several hundred thousand SNPs across the whole human genome. Nevertheless, genome-wide association studies (GWAS) explain only a small proportion of the heritability on an individual level.3 In The Lancet Respiratory Medicine, Daniel Belsky and colleagues4 report associations between SNPs selected from a recent GWAS and asthma in participants from the Dunedin cohort study, using data obtained between the ages of 9 and 38 years. A quantitative genetic risk score was computed by summing up risk alleles across 15 GWAS-identified SNPs, among them seven that were related to the chromosome
Lawrence Berkeley National Laboratory/Science Photo Library
Can genes forecast asthma risk?
See Articles page 453
425
Comment
17q12–21 locus (CHR17). Asthma was defined as a diagnosis of asthma in addition to positive symptoms within the past 12 months, and was characterised by related features such as atopy, airway hyperresponsiveness, and incompletely reversible airway obstruction. The results showed that the genetic risk score predicts persistence of asthma, relation to airway hyper-responsiveness and incompletely reversible airway obstruction, and interference with daily life, which is in line with previous findings regarding CHR17.5,6 Because the genetic risk score is driven by CHR17, its relation to CHR17-associated traits is not unexpected. The investigators’ novel composite score will increase the strength of the genetic signal only if the genetic effect of independent loci is linearly additive; if it is not, the genetic risk score might lead to overestimated effects. Conversely, summing up SNPs from independent loci with possibly opposite effects might cancel out the individual effects. Likewise, an umbrella definition of asthma based on a diagnosis and current symptoms might not adequately reflect the complexity of the asthma syndrome. Additional features such as airway hyperresponsiveness and lung function impairment describe the clinical presentation of asthma rather than the underlying biological mechanisms. These mechanisms, however, are more closely related to genetics than are clinical features, and are increasingly used to define several asthma phenotypes—eg, eosinophilic and neutrophilic, and Th2-mediated and non-Th2-mediated phenotypes.7 These phenotypes might have their own individual genetic determinants rather than reflect a sum of SNPs detected in GWAS studies. Likewise, future asthma therapies might be more effective when targeting subgroups of patients sharing similar phenotypes.8,9 A closer look at the genetic risk score calculated by Belsky and colleagues4 reveals a remarkable overlap between individuals with asthma and those without; about 50% of healthy individuals had between 14 and 25 asthma risk alleles without ever having been affected by asthma by age 38 years. Additionally, patients with asthma, atopy, and airway hyperresponsiveness carried on average only one more risk allele than controls, who carried a mean of 13·5 risk alleles. If 50% of individuals carry more than 426
14 asthma risk alleles without developing asthma, individual disease risk cannot be predicted from SNPs alone. However, genetic background does not have to be reduced to the detection of SNPs only. Rather, the regulation of genetic information at the geneexpression level, and other epigenetic mechanisms in different organs and tissues, might be as important as the changes in nucleotide sequences of the double helix. Moreover, environmental exposures are known to contribute to disease onset. After all, a family history of disease is often also a history of shared environmental exposures. Will genetic prediction ever become strong enough to have clinical relevance, or is the contribution of single genes inherently weak? In the context of a complex disease such as asthma, it might be more appropriate to view genes as a frame surrounding a complex network of biological processes. The frame delimits and supports the network, but the connections within the network determine its functions. In other words, asthma is likely to result from heavily interwoven biological processes, which might yield only weak signals when taken apart. We do not yet have the means to predict the onset and course of asthma in individuals. Markus J Ege, *Erika von Mutius Dr von Hauner Children’s Hospital, Ludwig Maximilian University, D 80337 Munich, Germany [email protected] EvM is a consultant for GlaxoSmithKline, Protectimmun, Novartis, Astellas Pharma Europe, and ALK-Abelló, and has received lecture fees from InfectoPharm and Nestlé Research. MJE declares that he has no conflicts of interest. 1 2
3
4
5
6 7 8 9
Vercelli D. Discovering susceptibility genes for asthma and allergy. Nat Rev Immunol 2008; 8: 169–82. Moffatt MF, Kabesch M, Liang L, et al. Genetic variants regulating ORMDL3 expression contribute to the risk of childhood asthma. Nature 2007; 448: 470–73. Moffatt MF, Gut IG, Demenais F, et al. A large-scale, consortium-based genomewide association study of asthma. N Engl J Med 2010; 363: 1211–21. Belsky DW, Sears MR, Hancox RJ, et al. Polygenic risk and the development and course of asthma: an analysis of data from a fourdecade longitudinal study. Lancet Respir Med 2013; 1: 453–61. Bisgaard H, Bonnelykke K, Sleiman PM, et al. Chromosome 17q21 gene variants are associated with asthma and exacerbations but not atopy in early childhood. Am J Respir Crit Care Med 2009; 179: 179–85. Binia A, Khorasani N, Bhavsar PK, et al. Chromosome 17q21 SNP and severe asthma. J Hum Genet 2011; 56: 97–98. Wenzel SE. Asthma phenotypes: the evolution from clinical to molecular approaches. Nat Med 2012; 18: 716–25. Corren J, Lemanske RF, Hanania NA, et al. Lebrikizumab treatment in adults with asthma. N Engl J Med 2011; 365: 1088–98. Wenzel S, Ford L, Pearlman D, et al. Dupilumab in persistent asthma with elevated eosinophil levels. N Engl J Med 2013; 368: 2455–66.
www.thelancet.com/respiratory Vol 1 August 2013
with treatment response. Low VEGF-D concentrations were associated with lack of disease progression in a proportion of patients given placebo, and poor response to sirolimus in those receiving the drug. Young and colleagues’ findings lead to several important questions. First, although VEGF-D seems to be a reliable marker of disease severity and response in about 75% of patients, concentrations are not increased in other patients. Could the 25% of patients with normal VEGF-D concentrations have a different molecular subtype of lymphangioleiomyomatosis that is not caused by TSC2 mutations and mTORC1 activation?12 Second, in patients with raised VEGF-D concentrations, determination of whether VEGF-D can serve as an acute marker of therapeutic response is important. Young and coworkers reported that 6 month VEGF-D concentrations did not correlate with 12 month FEV1 response to sirolimus, suggesting that VEGF-D will not serve this purpose. However, further study is highly worthwhile since an acute marker of response would be very useful in assessments of the benefits of novel treatments. Finally, is VEGF-D produced directly by LAM cells, and could VEGF-D not only be a biomarker but also a direct contributor to pathogenesis by causing lung parenchymal destruction through MMP enhancement? Although not likely in my view, in this case VEGF-D might become not only a biomarker but also a therapeutic target in lymphangioleiomyomatosis.
David Kwiatkowski Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA [email protected] I declare that I have no conflicts of interest. 1 2
3
4
5
6
7 8 9
10
11
12
McCormack FX. Lymphangioleiomyomatosis: a clinical update. Chest 2008; 133: 507–16. Hayashi T, Fleming MV, Stetler-Stevenson WG, et al. Immunohistochemical study of matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) in pulmonary lymphangioleiomyomatosis (LAM). Hum Pathol 1997; 28: 1071–78. Hayashi T, Kumasaka T, Mitani K, et al. Prevalence of uterine and adnexal involvement in pulmonary lymphangioleiomyomatosis: a clinicopathologic study of 10 patients. Am J Surg Pathol 2011; 35: 1776–85. Kumasaka T, Seyama K, Mitani K, et al. Lymphangiogenesis-mediated shedding of LAM cell clusters as a mechanism for dissemination in lymphangioleiomyomatosis. Am J Surg Pathol 2005; 29: 1356–66. Carsillo T, Astrinidis A, Henske EP. Mutations in the tuberous sclerosis complex gene TSC2 are a cause of sporadic pulmonary lymphangioleiomyomatosis. Proc Natl Acad Sci USA 2000; 97: 6085–90. Cudzilo CJ, Szczesniak RD, Brody AS, et al. Lymphangioleiomyomatosis screening in women with tuberous sclerosis. Chest 2013; published online March 28. DOI:10.1378/chest.12-2813. Henske EP, McCormack FX. Lymphangioleiomyomatosis—a wolf in sheep’s clothing. J Clin Invest 2012; 122: 3807–16. McCormack FX, Inoue Y, Moss J, et al. Efficacy and safety of sirolimus in lymphangioleiomyomatosis. N Engl J Med 2011; 364: 1595–606. Seyama K, Kumasaka T, Souma S, et al. Vascular endothelial growth factor-D is increased in serum of patients with lymphangioleiomyomatosis. Lymphat Res Biol 2006; 4: 143–52. Young LR, Vandyke R, Gulleman PM, et al. Serum vascular endothelial growth factor-D prospectively distinguishes lymphangioleiomyomatosis from other diseases. Chest 2010; 138: 674–81. Young LR, Lee H-S, Inoue Y, et al, for the MILES Trial Group. Serum VEGF-D concentration as a biomarker of lymphangioleiomyomatosis severity and treatment response: a prospective analysis of the Multicenter International Lymphangioleiomyomatosis Efficacy of Sirolimus (MILES) trial. Lancet Respir Med 2013; published online June 12. http://dx.doi.org/10.1016/S2213-2600(13)70090-0. Badri KR, Gao L, Hyjek E, et al. Exonic mutations of TSC2/TSC1 are common but not seen in all sporadic pulmonary lymphangioleiomyomatosis. Am J Respir Crit Care Med 2013; 187: 663–65.
The hunt for genes associated with the onset, progression, and course of asthma has been ongoing for several decades. Fuelled by the observation that asthma runs in families, many attempts using either hypothesis-driven or hypothesis-free approaches to decipher the disease’s genetic code have been made. Hypotheses about potential underlying mechanisms of asthma have been tested in candidate gene studies,1 in which the frequencies of single nucleotide polymorphisms (SNPs) in a particular gene were compared between patients with asthma and those without, although sample sizes were often very small. By contrast, hypothesis-free approaches aim to discover novel asthma genes.2 This approach has www.thelancet.com/respiratory Vol 1 August 2013
been boosted by the advent of increasingly affordable high-throughput techniques to genotype several hundred thousand SNPs across the whole human genome. Nevertheless, genome-wide association studies (GWAS) explain only a small proportion of the heritability on an individual level.3 In The Lancet Respiratory Medicine, Daniel Belsky and colleagues4 report associations between SNPs selected from a recent GWAS and asthma in participants from the Dunedin cohort study, using data obtained between the ages of 9 and 38 years. A quantitative genetic risk score was computed by summing up risk alleles across 15 GWAS-identified SNPs, among them seven that were related to the chromosome
Lawrence Berkeley National Laboratory/Science Photo Library
Can genes forecast asthma risk?
See Articles page 453
425
Comment
17q12–21 locus (CHR17). Asthma was defined as a diagnosis of asthma in addition to positive symptoms within the past 12 months, and was characterised by related features such as atopy, airway hyperresponsiveness, and incompletely reversible airway obstruction. The results showed that the genetic risk score predicts persistence of asthma, relation to airway hyper-responsiveness and incompletely reversible airway obstruction, and interference with daily life, which is in line with previous findings regarding CHR17.5,6 Because the genetic risk score is driven by CHR17, its relation to CHR17-associated traits is not unexpected. The investigators’ novel composite score will increase the strength of the genetic signal only if the genetic effect of independent loci is linearly additive; if it is not, the genetic risk score might lead to overestimated effects. Conversely, summing up SNPs from independent loci with possibly opposite effects might cancel out the individual effects. Likewise, an umbrella definition of asthma based on a diagnosis and current symptoms might not adequately reflect the complexity of the asthma syndrome. Additional features such as airway hyperresponsiveness and lung function impairment describe the clinical presentation of asthma rather than the underlying biological mechanisms. These mechanisms, however, are more closely related to genetics than are clinical features, and are increasingly used to define several asthma phenotypes—eg, eosinophilic and neutrophilic, and Th2-mediated and non-Th2-mediated phenotypes.7 These phenotypes might have their own individual genetic determinants rather than reflect a sum of SNPs detected in GWAS studies. Likewise, future asthma therapies might be more effective when targeting subgroups of patients sharing similar phenotypes.8,9 A closer look at the genetic risk score calculated by Belsky and colleagues4 reveals a remarkable overlap between individuals with asthma and those without; about 50% of healthy individuals had between 14 and 25 asthma risk alleles without ever having been affected by asthma by age 38 years. Additionally, patients with asthma, atopy, and airway hyperresponsiveness carried on average only one more risk allele than controls, who carried a mean of 13·5 risk alleles. If 50% of individuals carry more than 426
14 asthma risk alleles without developing asthma, individual disease risk cannot be predicted from SNPs alone. However, genetic background does not have to be reduced to the detection of SNPs only. Rather, the regulation of genetic information at the geneexpression level, and other epigenetic mechanisms in different organs and tissues, might be as important as the changes in nucleotide sequences of the double helix. Moreover, environmental exposures are known to contribute to disease onset. After all, a family history of disease is often also a history of shared environmental exposures. Will genetic prediction ever become strong enough to have clinical relevance, or is the contribution of single genes inherently weak? In the context of a complex disease such as asthma, it might be more appropriate to view genes as a frame surrounding a complex network of biological processes. The frame delimits and supports the network, but the connections within the network determine its functions. In other words, asthma is likely to result from heavily interwoven biological processes, which might yield only weak signals when taken apart. We do not yet have the means to predict the onset and course of asthma in individuals. Markus J Ege, *Erika von Mutius Dr von Hauner Children’s Hospital, Ludwig Maximilian University, D 80337 Munich, Germany [email protected] EvM is a consultant for GlaxoSmithKline, Protectimmun, Novartis, Astellas Pharma Europe, and ALK-Abelló, and has received lecture fees from InfectoPharm and Nestlé Research. MJE declares that he has no conflicts of interest. 1 2
3
4
5
6 7 8 9
Vercelli D. Discovering susceptibility genes for asthma and allergy. Nat Rev Immunol 2008; 8: 169–82. Moffatt MF, Kabesch M, Liang L, et al. Genetic variants regulating ORMDL3 expression contribute to the risk of childhood asthma. Nature 2007; 448: 470–73. Moffatt MF, Gut IG, Demenais F, et al. A large-scale, consortium-based genomewide association study of asthma. N Engl J Med 2010; 363: 1211–21. Belsky DW, Sears MR, Hancox RJ, et al. Polygenic risk and the development and course of asthma: an analysis of data from a fourdecade longitudinal study. Lancet Respir Med 2013; 1: 453–61. Bisgaard H, Bonnelykke K, Sleiman PM, et al. Chromosome 17q21 gene variants are associated with asthma and exacerbations but not atopy in early childhood. Am J Respir Crit Care Med 2009; 179: 179–85. Binia A, Khorasani N, Bhavsar PK, et al. Chromosome 17q21 SNP and severe asthma. J Hum Genet 2011; 56: 97–98. Wenzel SE. Asthma phenotypes: the evolution from clinical to molecular approaches. Nat Med 2012; 18: 716–25. Corren J, Lemanske RF, Hanania NA, et al. Lebrikizumab treatment in adults with asthma. N Engl J Med 2011; 365: 1088–98. Wenzel S, Ford L, Pearlman D, et al. Dupilumab in persistent asthma with elevated eosinophil levels. N Engl J Med 2013; 368: 2455–66.
www.thelancet.com/respiratory Vol 1 August 2013
