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What are we learning from genetic cohort studies?
PAEDIATRIC RESPIRATORY REVIEWS (2006) 7S, S90–S92
What are we learning from genetic cohort studies? Adnan Custovic* and Angela Simpson Academic Division of Medicine and Surgery South, University of Manchester, North West Lung Centre, Wythenshawe Hospital, Southmoor Road, Manchester M23 9LT, UK KEYWORDS gene-environment interactions; asthma; birth cohorts
Summary Although genetic component of asthma has been well recognised, genetics alone cannot explain the rise in asthma prevalence. This increase is likely a consequence of environmental factors increasing the risk in genetically susceptible individuals. As wheezing illness usually begins within months of birth, prospective birth cohorts with detailed measures of environmental exposures and objective measures of disease are essential to study gene-environment interactions in the development of different wheeze phenotypes. Such studies will enable identification of children at increased risk of disease because of a genetic predisposition when exposed to a particular environmental factor. Tailor-made evidence-based strategies for prevention of asthma and atopic sensitization applicable to individuals at risk (rather than the whole population) will then be developed to reduce the risk of asthma and allergy development. ß 2006 Elsevier Ltd. All rights reserved.
The inherited basis of disease due to single gene defects is well recognised, but these conditions are rare. The major burden of ill health is due to common diseases which have a complex aetiology, with multiple genes interacting with each other and with environmental factors. Asthma is the most common chronic disease of childhood, and has increased in prevalence over the last 3 to 4 decades.1 An estimated 5.1 million people in the UK are currently receiving treatment for asthma.2 A genetic component of asthma has been confirmed by twin studies.3 Whilst several genes have a moderate effect in asthma,4 genetics alone cannot explain the rise in prevalence. The time course of this increase has directed attention towards environmental changes which have occurred in parallel, including diet, microbial exposure, antibiotics, immunisations, childcare arrangements and changes to the home. The increase in asthma prevalence is likely a consequence * Corresponding author. Tel.: +44 161 291 2494; Fax: +44 161 291 5057. E-mail address: [email protected] (A. Custovic). 1526-0542/$ – see front matter ß 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.prrv.2006.04.164
of environmental factors increasing the risk in genetically susceptible individuals mediated through gene-environment interactions.
GENETIC COMPONENT OF ASTHMA Several genome-wide screens for asthma and its related traits have identified evidence for linkage on most chromosomes.5–10 Despite the fact that some regions of linkage have been replicated, it has proven difficult to identify susceptibility genes from a region of linkage. The first examples of susceptibility genes for an asthma phenotype identified using a positional cloning approach have recently been published.11,12 Association studies often focus on candidate genes likely to be involved in the immunological pathways of asthma, including IL-4 receptor,13 IL-13,14 FceR115 and glutathione S–transferase genes.16 Candidate genes may also be prioritised for investigation if they map to regions of linkage. A further refinement has been to identify candidate genes with plausible environmental interactions (e.g. CD14 with endotoxin17) to explain the increase in asthma prevalence.
WHAT ARE WE LEARNING FROM GENETIC COHORT STUDIES?
WHY DO WE NEED COHORT STUDIES? A study from Melbourne has clearly identified that patterns of lung function and asthma displayed at age 7 years track into adulthood.18 These deficits in lung function do not appear to be present soon after birth19 and are likely to be acquired in the first few years of life. As wheezing illness can begin within months of birth, to study gene-environment interactions in asthma development it is essential to utilise prospective birth cohorts with detailed measures of environmental exposures and objective measures of lung function in addition to parentally reported symptoms. The National Asthma Campaign Manchester Asthma and Allergy Study (NACMAAS) is a population-based prospective birth cohort study (n 1000) investigating risk factors for the development of asthma and allergies in children.20–31 Objective clinical outcome measures include lung function (specific airways resistance and spirometry), airway reactivity and atopic sensitization (skin tests and IgE). Subjective measures include questionnaire data on parentally-reported symptoms. Comprehensive measurements of environmental exposures include indoor allergens (mite, cat and dog), endotoxin, pet ownership and exposure, childcare arrangements, family size, antibiotic usage, maternal asthma medication usage during pregnancy and a detailed dietary questionnaire (Diet Q). We therefore have a unique opportunity to explore the interactions between genes and environment on the risk of asthma and atopic sensitisation. In a first study utilizing this strategy we have provided the first evidence that the association of ADAM33 with asthma may be mediated via its effects on lung function in childhood.31 Our data support the hypothesis that reduced early-life lung function is in part a genetically determined trait. Polymorphisms were associated with reduced lung function at both three and five years of age. In this study we were unable to show any association between ADAM33 SNPs and allergic sensitization, suggesting that separate genetic factors contribute to disordered airway function and the immunological component of asthma. Future studies will enable identification of children at increased risk of disease because of a genetic predisposition. Evidence-based strategies for prevention of asthma and atopic sensitization will then be developed to reduce the risk of asthma and allergy development.
REFERENCES 1. Omran M, Russell G. Continuing increase in respiratory symptoms and atopy in Aberdeen schoolchildren. BMJ 1996; 312: 34. 2. Anon. Out in the Open: the true picture of asthma in the United Kingdom today. The Asthma Journal 2001; 6(suppl): 5. 3. Duffy DL, Martin NG, Battistutta D, Hopper JL, Mathews JD. Genetics of asthma and hay fever in Australian twins. Am Rev Respir Dis 1990; 142: 1351–1358.
S91
4. Jenkins MA, Hopper JL, Giles GG. Regressive logistic modeling of familial aggregation for asthma in 7394 population-based nuclear families. Genetic Epidemiology 1997; 14: 317–332. 5. Daniels SE, Bhattacharrya S, James A, Leaves NI, Young A, Hill MR et al. A genome-wide search for quantitative trait loci underlying asthma. Nature 1996; 383: 247–250. 6. Ober C, Cox NJ, Abney M, Di Rienzo A, Lander ES, Changyaleket B et al. Genome wide search for asthma susceptibility loci in a founder population: the Collaborative study on Asthma Genetics. Human Molec Genet 1998; 7: 1393–1398. 7. Wjst M, Fischer G, Immervoll T, Jung M, Saar K, Rueschendorf F et al. A Genome wide search for linkage to asthma. German Asthma Genetics Group. Genomics 1999; 58: 1–8. 8. Hizawa N, Freidhoff LR, Chiu YF, Ehrlich E, Luehr CA, Anderson JL et al. Genetic regulation of Dermatophagoides pteronyssinus-specific IgE responsiveness: a genome wide multipoint linkage analysis in families recruited through 2 asthmatic sibs. Collaborative Study of Asthma (CSGA). J Allergy Clin Immunol 1998; 102: 436–442. 9. The Collaborative Study on the Genetics of Asthma (CSGA). A genome-wide search for asthma susceptibility loci in ethnically diverse populations. Nature Genetics 1997; 15: 389–392. 10. Dizier MH, Besse-Schmittler C, Guilloud-Bataille M, Annesi-Maesano I, Boussaha M, Bousquet J et al. Genome screen for asthma and related phenotypes in the French EGEA study. Am J Respir Crit Care Med 2000; 162: 1812–1818. 11. Van Eedewegh P, Little RD, Dupuis J, Del Mastro RG, Falls K, Simon J et al. Association of ADAM33 gene with asthma and bronchial hyperresponsiveness. Nature 2002; 418: 426–430. 12. Zhang Y, Leaves NI, Anderson GG, Ponting CP, Broxhome J, Holt R et al. Positional cloning of a quantitative trait locus on chromosome 13q14 that influences immunoglobulin E levels and asthma. Nat Genet 2003; 34: 181–186. 13. Deichmann K, Bardutzky J, Forster J, Heinzmann A, Keuhr J. Common polymorphisms in the coding part of the IL-4-receptor gene. Biochem Biophys Res Commun 1997; 231: 696–697. 14. Graves PE, Kasbech M, Halonen M, Holberg CJ, Baldini M, Fritzsch C et al. A cluster of seven tightly linked polymorphisms in the IL-13 gene is associated with total serum IgE levels in three populations of white children. J Allergy Clin Immunol 2000; 105: 506–513. 15. Hill MR, James AL, Faux JA. FceR1polymorphisms and risk of atopy in a general population sample. BMJ 1995; 311: 776–779. 16. Fryer AA, Bianco A, Hepple M, Jones PW, Starnge RC, Spiteri MA. Polymorphisms at the Glutathione S-transferase GSTP1 locus: a new marker for bronchial hyperresponsiveness and asthma. Am J Respir Crit Care Med 2000; 161: 1437–1442. 17. Baldini M, Lohman IC, Halonen M, Erickson RP, Holt PG, Martinez FD. A polymorphism in the 50 flanking region of the CD14 gene is associated with circulating soluble CD14 levels and with total serum IgE. Am J Respir Cell Mol Biol 1999; 20: 976–983. 18. Phelan PD, Roberton CF, Olinsky A. The Melbourne Asthma Study: 1964–1999. J Allergy Clin Immunol 2002; 109: 189–194. 19. Taussig LM, Wright AL, Holberg CJ, Halonen M, Morgan WJ, Martinez FD. Tucson children’s respiratory study:1980 to present. J Allergy Clin Immunol 2003; 111: 661–675. 20. Custovic A, Simpson BM, Murray CS, Lowe L, Woodcock A. The National Asthma Campaign Manchester Asthma and Allergy Study. Pediatr Allergy Immunol 2002; 13(Suppl. 15): 32–37. 21. Lowe L, Murray C, Custovic A, Simpson BM, Kissen P, Woodcock A. Specific airway resistance in three year old children. Lancet 2002; 359: 1904–1908. 22. Murray CS, Pipis SD, McArdle EC, Lowe L, Custovic A, Woodcock A. Lung function at one month as a risk factor for infant wheezing in a high risk population. Thorax 2002; 57: 388–392. 23. Calam R, Gregg L, Simpson B, Morris J, Woodcock A, Custovic A. Childhood asthma, behavior problems, and family functioning. J Allergy Clin Immunol 2003; 112: 499–504.
S92
24. Murray CS, Woodcock A, Smillie FI, Cain G, Kissen P, Custovic A. Tobacco smoke exposure, wheeze and atopy. Pediatr Pulmonol 2004; 37: 492–498. 25. Lowe L, Murray CS, Martin L, Deas J, Cashin E, Poletti G, Simpson A, Woodcock A, Custovic A. Reported versus confirmed wheeze and lung function in early life. Arch Dis Child 2004; 89: 540–543. 26. Woodcock A, Lowe LA, Murray CS, Simpson BM, Pipis SD, Kissen P, Simpson A, Custovic A. Early life environmental control: effect on symptoms, sensitization and lung function at age 3 years. Am J Respir Crit Care Med 2004; 170: 433–439. 27. Lowe LA, Woodcock A, Murray CS, Morris J, Simpson A, Custovic A. Lung function at age 3 years: effect of pet ownership and exposure to indoor allergens. Arch Ped Adolesc Med 2004; 158: 996–1001.
A. CUSTOVIC, AND A. SIMPSON
28. Lowe LA, Simpson A, Woodcock A, Morris J, Murray CS, Custovic A. Wheeze phenotypes and early life lung function. Am J Respir Crit Care Med 2005; 171: 231–237. 29. Calam R, Gregg L, Simpson A, Simpson B, Woodcock A, Custovic A. Behaviour Problems Antecede the Development of Wheeze in Childhood: A Birth Cohort Study. Am J Respir Crit Care Med 2005; 171: 323–327. 30. Simpson A, Soderstrom L, Ahlstedt S, Murray CS, Woodcock A, Custovic A. IgE antibody quantification and the probability of wheeze in pre-school children. J Allergy Clin Immunol 2005; 116: 744–749. 31. Simpson A, Maniatis N, Jury F, Cakebread JA, Lowe LA, Holgate ST et al. Polymorphisms in A Disintegrin and Metalloprotease 33 (ADAM33) Predict Impaired Early-Life Lung Function. Am J Respir Crit Care Med 2005; 172: 55–60.
What are we learning from genetic cohort studies? Adnan Custovic* and Angela Simpson Academic Division of Medicine and Surgery South, University of Manchester, North West Lung Centre, Wythenshawe Hospital, Southmoor Road, Manchester M23 9LT, UK KEYWORDS gene-environment interactions; asthma; birth cohorts
Summary Although genetic component of asthma has been well recognised, genetics alone cannot explain the rise in asthma prevalence. This increase is likely a consequence of environmental factors increasing the risk in genetically susceptible individuals. As wheezing illness usually begins within months of birth, prospective birth cohorts with detailed measures of environmental exposures and objective measures of disease are essential to study gene-environment interactions in the development of different wheeze phenotypes. Such studies will enable identification of children at increased risk of disease because of a genetic predisposition when exposed to a particular environmental factor. Tailor-made evidence-based strategies for prevention of asthma and atopic sensitization applicable to individuals at risk (rather than the whole population) will then be developed to reduce the risk of asthma and allergy development. ß 2006 Elsevier Ltd. All rights reserved.
The inherited basis of disease due to single gene defects is well recognised, but these conditions are rare. The major burden of ill health is due to common diseases which have a complex aetiology, with multiple genes interacting with each other and with environmental factors. Asthma is the most common chronic disease of childhood, and has increased in prevalence over the last 3 to 4 decades.1 An estimated 5.1 million people in the UK are currently receiving treatment for asthma.2 A genetic component of asthma has been confirmed by twin studies.3 Whilst several genes have a moderate effect in asthma,4 genetics alone cannot explain the rise in prevalence. The time course of this increase has directed attention towards environmental changes which have occurred in parallel, including diet, microbial exposure, antibiotics, immunisations, childcare arrangements and changes to the home. The increase in asthma prevalence is likely a consequence * Corresponding author. Tel.: +44 161 291 2494; Fax: +44 161 291 5057. E-mail address: [email protected] (A. Custovic). 1526-0542/$ – see front matter ß 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.prrv.2006.04.164
of environmental factors increasing the risk in genetically susceptible individuals mediated through gene-environment interactions.
GENETIC COMPONENT OF ASTHMA Several genome-wide screens for asthma and its related traits have identified evidence for linkage on most chromosomes.5–10 Despite the fact that some regions of linkage have been replicated, it has proven difficult to identify susceptibility genes from a region of linkage. The first examples of susceptibility genes for an asthma phenotype identified using a positional cloning approach have recently been published.11,12 Association studies often focus on candidate genes likely to be involved in the immunological pathways of asthma, including IL-4 receptor,13 IL-13,14 FceR115 and glutathione S–transferase genes.16 Candidate genes may also be prioritised for investigation if they map to regions of linkage. A further refinement has been to identify candidate genes with plausible environmental interactions (e.g. CD14 with endotoxin17) to explain the increase in asthma prevalence.
WHAT ARE WE LEARNING FROM GENETIC COHORT STUDIES?
WHY DO WE NEED COHORT STUDIES? A study from Melbourne has clearly identified that patterns of lung function and asthma displayed at age 7 years track into adulthood.18 These deficits in lung function do not appear to be present soon after birth19 and are likely to be acquired in the first few years of life. As wheezing illness can begin within months of birth, to study gene-environment interactions in asthma development it is essential to utilise prospective birth cohorts with detailed measures of environmental exposures and objective measures of lung function in addition to parentally reported symptoms. The National Asthma Campaign Manchester Asthma and Allergy Study (NACMAAS) is a population-based prospective birth cohort study (n 1000) investigating risk factors for the development of asthma and allergies in children.20–31 Objective clinical outcome measures include lung function (specific airways resistance and spirometry), airway reactivity and atopic sensitization (skin tests and IgE). Subjective measures include questionnaire data on parentally-reported symptoms. Comprehensive measurements of environmental exposures include indoor allergens (mite, cat and dog), endotoxin, pet ownership and exposure, childcare arrangements, family size, antibiotic usage, maternal asthma medication usage during pregnancy and a detailed dietary questionnaire (Diet Q). We therefore have a unique opportunity to explore the interactions between genes and environment on the risk of asthma and atopic sensitisation. In a first study utilizing this strategy we have provided the first evidence that the association of ADAM33 with asthma may be mediated via its effects on lung function in childhood.31 Our data support the hypothesis that reduced early-life lung function is in part a genetically determined trait. Polymorphisms were associated with reduced lung function at both three and five years of age. In this study we were unable to show any association between ADAM33 SNPs and allergic sensitization, suggesting that separate genetic factors contribute to disordered airway function and the immunological component of asthma. Future studies will enable identification of children at increased risk of disease because of a genetic predisposition. Evidence-based strategies for prevention of asthma and atopic sensitization will then be developed to reduce the risk of asthma and allergy development.
REFERENCES 1. Omran M, Russell G. Continuing increase in respiratory symptoms and atopy in Aberdeen schoolchildren. BMJ 1996; 312: 34. 2. Anon. Out in the Open: the true picture of asthma in the United Kingdom today. The Asthma Journal 2001; 6(suppl): 5. 3. Duffy DL, Martin NG, Battistutta D, Hopper JL, Mathews JD. Genetics of asthma and hay fever in Australian twins. Am Rev Respir Dis 1990; 142: 1351–1358.
S91
4. Jenkins MA, Hopper JL, Giles GG. Regressive logistic modeling of familial aggregation for asthma in 7394 population-based nuclear families. Genetic Epidemiology 1997; 14: 317–332. 5. Daniels SE, Bhattacharrya S, James A, Leaves NI, Young A, Hill MR et al. A genome-wide search for quantitative trait loci underlying asthma. Nature 1996; 383: 247–250. 6. Ober C, Cox NJ, Abney M, Di Rienzo A, Lander ES, Changyaleket B et al. Genome wide search for asthma susceptibility loci in a founder population: the Collaborative study on Asthma Genetics. Human Molec Genet 1998; 7: 1393–1398. 7. Wjst M, Fischer G, Immervoll T, Jung M, Saar K, Rueschendorf F et al. A Genome wide search for linkage to asthma. German Asthma Genetics Group. Genomics 1999; 58: 1–8. 8. Hizawa N, Freidhoff LR, Chiu YF, Ehrlich E, Luehr CA, Anderson JL et al. Genetic regulation of Dermatophagoides pteronyssinus-specific IgE responsiveness: a genome wide multipoint linkage analysis in families recruited through 2 asthmatic sibs. Collaborative Study of Asthma (CSGA). J Allergy Clin Immunol 1998; 102: 436–442. 9. The Collaborative Study on the Genetics of Asthma (CSGA). A genome-wide search for asthma susceptibility loci in ethnically diverse populations. Nature Genetics 1997; 15: 389–392. 10. Dizier MH, Besse-Schmittler C, Guilloud-Bataille M, Annesi-Maesano I, Boussaha M, Bousquet J et al. Genome screen for asthma and related phenotypes in the French EGEA study. Am J Respir Crit Care Med 2000; 162: 1812–1818. 11. Van Eedewegh P, Little RD, Dupuis J, Del Mastro RG, Falls K, Simon J et al. Association of ADAM33 gene with asthma and bronchial hyperresponsiveness. Nature 2002; 418: 426–430. 12. Zhang Y, Leaves NI, Anderson GG, Ponting CP, Broxhome J, Holt R et al. Positional cloning of a quantitative trait locus on chromosome 13q14 that influences immunoglobulin E levels and asthma. Nat Genet 2003; 34: 181–186. 13. Deichmann K, Bardutzky J, Forster J, Heinzmann A, Keuhr J. Common polymorphisms in the coding part of the IL-4-receptor gene. Biochem Biophys Res Commun 1997; 231: 696–697. 14. Graves PE, Kasbech M, Halonen M, Holberg CJ, Baldini M, Fritzsch C et al. A cluster of seven tightly linked polymorphisms in the IL-13 gene is associated with total serum IgE levels in three populations of white children. J Allergy Clin Immunol 2000; 105: 506–513. 15. Hill MR, James AL, Faux JA. FceR1polymorphisms and risk of atopy in a general population sample. BMJ 1995; 311: 776–779. 16. Fryer AA, Bianco A, Hepple M, Jones PW, Starnge RC, Spiteri MA. Polymorphisms at the Glutathione S-transferase GSTP1 locus: a new marker for bronchial hyperresponsiveness and asthma. Am J Respir Crit Care Med 2000; 161: 1437–1442. 17. Baldini M, Lohman IC, Halonen M, Erickson RP, Holt PG, Martinez FD. A polymorphism in the 50 flanking region of the CD14 gene is associated with circulating soluble CD14 levels and with total serum IgE. Am J Respir Cell Mol Biol 1999; 20: 976–983. 18. Phelan PD, Roberton CF, Olinsky A. The Melbourne Asthma Study: 1964–1999. J Allergy Clin Immunol 2002; 109: 189–194. 19. Taussig LM, Wright AL, Holberg CJ, Halonen M, Morgan WJ, Martinez FD. Tucson children’s respiratory study:1980 to present. J Allergy Clin Immunol 2003; 111: 661–675. 20. Custovic A, Simpson BM, Murray CS, Lowe L, Woodcock A. The National Asthma Campaign Manchester Asthma and Allergy Study. Pediatr Allergy Immunol 2002; 13(Suppl. 15): 32–37. 21. Lowe L, Murray C, Custovic A, Simpson BM, Kissen P, Woodcock A. Specific airway resistance in three year old children. Lancet 2002; 359: 1904–1908. 22. Murray CS, Pipis SD, McArdle EC, Lowe L, Custovic A, Woodcock A. Lung function at one month as a risk factor for infant wheezing in a high risk population. Thorax 2002; 57: 388–392. 23. Calam R, Gregg L, Simpson B, Morris J, Woodcock A, Custovic A. Childhood asthma, behavior problems, and family functioning. J Allergy Clin Immunol 2003; 112: 499–504.
S92
24. Murray CS, Woodcock A, Smillie FI, Cain G, Kissen P, Custovic A. Tobacco smoke exposure, wheeze and atopy. Pediatr Pulmonol 2004; 37: 492–498. 25. Lowe L, Murray CS, Martin L, Deas J, Cashin E, Poletti G, Simpson A, Woodcock A, Custovic A. Reported versus confirmed wheeze and lung function in early life. Arch Dis Child 2004; 89: 540–543. 26. Woodcock A, Lowe LA, Murray CS, Simpson BM, Pipis SD, Kissen P, Simpson A, Custovic A. Early life environmental control: effect on symptoms, sensitization and lung function at age 3 years. Am J Respir Crit Care Med 2004; 170: 433–439. 27. Lowe LA, Woodcock A, Murray CS, Morris J, Simpson A, Custovic A. Lung function at age 3 years: effect of pet ownership and exposure to indoor allergens. Arch Ped Adolesc Med 2004; 158: 996–1001.
A. CUSTOVIC, AND A. SIMPSON
28. Lowe LA, Simpson A, Woodcock A, Morris J, Murray CS, Custovic A. Wheeze phenotypes and early life lung function. Am J Respir Crit Care Med 2005; 171: 231–237. 29. Calam R, Gregg L, Simpson A, Simpson B, Woodcock A, Custovic A. Behaviour Problems Antecede the Development of Wheeze in Childhood: A Birth Cohort Study. Am J Respir Crit Care Med 2005; 171: 323–327. 30. Simpson A, Soderstrom L, Ahlstedt S, Murray CS, Woodcock A, Custovic A. IgE antibody quantification and the probability of wheeze in pre-school children. J Allergy Clin Immunol 2005; 116: 744–749. 31. Simpson A, Maniatis N, Jury F, Cakebread JA, Lowe LA, Holgate ST et al. Polymorphisms in A Disintegrin and Metalloprotease 33 (ADAM33) Predict Impaired Early-Life Lung Function. Am J Respir Crit Care Med 2005; 172: 55–60.