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Adnan Custovic MSc DM MD PhD Professor of Allergy University of Manchester, UK

Adnan Custovic MSc DM MD PhD Professor of Allergy University of Manchester, UK. Asthma – Linear Model. Bronchial hyper-reactivity. Airway inflammation. (repeated cycles). ASTHMA. Airway remodelling. Asthma – Linear Model. Airway inflammation. Net Result of This Approach.

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Adnan Custovic MSc DM MD PhD Professor of Allergy University of Manchester, UK

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  1. Adnan Custovic MSc DM MD PhD Professor of Allergy University of Manchester, UK

  2. Asthma – Linear Model Bronchial hyper-reactivity Airway inflammation (repeated cycles) ASTHMA Airway remodelling

  3. Asthma – Linear Model Airway inflammation

  4. Net Result of This Approach

  5. Genetic Model Genetic Variant Disease

  6. Asthma is Heritable But the Results of Genetic Studies Are Inconsistent Linkage in 1 study Linkage replicated in >1 study

  7. Asthma Has Increased in Prevalence Prevalence (%) Beasley R, JACI 2000; 105: S466-472

  8. Environmental Model Environmental exposure Effect

  9. Allergy Epidemic is Environmental But Inconsistencies re. the Role of Environmental Exposures • Breast Feeding • Protects (Kull et al, JACI 2005;116:657-61) • Increases the risk (Sears et al, Lancet 2002;360:901-7) • Does not matter (Burgess et al, Pediatrics 2006;117:e787-92) • Cat ownership • Good (Hesselmar et al, CEA 1999;29:611-7) • Bad (Noertjojo et al, JACI 1999;103:60-65) • Does not matter (Rhodes et al, JACI 2001;108:720-5)

  10. Three Tales On Genes and Environment 1. A Tale of Two Molecules

  11. Endotoxin Exposure & Atopy:Protects, Has No Effect, Increases the Risk NEJM 2002; 347: 669-79 CEA 2003; 33: 295 PAI 2006;17:17-21

  12. CD14 • Pattern recognition receptor-part of receptor complex for endotoxin • Soluble or membrane bound CD14 • Activation of pathway→ IL12 →↓allergy • Maps to 5q32 - region of linkage to asthma

  13. sCD14 Varies With CD14 Genotype CC TT Baldini et al, AJRCMB 1999; 20: 976

  14. No Association Between CD14 and IgE in German Children IgE CCCTTT CCCTTT CCCTTT CCCTTT Kabesch et al, Allergy 2004; 59: 520

  15. CD14/-159 in the Hutterites • Founder population South Dakota • Descended from 64 founders (1700s) • Communal agrarian lifestyle • Asthma very common • T allele associated with positive skin tests (p<0.001) Ober et al, Am J Hum Genet 2000; 67: 1154-62

  16. CD14/-159 Genotype and AtopyAssociation In Some Populations But Not Others C allele associated T allele associated No association

  17. Inconsistencies in Results for CD14 and Endotoxin • CD14 polymorphisms • associated with allergic sensitisation in some populations but not other • risk allele different in different populations • Endotoxin • protective in some populations but not others Baldini et al: Am J Res Cell Mol Biol 1999 20 (5) 976-83 Goa et al : Clin Genetic 1999 56 (2) 164-5 Koppelman et al: Am J Res Crit Care Med 2001 163 965-969 Ober et al: Am J Hum Genet 2000 67 1154-62 Sengler et al Clin Exp Allergy 2003 33 166 -169

  18. Population-based birth cohort • Commenced in 1995 • Subjects recruited in utero • parents skin tested + questionnaire • Nested within the cohort - primary prevention study of the effect of stringent environmental control • high risk children without pets • 1085 children born into the study • 952 Observational cohort • 133 Intervention • Reviews at age 1, 3, 5 and 8 years • 1030 children reviewed at age 8 years • 94% follow-up rate

  19. MAAS: No Association Between Allergic Sensitisation and CD14 Genotype P>0.3 Simpson et al, AJRCCM 2006;174:386-92

  20. MAAS: Endotoxin Exposure Decreases the Risk of IgE Mediated Sensitisation 1.0 0.8 0.6 Predicted probability for sensitisation P=0.005 0.4 0.2 0.0 1.0 7.4 54.6 22000 162755 403.4 1.2x106 2981 Endotoxin Load (EU/m2) Simpson et al, AJRCCM 2006;174:386-92

  21. CD 14 Promoter Polymorphism, Endotoxin Exposure and Sensitization 1.0 0.8 0.6 Predicted probability for sensitisation 0.4 P=0.7 0.2 0.0 1.0 7.4 54.6 22000 162755 403.4 1.2x106 2981 Endotoxin Load (EU/m2) Simpson et al, AJRCCM 2006;174:386-92

  22. CD 14 Promoter Polymorphism, Endotoxin Exposure and Sensitization 1.0 0.8 0.6 Predicted probability for sensitisation P=0.2 0.4 P=0.7 0.2 0.0 1.0 7.4 54.6 22000 162755 403.4 1.2x106 2981 Endotoxin Load (EU/m2) Simpson et al, AJRCCM 2006;174:386-92

  23. CD 14 Promoter Polymorphism, Endotoxin Exposure and Sensitization 1.0 P=0.004 0.8 0.6 Predicted probability for sensitisation P=0.2 0.4 P=0.7 0.2 0.0 1.0 7.4 54.6 22000 162755 403.4 1.2x106 2981 Endotoxin Load (EU/m2) Simpson et al, AJRCCM 2006;174:386-92

  24. High Endotoxin Exposure: T allele is the Risk Allele for Sensitisation 1.0 0.8 0.6 Predicted probability for sensitisation 0.4 0.2 0.0 1.0 7.4 54.6 22000 162755 403.4 1.2x106 2981 Endotoxin Load (EU/m2) Simpson et al, AJRCCM 2006;174:386-92

  25. Low Endotoxin Exposure: C allele is the Risk Allele for Sensitisation 1.0 0.8 0.6 Predicted probability for sensitisation 0.4 0.2 0.0 1.0 7.4 54.6 22000 162755 403.4 1.2x106 2981 Endotoxin Load (EU/m2) Simpson et al, AJRCCM 2006;174:386-92

  26. Moderate Endotoxin Exposure: No Association Between CD14 Genotype and Sensitisation 1.0 0.8 0.6 Predicted probability for sensitisation 0.4 0.2 0.0 1.0 7.4 54.6 22000 162755 403.4 1.2x106 2981 Endotoxin Load (EU/m2) Simpson et al, AJRCCM 2006;174:386-92

  27. Tale 2: Dirty Pretty Things

  28. Opposite Effect of Day-care on Atopic Phenotypes in Different Populations Hagerhed-Engman et al, Allergy 2006;61:447-53 Ball TM, NEJM 2000;343:538-43

  29. Asthma and TLR2-16934 Genotype In Farmers’ and Non-farmers’ Children ALEX-Study Eder et al, JACI 2004; 113: 482-8

  30. Hypothesis • The same genetic variant which confers a reduction in risk of allergic phenotypes in the farming environment (TLR2/−16934,rs4696480) may be associated with a reduction in risk amongst urban children purportedly exposed to microbial agents in day-care

  31. TLR2/−16934 (rs4696480 ) No significant associations between genotype and any of the clinical outcomes at any age • Day-care attendance Significantly associated with reduced wheezing at ages 5 and 8 and reduced atopic wheeze at age 8

  32. Opposite Effect of Day-care on Atopy With Different TLR2 Variants % sensitised TLR2*day-care in the longitudinal model, p=0.038 (adjusted) Custovic, Rothers, Simpson, Martinez et al, 2008

  33. Day-care Attendance Protects Against Atopic Wheezing at Age 8 Years p=0.005 Custovic, Rothers, Simpson, Martinez et al, 2008

  34. Opposite Effect of Day-care on Atopic Wheezing With Different TLR2 Variants TLR2*day-care, p=0.005 Custovic, Rothers, Simpson, Martinez et al, 2008

  35. IIS: Opposite Effect of Day-care on Atopic Wheezing With Different TLR2 Variants TLR2*day-care in the longitudinal model, p=0.005 (adjusted) Custovic, Rothers, Simpson, Martinez et al, 2008

  36. Differing Effects of Day-care Among Children With Different TLR2 Genotype • The associations between day care attendance and allergic phenotypes are dependent on the variant in TLR2 gene • Day-care was protective, but only amongst children carrying the T allele for TLR2/−16934 • The association tended to be in the opposite direction among AA homozygotes • Children with T allele for TLR2/−16934 may benefit from attending day-care, whereas for those who are AA homozygotes being cared for at home may prove beneficial

  37. Tale 3:On Eczema and Cats

  38. Cumulative Risk of Eczema Stratified on FLG Mutant Allele p <0.0001 Mutant allele Wild type Bisgaard et al, PLoS Med 2008:5(6): e131

  39. No Effect of Cat Ownership at Birth on the Development of Eczema Cat Owner at birth No cats at birth Bisgaard et al, PLoS Med 2008:5(6): e131

  40. Cat at Birth Increases the Risk of Eczema, but Only With FLG Mutation p for interaction: 0.01 Cat Owner at birth No cats at birth Bisgaard et al, PLoS Med 2008:5(6): e131

  41. Cat at Birth Increases the Risk of Eczema, but Only With FLG Mutation p for interaction: 0.0006 Cat Owner at birth No cats at birth Bisgaard et al, PLoS Med 2008:5(6): e131

  42. Increasing Sample Size: Antidote to the Lack-of-Replication Problem? • Analyze populations adequate size adequate for fully powered calculations1,2 • The size should be established case by case based on e.g. expected relative risk and allele frequency of the polymorphism(s)1,2 • As-yet undetected gene-environment interactions might contribute to the problems of replication in genetic association studies3 • Even very large sample size may fail to compensate for heterogeneity of environment3 BUT 1Nat Genet 2005; 27: 1153; 2Hall & Blakey, Thorax 2005; 60: 357–359 3Vercelli & Martinez, JACI 2006; 117: 1303-5

  43. How Should We Search for the Cure of Asthma? • The relationship between genotype and phenotype in asthma: • Not linear or unidirectional • Modulated by a number of environmental factors • In asthma (and other complex diseases) • Genetic predisposition needs to be taken into account when assessing the effect of environmental exposures • Relevant environmental exposures need to be factored into the genetic association studies

  44. How Should We Search for the Cure of Asthma? • We use epidemiological data to identify potentially modifiable risk factors to devise primary prevention strategies • In asthma: • Only individuals with particular susceptibility will benefit from a specific intervention • The same intervention amongst individuals with different susceptibility may cause harm • Develop methods/tests to identify susceptible individuals who may benefit from any particular intervention/drug

  45. How Should We Search for the Cure of Asthma? • We use epidemiological data to identify potentially modifiable risk factors to devise primary prevention strategies • In asthma: • Only individuals with particular susceptibility will benefit from a specific intervention • The same intervention amongst individuals with different susceptibility may cause harm • Develop methods/tests to identify susceptible individuals who may benefit from any particular intervention/drug

  46. How Should We Search for the Cure of Asthma? Inflammation BHR Asthma Genetic Variant Disease Environmental exposure Effect

  47. How Should We Search for the Cure of Asthma? Inflammation BHR Asthma Genetic Variant Disease Environmental exposure Effect

  48. How Should We Search for the Cure of Asthma? • Back to the drawing board • Develop tailor-made individualized measures to target susceptible individuals • Abandon the concept of ”one size fits all” in favour of the individualized interventions and treatments • Study gene-environment interactions in very carefully defined populations • Meticulous longitudinal phenotyping • Contemporaneous measure of environmental exposures

  49. Why Birth Cohorts? • Asthma starts early in life • Asthma is an unstable phenotype • Symptoms may progress or remit over time • Population-based birth cohort • Overcomes problems of recall bias • Permits careful longitudinal phenotyping • Lung function, airway responsiveness, allergic status, physician diagnosis and medication usage can be accurately defined • Contemporaneous measurement of environmental exposures • essential for the study of gene-environment interactions

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