Causes of asthma and allergy in children. Göran Pershagen Institute of Environmental Medicine

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1 Causes of asthma and allergy in children Göran Pershagen Institute of Environmental Medicine

2 Determinants of childhood allergy / asthma Respiratory infections Allergens Micro-biological exposure Male sex Heredity + Heredity - Certain viruses ETS Air pollution Certain gut flora Diet / breast feeding High risk Low risk

3 Gene Locus Predicted primary function Suggested role in asthma Publication ADAM33 20p13 Metalloproteinase Airway remodelling Van Eerdewegh et al. Nature 2002 PHF11 13q14 Zinc finger transcription factor Immunoregulation Zhang et al. Nature Genetics 2003 DPP10, DRPR3 2q14 Dipeptidyl peptidase Cytokine processing Allen et al. Nature Genetics 2003 GPRA / NPSR1 7p14 G-protein coupled receptor Immunoregulation, neural regulation Laitinen et al. Science 2004 HLA-G 6p21 Human leukocyte antigen Antigen presenting, Immunoregulation Nicolae et al American Journal of Human Genetics CYFIP2 5q33 Cytoplasmic protein interaction T cells Noguchi et al. AJRCCM 2005 ORMDL3 17q21 Transmembrane protein anchored in the ER Unknown Moffatt et al. Nature 2007

4 Allergy in children of farmers in Austria, Germany and Switzerland Exposure during Asthma Hay fever Sensitization first year of life OR (95%CI) OR (95%CI) OR (95%CI) Visit to stable No milk from farm ( ) ( ) ( ) No visit to stable Milk from farm ( ) ( ) ( ) Visit to stable Milk from farm ( ) ( ) ( ) From Riedler et al. 2001

5 Determinants of atopic and nonatopic asthma among children in rural areas of 5 European countries From Ege et al. 2006

6 Anthroposophy Rudolf Steiner Steiner schools Holistic medicine Biodynamic diet Restrictive use of: antibiotics antipyretics vaccinations

7 Allergy in children of Steiner schools and Public schools Steiner schools Public schools % Clinical Skin prick test IgE From Alm et al. 1999

8 Characteristics of the anthroposophic lifestyle Steiner schools Public Schools % Antibiotics Antipyretics MMRvaccination No vaccination Measles Fermented vegetables From Alm et al. 1999

9 Particles: PM10, PM2.5, PNC Gases: Nitrogen oxides (NOx) Carbon monoxide (CO) Ozone (O3) Particulate constituents: Metals PAH.. Origin Local Regional Transboundary

10 Number of particles / cc dn/dlogdp PNC & PM10 at Hornsgatan, Stockholm PNC PM City Diesel street & number gasoline exhaust Street Local mass road dust emissions Background non-local PM 40 0,01 0,10 1,00 10,00 Particle diameter (um)

11 NO 2 from traffic (µg/m 3 ) SO 2 from heating (µg/m 3 ) Long term exposure to air pollution Residential history for study subjects Geocoding and linking coordinates to dispersion models Mean (area) Mean (population) 10th to 90th percentile (population) Year PM Mean (area) 5 Mean (population) 10th to 90th percentile (population) Year Emission databases (EDB) 1960, 1970, 1980, 1990, 2000 NO 2 CO SO 2 10

12 2000 NOx

13 2000 NOx

14 2000 NOx

15 2000 NOx

16 2000 NOx

17 Air pollution and air way disease in preschool children (BAMSE) Exposure questionnaire and dust % 1 year symptom questionnaire % 4 year follow up questionnaire % dust % PEF % Blood % and Spec IgE Peak Expiratory Flow 2 year symptom questionnaire % Transient wheeze Late onset wheeze Persistent wheeze Sensitization to specific IgE s Stockholm Centre for Public Health and Institute of Environmental Medicine, Karolinska Institutet

18 Wheeze in relation to air pollution exposure among children in Stockholm Odds Ratio (95% CI) 4 Exposure 1:st year of life. Outcome up to 4 yrs of age ORs calculated for a change in pollution level from the 5 th to the 95 th percentile From: Nordling et al Stockholm Centre for Public Health and Institute of Environmental Medicine, Karolinska Institutet

19 Peak Expiratory Flow in relation to air pollution exposure among children in Stockholm Mean PEF: 169 l/min, SD 29 l/min Effect on PEF (l/m) Traffic-PM 10 Traffic-NO x Point estimate* (95%CI) (-10.67, -0.05) (-6.84, 0.68) * Calculated for a change in pollution level from the 5th-95th percentile From: Nordling et al Stockholm Centre for Public Health and Institute of Environmental Medicine, Karolinska Institutet

20 Sensitization in relation to air pollution exposure among children in Stockholm Odds Ratio (95% CI) 4 Exposure 1:st year of life. Outcome up to 4 yrs of age 2 1 ORs calculated for a change in pollution level from the 5 th to the 95 th percentile.6 From: Nordling et al Stockholm Centre for Public Health and Institute of Environmental Medicine, Karolinska Institutet

21 Odds Ratio (95% CI) NO x -exposure, GSTP1 Ile105Val and sensitization at 4 years of age among children from Stockholm OR and 95% CI From: Melén et al, 2008 Genomsnittlig effekt GSTP1 105 Ile/Ile GSTP1 105 Ile/Val, Val/Val Overall effect GSTP1 105 Ile/Ile 45% av barnen GSTP1 105 Ile/Val, Val, Val 55% av barnen 45% of children 55% of children

22 OR and 95% CI NOx-exposure, GSTP1 Ile105Val, TNF G-308A and sensitization at 4 years of age among children from Stockholm GSTP1 Ile/Ile Val/Ile, Val/Val Ile/Ile Val/Ile, Val/Val TNF GG GG AG/AA AG/AA 105 I/I & -308 GG 105 V/I,V/V & -308 GG 105 I/I & -308 GA, AA 105 V/I,V/V & -308 GA, AA ~15% of the children From: Melén et al, 2008

23 Conclusions Protective factors for asthma and allergy in children are associated with farming and an anthroposophic life style Exposure to traffic related air pollution may affect respiratory symptoms, lung function and sensitization in children Interactions between environmental exposures and genetic factors are important for induction asthma and allergy in children

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25 Relative risk for lung cancer among men in Stockholm associated with exposure to ambient air pollution (20 year lag) NO 2 from traffic (per 10 ug/m 3 ) 1.15 ( ) (> 29 ug/m 3 ) 1.60 ( ) SO 2 from heating (per 10 ug/m 3 ) 0.99 ( ) (> 129 ug/m 3 ) 0.95 ( ) From: Nyberg et al. 2000

26 OR (95% CI) Risk of myocardial infarction in relation to air pollution exposure in Stockholm 4 NO 2 from traffic 4 CO from traffic PM 10 from traffic 4 SO 2 from heating From: Rosenlund et al. 2006

27 Air pollution and asthma/allergy Acute respiratory symptoms Lung function effects Development of asthma Sensitization

28 Average growth in FEV1 from 1993 to 2001 (10-18 y) in relation to NO 2 levels in 12 southern California communities From: Gauderman et al. 2004

29 Association between distance to nearest major road and sensitization at 6 years of age in Munich From: Morgenstern et al. 2008

30 Air pollution, genes and asthma/allergy Ozone, particulate matter, NOx etc Oxidative stress genes Inflammatory genes Experimental studies Epidemiological studies