1. Gene Environment Interactions With Air Pollution María Eugenia Vargas Camaño M. D. Chief of Allergy and Clinical Immunology Service CMN 20 de Noviembre ISSSTE México, D. F.

2. Asthma: Chronic, Inflammatory Multifactorial disease. Represents a huge socioeconomic burden Public health: probably the most important allergy- related disease.

3. Interaction of genetic and environmental factors lead to its clinical expression

4. Casual Model for Asthma Choudhry, Seibold, Borrell, et al.: Latinos, Epidemiology and Asthma Proc Am Thorac Soc 2007; 4: 226–233,

5. Genetics of Asthma Multiple genes identified and involved Each gene has a modest effect in the disease Genetic variation often differs between races and ethnic groups Difficulty in identifying a consistent phenotype across population groups Clearly defining disease phenotype is a central issue. There is no uniform phenotypic definition for asthma It iss useful to evaluate phenotypes associated with the disease

6. Individual EnvironmentalGenetics Gene-by-environment interactions: ‘‘because of their genetic differences, two or more individuals, families or genotypic lines respond differently, or to different extents, to changes in the environment.’’ Caligari PD, Mather K. Genotype–environment interaction, III: interactions in Drosophila melanogaster. Proc R Soc Lond B Biol Sci 1975;191:387-411.

7. Phenotypes associated with asthma Atopic sensitization: High levels of IgE antibodies or skin-test responsiveness to common allergens. Wheeze: Noisy, labored breathing due to air moving through narrowed tracheobronchial airways. Bronchial hyperresponsiveness: state where bronchi constrict easily and excessively, on exposure to specific (allergen) and non-specific (chemical and physical) stimuli. Other allergic disorders: Characterized by an immunologically mediated adverse reaction to a foreign substance. Sadeghnejad A, Bleecker E, Meyers DA Principles of Genetics in Allergic Diseases and Asthma Adkinson: Middleton's Allergy: Principles and Practice, 7th ed.2008 pp.59-69

8. Phenotypes associated with asthma Wardlaw AJ, Dunnette S, Gleich GJ, et al. Eosinophils and mast cells in bronchoalveolar lavage in subjects with mild asthma: Relationship to bronchial hyperreactivity. Am Rev Respir Dis 1988; 137:62–69.

9. 1.Hayden,Le Souëf.Clin Pulm Med 2007; 14:249-257 2 Daniels SE, Bhattacharrya S, James A, et al.. Nature. 1996;383:247–250. 3 Altmuller J, Seidel C, Lee YA, et al. BMC Pulm Med. 2005;5:1. 4 Meyers DA, Postma DS, Stine OC, et al.. J Allergy Clin Immunol. 2005; 115: 1169 –1175. 5 Postma DS, Meyers DA,. Am J Respir Crit Care Med. 2005;172:446–452. Asthma: Genome-Wide Screens 1 Identify chromosomal regions linked with disease in families from which candidate genes or positionally cloned genes are identified. First study published in 1996 2. Most of the studies used asthma-affected sibling pairs for the identification of regions linked to the phenotypes of interest. Phenotype studied Ascertainment Chromosomes linked Total IgE Siblings pairs with asthma 1, 7, 11 3 BHR Asthmatic probands and their families 3p 5q 4 FEV1% VC Asthmatic probands and their families 2q 5

10. 1. Hayden,Le Souëf. Clin Pulm Med 2007; 14:249-257 2 Van Eerdewegh P, Little RD, Dupuis J, et al.. Nature.2002;418:426–430. 3 Noguchi E, Yokouchi Y, Zhang J, et al.. Am J Respir Crit Care Med. 2005;172:183–188. 4 Allen M, Heinzmann A, Noguchi E, Nat Genet. 2003;35: 258–263. 5 Laitinen T, Polvi A, Rydman P, et al. Science. 2004;304:300304. 6 Nicolae D, Cox NJ, Lester LA, et al.. Am J Hum Genet. 2005;76:349 –357 7 Zhang Y, Leaves NI, Anderson GG, et al. Nat Genet. 2003;34:181–186. 8 Brasch-Andersen C, Tan Q, Borglum AD, et al. Thorax. 2006;61:874–879 Asthma: Candidate Gene/Association Studies 1 In genome-wide screens chromosomal regions linked with asthma are identified. Candidate genes within those regions can be screened for polymorphisms that may then be associated with asthma-related phenotypes via association studies

11. Genome Wide Association Studies First study in asthma 1 >300 000 SNPs map association with childhood asthma 994 patients and 1243 non-asthmatics Multiple markers on chromosome 17q21 strongly associated with childhood-onset asthma 1 Moffatt M.F., Kabesch M., Liang L., et al: Genetic variants regulating ORMDL3 expression contribute to the risk of childhood asthma. Nature 2007; 448:470-473.

12. Convincing evidence Air pollutants (fine particles and ozone): 1)Exacerbate existing asthma, 2)Increase the risk for asthma hospitalization and emergency department visits, 3)Impair lung function 1-3. Few studies have addressed interactions between air pollutants and genetics in relation to asthma. 4-5 Gene-environment interactions with air pollution 1 Downs SH, Schindler C, Liu LJ, Keidel D, Bayer-Oglesby L, Brutsche MH, et al. Reduced exposure to PM10 and attenuated age-related decline in lung function. NEngl J Med 2007;357:2338-47. 2 Atkinson RW. Acute effects of air pollution on admissions: reanalysis of APHEA2. Am J Respir Crit Care Med 2004;169:1257-8. 3 Atkinson RW, Anderson HR, Sunyer J, Ayres J, Baccini M, Vonk JM, et al. Acute effects of particulate air pollution on respiratory admissions: results from APHEA 2 project. Air Pollution and Health: a European Approach. Am J Respir Crit Care Med 2001;164:1860-6. 4 London SJ. Gene-air pollution interactions in asthma. Proc Am Thorac Soc 2007;4; 217-20. 5 Yang IA, Savarimuthu S, Kim ST, Holloway JW, Bell SC, Fong KM. Gene-environmental interaction in asthma. Curr Opin Allergy Clin Immunol 2007;7:75-82.

13. Gene-environment interactions with air pollution Acute exposure studies: 24 healthy volunteers 2-hour bicycle ride at ambient summer ozone concentrations, before and after: Decreases in lung function parameters > in subjects with the combined GSTM1- null and the NAD(P):quinone oxidoreductase wild- type genotype 1 Similar results: cross-sectional study in a Mexico City population High lifetime exposure to ozone. The NAD(P):quinone oxidoreductase TT reduced activity genotype was protective for asthma only among the GSTM1-null individuals 2. There is also some evidence that the GSTM1 and GSTP1 genotypes alone or in combination may modify the acute respiratory response to ozone in individuals with asthma 3 1 Bergamaschi E, De Palma G, Mozzoni P, Vanni S, Vettori MV, Broeckaert F, et al. Polymorphism of quinone- metabolizing enzymes and susceptibility to ozone inducedacute effects. Am J Respir Crit Care Med 2001;163:1426- 31 2 David GL, Romieu I, Sienra-Monge JJ, Collins WJ, Ramirez-Aguilar M, del Rio-Navarro BE, et al. Nicotinamide adenine dinucleotide (phosphate) reduced:quinone oxidoreductase and glutathione S-transferase M1 polymorphisms and childhood asthma. Am J Respir Crit Care Med 2003; 168:1199-204. 3 Romieu I, Ramirez-Aguilar M, Sienra-Monge JJ, Moreno-Macias H, del Rio-Navarro BE, David G, et al. GSTM1 and GSTP1 and respiratory health in asthmatic children exposed to ozone. Eur Respir J 2006;28:953-9.

14. Gene-environment interactions with air pollution Acute exposure studies: 51 individuals undergoing ozone challenge Genotyped for 4 polymorphisms across the TNF gene. 1 Mean reduction in FEV1 with ozone challenge > in TNF-308GG individuals compared with the other genotypes. TNF polymorphism in susceptibility to childhood asthma: Large Child’s Health Study in the United States. 2 Children with TNF-308 GG had decreased risk of asthma and lifetime wheezing. The protective effects of GG genotype on wheezing outcomes > in lower than higher ozone communities. The reduction of the protective effect from the -308 GG genotype with higher ozone exposure was most marked in the GSTM1-null and GSTP1 Ile/Ile groups 1 Yang IA, Holz O, Jorres RA, Magnussen H, Barton SJ, Rodriguez S, et al. Association of tumor necrosis factor-alpha polymorphisms and ozone-induced changein lung function. Am J Respir Crit Care Med 2005;171:171-6. 2 Cameron L, Webster RB, Strempel JM, Kiesler P, Kabesch M, Ramachandran H, et al. Th2 cell- selective enhancement of human IL13 transcription by IL13- 1112C>T, a polymorphism associated with allergic inflammation. J Immunol 2006; 177: 8633-42

15. 205 non-asthmatic and asthmatic children, (9-12 ys) Detroit, Michigan: Environmental measures (indoor and outdoor air, vacuum dust) Biomarkers of exposure (cotinine, metals, total and allergen specific Ig E, polycyclic aromatic hydrocarbons, volatile organic carbon metabolites) Clinical indicators of health outcome (immunological, cardiovascular and respiratory) Blood gene expression and candidate SNP analyses were conducted. MICA study provides an opportunity to evaluate complex relationships between environmental factors, physiological biomarkers, genetic susceptibility and health outcomes

17. Is the process of urbanisation involved in differences in asthma prevalence in transitional communities in north-eastern Ecuador? This is an ecological study conducted in 59 communities in Esmeraldas Province, Ecuador. Indicators of urbanisation were grouped into three indices representing the processes associated with urbanisation: 1)Socioeconomic 2)Lifestyle 3)Urban infrastructure. Thorax 2011;66:1043-1050

18. Socioeconomic Lifestyle Summary Urbanisation Indices Asthma Prevalence and Urbanisation Significant associations with community asthma prevalence: 1) Socioeconomic (r= 0.295, p= 0. 023) 2) Lifestyle (r= 0.342, p= 0.008) 3) Summary urbanisation index (r= 0.355, p= 0.006).

19. von Mutius E. Gene-environment interactions in asthmaJ Allergy Clin Immunol 2009;123: 3-11.