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The Egea study

Genes and the Environment: The Genesis of Asthma and Allergy Workshop March 1-3, 2009 - Vancouver. The Egea study. Francine Kauffmann Respiratory and Environmental Epidemiology Inserm, U780 - Epidemiology and Biostatistics Villejuif, France. General objectives

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The Egea study

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  1. Genes and the Environment: The Genesis of Asthma and Allergy Workshop March 1-3, 2009 - Vancouver The Egea study Francine Kauffmann Respiratory and Environmental Epidemiology Inserm, U780 - Epidemiology and Biostatistics Villejuif, France

  2. General objectives • To determine genetic factors of asthma and related traits (atopy and bronchial responsiveness) • To determine environmental factors and the interactions of these 2 types of factors 3) To clarify the heterogenetiy of asthma

  3. Segregation Families of asthmatic cases Association Linkage Large nb of « usual » asthma nuclear families Prevalence => hospital recruitment Detailed data on phenotypes => Asthmas Controls. Further, interest to estimate the allelic frequency of genetic markers and for association studies Detailed data on environment (personal, familial, general, childhood, adulthood) Question => Design Genetics Heterogeneity Environment Clin Experim Allergy 1995

  4. Egea - A multicentric study

  5. Case-control study- 5 cities in France+Family study of asthmatic probands + families with affected sibs =>In total 2105 subjects

  6. A longitudinal study

  7. First survey Egea1 N = 2047 ..with a good follow-up Dead N = 45 (2.2%) Alive N = 2002 Refusals and lost N= 157 (7.8%) Overall follow-up N = 1845 (92.2%) Only short questionnaire (step1) N = 302 (15.1%) Long questionnaire (step 2) N = 1543 (77.1 %)

  8. In summary • Case-control + family - 2105 subjects (388 asthmatic families + 415 controls), 7- 70 years in 1992, French multicentric • Longitudinal- Egea1 1992/5 - Egea2 2003/7 (77% with exam, 92% with simple info) • Health data (respiratory and allergy) (ECRHS-like) asthma - rhinitis - eczema - lung function - allergic tests ~1500 var x 2 • Environment : smoking, occupational and residential histories, indoor exposure, fam animals and pets, job exposure matrix/ expert, air pollution (FP7 Escape ; PI B Brunekreef), diet, physical activity • Genetic program (DNA 97%) 400 µsat + 3500 snps + GWA 550K snps (FD coord, CNG ; FP6 Gabriel PI B Cookson) • Biological collection : RNA 1400 (egea2) + aliquotes serum, plasma, erythrocytes or exhaled breath condensate 70 000 (1/5 egea1, 4/5 egea2) Egea collection 2105 Founders/offspring 897/1207 Asthma,ever 2104 [99.9%] N (%)902 (43%) DNA 2034 [97%] RNA 1398 [66%] Serum Egea1 1953 [93%] Serum Egea2 1427 [68%] Exhaled Breath Condensate Egea2 1336 [63%]

  9. Among potential areas of international collaborations Environment Genetics

  10. Occupation - EgeaEnvironmental factor usually not shared by family members Complete occupational history - All jobs coded Description of tasks, used to improve evaluation of exposures by the Asthma Job exposure matrix* to asthmogens through expert step Detailed information regarding exposures for specific jobs (cleaning, nurses,..) with interest in cleaning and disinfecting agents Information on health-related changes in jobs *Kennedy et al Asthma JEM (OEM), described in Egea in 2000, now internationally used.

  11. Air pollution - EgeaEnvironmental factor usually shared by family members Complete residential history : address egea1 et ege2 (all geocoded), commune all life (birth included) Exposure modelled estimates available for France • Géovariances (French map 4 km2 NO2, SO2, O3 and PM10 (models - cokriging, i.e interpolation between fixed stations improved by considering local land characteristics) - Publications Rage et al.2008/9 • APMoSHERE (European map based on 1 km2 D Briggs) 2001 NO2 and O3 European collaboration - B Jacquemin ECRHS • Futur Escape (EU FP7) - Land use regression for specific locations covering most of Egea - Evaluations available in 2011

  12. Genetics - Egea A program which started in 1994 - Microsatellites and SNPS - Genome wide linkage analyses - Candidate genes - Numerous publications Part of Gabriel Interest in candidate gene studies, in genome wide approaches, with methodological developments, in gene environment interactions, in case-control comparisons, in familial data analyses, ..

  13. Exposed p<10-5 Unexposed Risk of asthma before age 4 Age of Onset of Asthma & Env Tobacco Smoke Exposure Asthma onset  4 yrs Bouzigon et al, New Engl J Med, 2008 17q21 locus associated with early-onset asthma ( 4 yrs)  risk of early-onset asthma with ETS exposure • Exploration of genetic heterogeneity according to age of onset of asthma in regions detected by meta-analysis of asthma GWAS • Genome-wide association analysis of age of onset of asthma  Investigation of G x Exposure to passive smoking in this context

  14. PARENT-OF-ORIGIN EFFECT / IMPRINTING Pooled genome-wide linkage analysis of French, Italian and UK Family data has investigated parent-of-origin effects for asthma, skin tests, IgE Malerba, Bouzigon et al, GABRIEL exchange programme 3 teams: France (F Demenais), Italy (P Pignatti), UK (W Cookson) Several regions show parent-of-origin effects for asthma, SPT, IgE Proposal: GWAS to investigate imprinting in pooled family data sets

  15. GENES WITH PLEIOTROPIC EFFECTS Previous EGEA linkage scans have characterized regions of linkage common to several asthma-related phenotypes, suggesting pleoitropic effect of genes. Some of these linkages are sex-specific & show Gxsmoking interactions (Bouzigon et al, Hum Mol Genet, 2004, Bouzigon et al, Hum Genet, 2007; Aschard et al, submitted) Proposal: GWAS for identifying pleiotropic genes influencing asthma-related phenotypes (eg asthma onset, FEV1, Skin tests) possibly taking into account GXE (smoking, gender…)

  16. Strengths - Egea • Families and population-based controls • Phenotypic characterisation (detailed and longitudinal) • Environment • Biological collection

  17. Limitations - Egea • Complexity of design - numerous strategies (internal replication, but complex) need to learn how to work with the study - post doc • Sample size - 2000 not 20 000, but 902 asthmatics, precision (power) • Limited biological data evaluating environment - but validated measures are few • Funding insufficient for maintaining data sets, web site,.. (infrastructure), statistical analyses,… and post doc

  18. Egea cooperative group Respiratory epidemiology : Inserm U 700, Paris M Korobaeff (Egea1), F Neukirch (Egea1); Inserm U 707, Paris : I Annesi-Maesano ; Inserm U 780, Villejuif : F Kauffmann, N Le Moual, R Nadif, MP Oryszczyn ; Inserm U 823, Grenoble : V Siroux Genetics : Inserm U 393, Paris : J Feingold ; Inserm U 535, Villejuif : MH Dizier ; Inserm U 946, Paris : E Bouzigon , F Demenais ; CNG, Evry : I Gut , M Lathrop. Clinical centers : Grenoble : I Pin, C Pison; Lyon : D Ecochard (Egea1), F Gormand, Y Pacheco ; Marseille : D Charpin (Egea1), D Vervloet ; Montpellier : J Bousquet ; Paris Cochin : A Lockhart (Egea1), R Matran (now in Lille) ; Paris Necker : E Paty, P Scheinmann ; Paris-Trousseau : A Grimfeld, J Just. Data and quality management : Inserm ex-U155 (Egea1) : J Hochez ; Inserm U 780, Villejuif : N Le Moual, C Ravault ; Inserm ex-U 794 : N Chateigner ; Grenoble : J Ferran Coordination : F Kauffmann; F Demenais (genetics); I Pin (clinical aspects).

  19. For further information, .. Web site of the study (design, questionnaires, list of publications and communications) http://ifr69.vjf.inserm.fr/~egeanet/ As Canada is a bilingual country, please note that All abstracts of papers are in English and French on egeanet Articles de synthèse en français (données Egea1) Siroux V, et coll. Rev Mal Respir 2007 ; 24 : 599-608 (soon in English,..) Kauffmann F, et coll. Rev Mal Respir 2002 ;19:63-72

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