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International Laboratory in Respiratory and Environmental Epidemiology (ILRE)

Laboratoire International d’Epidémiologie Respiratoire

et Environnementale

Laboratori Internacional en Epidemiologia Respiratória i ambiantal

INSERM UMR-S 1018, Villejuif (Director D Hémon) INSERM UMR-S 823, Grenoble (Director C Brambilla)

CREAL, Barcelona (Director JM Antó)

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A) Participating teams (2 pages per team) The association concerns groups from two institutions (Inserm in Villejuif and in Grenoble), France and the Centre for Research in Environmental Epidemiology (CREAL) in Barcelona, Spain. The European Associate Laboratory (EAL) is codirected by F Kauffmann (Inserm) and JM Antó (CREAL).

Inserm Teams Respiratory and Environmental Epidemiology Inserm team (Director F Kauffmann) (CESP/UMRS1018 - Center of Epidemiology and Population Health, Director D Hémon) 16, avenue PV Couturier F94807 Villejuif, France and Environmental epidemiology applied to reproduction and respiratory health (Director R Slama) (Inserm Institut Albert Bonniot/UMR-S Inserm/Univ J Fourier 823 , Director C Brambilla) BP 170, 38042 Grenoble Cedex 9, France V Siroux is the representative for the project of the Grenoble team

CV of the Inserm Principal Investigator Francine Kauffmann, MD, DRE Inserm, Director of the Respiratory and Environmental Epidemiology Inserm team Date of birth : 21 July 1948 Tel 33 1 45 59 50 72 Email : francine.kauffmann@.inserm.fr

Training 1970 M.S Université of Paris, France 1971 AEA (Méthodologie statistique approfondie) University de Paris, France 1974 MD University de Paris, France

Professional appointments 1975-1978: Attachée de recherches - Inserm U68 (pneumology), Paris, France 1978-1980: Attachée de recherches – Inserm U169 (epidemiology), Villejuif, France 1981-1986: Chargée de recherches - Inserm U169 Villejuif, France. Oct 1984- Oct 1985: Channing Laboratory, Harvard Medical School, Boston 1986-1999: Director of research, DR2 Inserm, U169, then U780, Villejuif, France 1999- 2010: Director of research, DR1 Inserm U780, then U1018 Villejuif, France 2011 - now: Director of research, DRE Inserm U1018, Villejuif, France 2007 - now : Co-director of the European associated laboratory (Inserm CREAL, Barcelone) "International Laboratory in Respiratory Epidemiology Committee Assignments in Professional Societies, and network - Editorial activities 1997-1999 Chair of the Long range planning Comittee, Assembly of Epidemiology, European Respiratory Society 2004-2010 Work package leader for WP on genetics, genomics and post genomics of the Ga2len (Global allergy and asthma European network) European network of excellence 1991-1994 Associate Editor, European Respiratory Journal 1994-1999 Associate Editor, American Journal of Respiratory and Critical Care Medicine

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Inserm Villejuif team Inserm CESP/ UMR-S Inserm/Univ Paris Sud 1018, Respiratory and Environmental Epidemiology team, Villejuif, France

Profile of the Research Unit members which will be involved in the project (name, position, expertise relevant to the proposal) Jean Bousquet, MD, PhD, PU-PH – Chest physician Francine Kauffmann, MD, DRE Inserm – Respiratory epidemiology Bénédicte Jacquemin, MD, PhD, CR1 Inserm – Respiratory epidemiology – Air pollution Nicole Le Moual, PhD, IR2 – Respiratory epidemiology – Occupational hazards Rachel Nadif, PhD, CR1 – Respiratory epidemiology – Genetics and biomarkers Raphaëlle Varraso, PhD, CR1 – Respiratory epidemiology – Nutrition

Main findings of the last 4 years of the research team (10 most relevant publications and patents, ) 1. Dumas O, Smit LAM, Kromhout H, Siroux V, Nadif R, Vermeulen R, Heederik D, Hery M,

Choudat D, Kauffmann F, Le Moual N, on behalf of the Epidemiological Study on the Genetics and Environment of Asthma. Do young adults with childhood asthma avoid occupational exposures at first hire ? Eur Respir J 2010 Sept 30 [Epub a head of print]

2. Donnay C, Denis MA, Magis R, Fevotte J, Massin N, Dumas O, Pin I, Choudat D, Kauffmann F, Le Moual N. Under-estimation of self-reported occupational exposure by questionnaire in hospital workers. Occup Env Med 2011 (in press)

3. Varraso R, Willett WC, Camargo CA Jr. Prospective study of dietary fiber and risk of chronic obstructive pulmonary disease among US women and men. Am J Epidemiol 2010 ;171 :776-84

4. Bousquet J, Mantzouranis E, Cruz AA, Aït-Khaled N, Baena-Cagnani CE, Bleecker ER, Brightling CE, Burney P, Bush A, Busse WW, Casale TB, Chan-Yeung M, Chen R, Chowdhury B, Chung KF, Dahl R, Drazen JM, Fabbri LM, Holgate ST, Kauffmann F, Haahtela T, Khaltaev N, Kiley JP, Masjedi MR, Mohammad Y, O'Byrne P, Partridge MR, Rabe KF, Togias A, van Weel C, Wenzel S, Zhong N, Zuberbier T. Uniform definition of asthma severity, control, and exacerbations: document presented for the World Health Organization Consultation on Severe Asthma. J Allergy Clin Immunol 2010 ;126:926-38

5. Moffatt MF, Gut IG, Demenais F, Strachan DP, Bouzigon E, Heath S, von Mutius E, Farrall M, Lathrop M, Cookson WOCM, for the GABRIEL Consortium* (F Kauffmann member). A Large-Scale, consortium-based Genomewide Association study of asthma. N Engl J Med 2010; 363 : 1211-21

6. Nadif R, Matran R, Maccario J, Bechet M, Le Moual N, Scheinmann P, Bousquet J, Kauffmann F, Pin I. Passive and active smoking and exhaled nitric oxide levels according to asthma and atopy in adults. Ann Allergy Asthma Immunol 2010 ;104:385-93

7. Nadif R, Siroux V, Oryszczyn MP, Ravault C, Pison C, Pin I, Kauffmann F; Epidemiological study on the Genetics and Environment of Asthma (EGEA). Heterogeneity of asthma according to blood inflammatory patterns. Thorax 2009 ;64:374-80.

8. Varraso R, Kauffmann F, Leynaert B, Le Moual N, Boutron-Ruault MC, Clavel-Chapelon F, Romieu I. Dietary patterns and asthma in the E3N study. Eur Respir J 2009 ;33:33-41

9. Jacquemin B, Sunyer J, Forsberg B, Aguilera I, Briggs D, García-Esteban R, Götschi T, Heinrich J, Järvholm B, Jarvis D, Vienneau D, Künzli N. Home outdoor NO2 and new onset of self-reported asthma in adults. Epidemiology 2009 ;20:119-26.

10. Bouzigon E, Corda E, Aschard H, Dizier MH, Boland A, Bousquet J, Chateigner N, Gormand F, Just J, Le Moual N, Scheinmann P, Siroux V, Vervloet D, Zelenika D, Pin I, Kauffmann F, Lathrop M, Demenais F. Effect of 17q21 Variants and Smoking Exposure in Early-Onset Asthma. N Engl J Med 2008 ;359:1985-94.

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Inserm Grenoble team Inserm Institut Albert Bonniot/UMR Inserm/Univ J Fourier 823 Environmental epidemiology applied to reproduction and respiratory health, Grenoble, France

Profile of the Research Unit members which will be involved in the project (name, position, expertise relevant to the proposal) Valérie Siroux, PhD, CR1 - Respiratory epidemiology – Air pollution – Genetics Isabelle Pin, MD, PhD, PH - Chest physician, pediatrician Rémy Slama, PhD, CR1 – Environmental epidemiology – Air pollution – Reproduction - Methodology

Main findings of the last 4 years of the research team (10 most relevant publications and patents, )

1. Smit LAM, Bouzigon E, Bousquet J, Le Moual N, Nadif R, Pin I, Lathrop M, Demenais F, Kauffmann F, Siroux V, on behalf of the Epidemiological Study on the Genetics and Environment of Asthma. Mold allergen sensitization in adult asthma according to ITGB3 polymorphisms and TLR2/+596 genotype. J Allergy Clin Immunol 2011 (in press)

2. Siroux V, Basagaña X, Boudier A, Pin I, Garcia-Aymerich J, Vésin A, Slama R, Jarvis D, Antó JM, Kauffmann F, Sunyer J. Identifying clinical phenotypes of asthma using clustering approach. Eur Respir J 2010 (in press)

3. Slama R, Gräbsch C, Lepeule J, Siroux V, Cyrys J, Sausenthaler S, Herbarth O, Bauer M, Borte M, Wichmann HE, Heinrich J. Maternal fine particulate matter exposure, polymorphism in xenobiotic-metabolizing genes and offspring birth weight. Reprod Toxicol 2010 ;30:600-12

4. Lepeule J, Caïni F, Bottagisi S, Galineau J, Hulin A, Marquis N, Bohet A, Siroux V, Kaminski M, Charles MA, Slama R; EDEN Mother–Child Cohort Study Group. Maternal exposure to nitrogen dioxide during pregnancy and offspring birth weight: comparison of two exposure models. Environ Health Perspect 2010 ;118:1483-9

5. Moffatt MF, Gut IG, Demenais F, Strachan DP, Bouzigon E, Heath S, von Mutius E, Farrall M, Lathrop M, Cookson WOCM, for the GABRIEL Consortium* (V Siroux, I Pin members). A Large-Scale, consortium-based Genomewide Association study of asthma. N Engl J Med 2010; 363 : 1211-21

6. Nadif R, Matran R, Maccario J, Bechet M, Le Moual N, Scheinmann P, Bousquet J, Kauffmann F, Pin I. Passive and active smoking and exhaled nitric oxide levels according to asthma and atopy in adults. Ann Allergy Asthma Immunol 2010 ;104:385-93

7. Siroux V, Boudier A, Bousquet J, Bresson JL, Cracowski JL, Ferran J, Gormand F, Just J, Le Moual N, Morange S, Nadif R, Oryszczyn MP, Pison C, Scheinmann P, Varraso R, Vervloet D, Pin I, Kauffmann F; Epidemiological Study on the Genetics and Environment of Asthma. Phenotypic determinants of uncontrolled asthma. J Allergy Clin Immunol 2009;124:681-7

8. Marcon A, Corsico A, Cazzoletti L, Bugiani M, Accordini S, Almar E, Cerveri I, Gislason D, Gulsvik A, Janson C, Jarvis D, Martínez-Moratalla J, Pin I, de Marco R; Therapy and Health Economics Group of the European Community Respiratory Health Survey. Body mass index, weight gain, and other determinants of lung function decline in adult asthma. J Allergy Clin Immunol 2009;123:1069-74, 1074.e1-4.

9. Bouzigon E, Corda E, Aschard H, Dizier MH, Boland A, Bousquet J, Chateigner N, Gormand F, Just J, Le Moual N, Scheinmann P, Siroux V, Vervloet D, Zelenika D, Pin I, Kauffmann F, Lathrop M, Demenais F. Effect of 17q21 variants and smoking exposure in early-onset asthma. N Engl J Med 2008 ;359:1985-94.

10. Smit LAM, Siroux V, Bouzigon E, Oryszczyn MP, Lathrop M, Demenais F, Kauffmann F on behalf of the EGEA cooperative group. CD14 and Toll-like receptor gene polymorphisms, country living, and asthma in adults. Am J Respir Crit Care Med 2009 ;179:363-8.

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CV of the CREAL Principal Investigator Josep Maria Antó Boque, MD, PhD Date of birth : 17 august 1952 Current position : 1 Director, CREAL-Centre de Recerca en Epidemiologia Ambiental, Doctor Aiguader, 88 | 08003 Barcelona

2 Professor of Medicine, Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Spain

Training Degree Institution Years(s) Specialist (Preventive Medicine and Public Health)

Misterio de Educación 2003

Ph. D Universitat Autònoma de Barcelona 1990 Specialist (Pneumology) Universitat Autònoma de Barcelona 1979 M.D. Universitat Autònoma de Barcelona 1975 Professional and Academic positions 2005 - present Director of the Centre for Research in Environmental Epidemiology (CREAL) 2006 - 2010 Director of the CIBER of Epidemiology and Public Health (CIBERESP) 2005 - 2006 Director of the Institut Municipal d’Investigació Mèdica (IMIM-IMAS) 1996 - 2005 Head of the Respiratory and Environmental Health Research Unit, Institut Municipal

d’Investigació Mèdica (IMIM-IMAS). 1987 - 1996 Head of the Department of Epidemiology and Public Health, Institut Municipal

d’Investigació Mèdica (IMIM-IMAS). 1986 - 1987 Head of the Department of Epidemiological and Environmental Studies, Barcelona

City Council. 1981-1985 Epidemiologist, Municipal Institut of Public Health, Barcelona City Council. 2001- present Professor of Medicine Department of Experimental and Health Science, Universitat

Pompeu Fabra 1993 - present Professor of Environmental Epidemiology, European Educational Programme in

Epidemiology, Florence (Italy), Summer Programme IARC, WHO. 2002 - 2003 Vice-rector of Research, Universitat Pompeu Fabra 1998 - 2001 Director of PhD Programme in Health and Life Sciencies and Head of MSC

Programm in Public Health, Universitat Pompeu Fabra. 1996 - 2001 Associate Professor of Medicine, Department of Experimental and Health Sciences,

Universitat Pompeu Fabra 1996 - 1998 Associate Professor of Medicine, Department of Medicine, Universtitat Autònoma de

Barcelona 1988 -1996 Assistant Professor of Preventive Medicine and Public Health, Department of

Medicine, Universitat Autònoma de Barcelona Honours & others professional activities Cournand Lecture 1994, European Respiratory Society. Josep Truteta Award 1995, given by the Catalan Academy of Medical Sciences. Narcís Monturiol Medall 1996, given by the Catalan Government. Barcelona City Award (Science) 1999, given by the Barcelona City Council. Cornellà City Award (Humanities) 1999, given by the Cornellà City Council. Manuel Tapia Lecture 2000, Spanish Society of Respiratory Diseases. Josep Trueta Medall 2009, given by the Catalan Government. Alice Hamilton Medical Grounds Lecture, San Francisco, US, 2009 (The Environmental Determinants of Asthma). ERS Congress Chair Award 2010, given by the European Respiratory Society. Editorial activity in different periods: Gac Sanit (Editor in Chief), Am J Epidemiol (Editorial Board), Thorax (International Board), Eur J Pub Health (International Board), Eur R J (Associate Editor).

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Chairing of several committees: Scientific Board of the Catalan Agency of Health Technology Assessment, Director Plan of Respiratory Diseases of Catalunya, Public Health Law of Catalunya Working Group, Long Range Planning Committee of the European Respiratory Society.

Profile of the Research Unit members which will be involved in the project (name, position, expertise relevant to the proposal) Josep M Antó, MD, PhD – Professor (Director) – Head, respiratory epidemiology program Jordi Sunyer, MD, PhD – Professor (Co-director) - Respiratory Epidemiology – Head, air pollution program - Chidren Manolis Kogevinas, MD, PhD - Professor (Co-director) – Head, cancer epidemiology program – Genetics - Occupation Xavier Basagaña, PhD - Assistant Research Professor - Biostatistics. Elisabeth Cardis, PhD - Research Professor – Head, radiation epidemiology program - Environmental epidemiology Judith Garcia-Aymerich, MD, PhD - Assistant Research Professor - Respiratory Epidemiology – COPD - Statistics Juan Ramón Gonzalez, PhD - Assistant Research Professor - Biostatistics - Genetics Stefano Guerra, MD, PhD, Chest physician - Associate Research Professor - Respiratory Epidemiology– Genetics and biomarkers - COPD Michelle Mendez, PhD - Staff scientist - Nutrition Mark Nieuwenhuijsen, PhD - Research Professor, Head, water epidemiology program - Occupational and environmental exposure assessment Cristina Villanueva, PhD - Assistant Research Professor - Environmental epidemiology – Water epidemiology Martine Vrijheld, PhD - Associate Research Professor – Environment epidemiology – Childhood epidemiology Jan-Paul Zock, PhD - Associate Research Professor - Respiratory Epidemiology - Occupation - Environment

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Main findings of the last 4 years of the research teams (10 most relevant publications and patents, ) 1. Garcia-Aymerich J, Gómez FP, Benet M, Farrero E, Basagaña X, Gayete A, Paré C, Freixa X,

Ferrer J, Ferrer A, Roca J, Gáldiz JB, Sauleda J, Monsó E, Gea J, Barberà JA, Agustí A, Antó JM; on behalf of the PAC-COPD Study Group.. Identification and prospective validation of clinically relevant chronic obstructive pulmonary disease (COPD) subtypes. Thorax 2010 Dec 21. [Epub ahead of print]

2. Font-Ribera L, Villanueva CM, Nieuwenhuijsen MJ, Zock JP, Kogevinas M, Henderson J. Swimming Pool Attendance, Asthma, Allergies and Lung Function in the ALSPAC Child Cohort. Am J Respir Crit Care Med 2010 Oct 1. [Epub ahead of print]

3. Font-Ribera L, Kogevinas M, Zock JP, Gómez FP, Barreiro E, Nieuwenhuijsen MJ, Fernandez P, Lourencetti C, Pérez-Olabarría M, Bustamante M, Marcos R, Grimalt JO, Villanueva CM. Short-Term Changes in Respiratory Biomarkers after Swimming in a Chlorinated Pool. Environ Health Perspect 2010 Sep 12. [Epub ahead of print]

4. Siroux V, Basagaña X, Boudier A, Pin I, Garcia-Aymerich J, Vésin A, Slama R, Jarvis D, Antó JM, Kauffmann F, Sunyer J. Identifying clinical phenotypes of asthma using clustering approach. Eur Respir J 2011 Jan 13. [Epub ahead of print].

5. Aguilera I, Garcia-Esteban R, Iñiguez C, Nieuwenhuijsen MJ, Rodríguez A, Paez M, Ballester F, Sunyer J. Prenatal exposure to traffic-related air pollution and ultrasound measures of fetal growth in the INMA Sabadell cohort. Environ Health Perspect 2010 ;118:705-11.

6. Puhan MA, Garcia-Aymerich J, Frey M, ter Riet G, Antó JM, Agustí AG, Gómez FP, Rodríguez-Roisín R, Moons KG, Kessels AG, Held U. Expansion of the prognostic assessment of patients with chronic obstructive pulmonary disease: the updated BODE index and the ADO index. Lancet 2009;374(9691):704-11.

7. Castro-Giner F, Kogevinas M, Imboden M, de Cid R, Jarvis D, Mächler M, Berger W, Burney P, Franklin KA, Gonzalez JR, Heinrich J, Janson C, Omenaas E, Pin I, Rochat T, Sunyer J, Wjst M, Antó JM, Estivill X, Probst-Hensch NM. Joint effect of obesity and TNFA variability on asthma: two international cohort studies. Eur Respir J 2009; 33: 1003-9.

8. Zock JP, Plana E, Antó JM, Benke G, Blanc PD, Carosso A, Dahlman-Höglund A, Heinrich J, Jarvis D, Kromhout H, Lillienberg L, Mirabelli MC, Norbäck D, Olivieri M, Ponzio M, Radon K, Soon A, van Sprundel M, Sunyer J, Svanes C, Torén K, Verlato G, Villani S, Kogevinas M. Domestic use of hypochlorite bleach, atopic sensitization, and respiratory symptoms in adults. J Allergy Clin Immunol 2009; 124: 731-8.

9. Castro-Giner F, M. Kogevinas, M. Ma¨chler, R. de Cid, K. Van Steen, M. Imboden, C. Schindler, W. Berger, J.R. Gonzalez, K.A. Franklin, C. Janson, D. Jarvis, E. Omenaas, P. Burney, T. Rochat, X. Estivill, J.M. Antó, M. Wjst and N.M. Probst-Hensch. TNFA -308G>A in two international population-based cohorts and risk of asthma. Eur Respir J 2008; 32: 350-61

10. Kogevinas M, Zock JP, Jarvis D, Kromhout H, Lillienberg L, Plana E, Radon K, Torén K, Alliksoo A, Benke G, Blanc PD, Dahlman-Hoglund A, D'Errico A, Héry M, Kennedy S, Kunzli N, Leynaert B, Mirabelli MC, Muniozguren N, Norbäck D, Olivieri M, Payo F, Villani S, van Sprundel M, Urrutia I, Wieslander G, Sunyer J, Antó JM. Exposure to substances in the workplace and new-onset asthma: an international prospective population-based study (ECRHS-II). Lancet 2007; 307: 336-341

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B) Previous collaborations (2 pages) Or bilan

Exchange of researchers, assistant researchers, post doctoral fellows, joint PhD

Senior and junior researchers Numerous short visits (15/year) PhD students Estelle Rage (Inserm, Villejuif) – Thesis defended in 2008 – collaboration with Nino Künzli; PhD cosupervised by F Kauffmann (Inserm/Univ Paris Sud) and J Sunyer (CREAL/Univ Pompeu Fabra) Orianne Dumas (Inserm, Villejuif) – Collaboration in progress with Xavier Basagaña (2010-2012) David Vizcaya (CREAL) – Collaboration planned with Nicole Le Moual (2011-)

Post doctorants

Format  1  :  Exchange  

From CREAL to INSERM : from October 2007, Benedicte Jacquemin a postdoctoral researcher from CREAL has joined INSERM for 2 years to collaborate in the study of allergy, asthma and air pollution.

From INSERM to CREAL : from the other side, at the beginning of April ’08 Raphaelle Varraso from INSERM has been incorporated to CREAL team to work on nutrition and respiratory diseases (asthma and COPD). Both have been recruited as CR1 Inserm researchers in 2009 and 2008 respectively It appeared difficult to find new post doc for a second exchange and a new format to develop the EAL has been implemented based on combined projects with a 2/3 (major) 1/3 (minor) reciprocal stays in both institutions

Format  2  :  Combined  projects  

Major CREAL, minor INSERM (funding CREAL) : From April 2010, Marie Pedersen from Copenhagen has started a 2-year post doc, on the topic of air pollution and respiratory diseases in childhood. She is working in CREAL in Newgeneris EU project (biomarkers) with M Kogevinas and on the INMA cohort with J Sunyer and at Inserm Grenoble on the EDEN study with V Siroux and R Slama (impact of air pollution on respiratory health in the first year of age)

Major INSERM, minor CREAL (funding Inserm) : From June 2010, Marta Rava from Verona has started a 1-year post doc on the topic of molecular epidemiology in respiratory diseases among adults. She is working with R Nadif in Inserm on the EGEA study and will work in CREAL with S Guerra on a parallel project involving biomarkers in the ECRHS study. The post doc has been extended for a second year in the same conditions through an ANR grant obtained by R Nadif.

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Collaborative grants (including European and/or International ones) Obtained (Inserm participants in blue, Creal participants in red) 1. Contrat européen MedAll (4 ans, 12 M€) – Mars 2010 : Mechanisms of the Development of

Allergy - Coordinateur : J Bousquet (Inserm CESP/U1018), co-cordinateur : J M Antó (CREAL). Kick-off meeting 24-26 January 2011.

2. Contrat ANR – PRSP - 2010 : (3 ans 267 K€ ) IAGO Interactions gènes x risques

professionnels dans l'asthme – Novembre 2009 - Demandeur : F Kauffmann (CESP/U1018). Equipes participantes : V Siroux (U823), M Kogevinas, F Castro-Giner, JM Antó (CREAL – sans financement) et 2 autres équipes. Kick-off meeting 12 January 2011.

3. Contrat Associatif Agir à dom – 2010 (2 ans, 20 K€ ) Identification de sous phénotypes

d'asthme par l'analyse en classes latentes et étude d’association génétique de ces phénotypes avec des gènes candidats – Juin 2010 – Demandeur V Siroux (U823). Equipes participantes :F Kauffmann (CESP/U1018), Jordi Sunyer, X Basagaña, (CREAL – sans financement), et 1 autre équipe.

4. Contrat ADEME (France)– 2010-2012 (64.342€) Étude des correlations et comparison entre

trois villes européennes : trafic air bruit et sante (TRI-TABS). Equipes participantes : R Slama (Inserm U823, Grenoble), X Basagaña (CREAL), N Künzli (Basel)

5. Contrat AFSSET (now ANSES) (France)– Novembre 2009 (3 ans 150 K€) Rôle des

expositions professionnelles et domestiques aux produits de nettoyage et de désinfection dans l’asthme (NETA) – Enquête EGEA. Coordinateur : N Le Moual (CESP/U1018). Equipes participantes : V Siroux, I Pin (Inserm U823, Grenoble), JP Zock, S Guerra, M Kogevinas (CREAL – sans financement), et 2 autres équipes.

6. Contrat FIS (Espagne) – 2009 - Epidemiologia molecular de la funcion pulmonar : un abordaje

integral : S Guerra (CREAL), R Nadif (CESP/U1018 – sans financement).

7. Contrat EU FP7 - 2009 (2 ans 919 K€) - ENRIECO - Evaluation of environmental health data

in European birth cohorts. Coordinateur : M Nieuwenhuijsen (PI), M Kogevinas, M Vrijheld (CREAL), R Slama (Inserm U823, Grenoble, WP leader) and 6 other teams.

8. ERS/Ga2len research seminar nov 2007 : Post genome respiratory Epidemiology II : an

interdisciplinary challenge. F Kauffmann (chair), M Kogevinas (member) scientific committee. Meeting took place 6-8 november 2008 Abbaye des Vaulx de Cernay, France

9. EU FP7 Environment large scale project 2007 : ESCAPE - European Study of Cohorts for Air

Pollution Effects (B Brunekreef, NL Coordinator). N Künzli (WP4 (respiratory) leader), F Kauffmann, B Jacquemin (Inserm CESP/U1018) members WP4, R Slama (Inserm U823, Grenoble) member WP3.

Other grant applications (submitted pending or in preparation)

10. EU FP7 ClimALL (Climate change and allergy: Science to Policy). J Bousquet, PI 4 ans 3.5 M €

(avec F Kauffmann, B Jacquemin ; CREAL équipe participante JM Antó WP leader– 20 partners (soumission nov 2010) – Note 13,5/15, classé 2ème, décision finale attendue courant 2011.

11. NIH R01 : Impact of Occupational Exposure to Disinfectant or Cleaning Agents on Asthma (C

Camargo PI, N Le Moual CoPI, R Varraso, F Kauffmann ; JP Zock participant) (soumission juin

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2010, non obtenu). Nouveau dossier en préparation pour le NIOSH (soumission prévue en juin 2011)

12. ANSES : Allergie et pollution atmosphérique dans trois cohortes européennes : EGEA,

SAPALDIA et ECRHS. B Jacquemin, PI (avec F Kauffmann, J Bousquet, V Siroux ; CREAL équipe participante J Sunyer) (soumission lettre d’intention en mars 2011)

13. ANSES: Perfluorokids-Impact of perfluorinated compounds on prenatal and postnatal health. M.

Vrijheid, PI (CREAL), with R. Slama (Inserm Grenoble). Letter of intent submitted in March 2011.

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Common publications (with + if the paper is a direct consequence of EAL)

Published papers (Inserm authors in blue, Creal authors in red)

1. + Jacquemin B, Kauffmann F, Pin I, Le Moual N, Bousquet J, Gormand F, Just J, Nadif R, Pison C, Scheinmann P, Vervloet D, Künzli N, Siroux V. Air pollution and asthma control in the Epidemiological study on Genetics and Environment of Asthma. J Epidemiol Com Health (in press)

2. + Benet M, Varraso R, Kauffmann F, Romieu I, Antó JM, Clavel-Chapelon F, Garcia-Aymerich J. The effects of regular physical activity on adult asthma incidence in women. Respir Med 2011 Apr 12. [Epub ahead of print]

3. Rebordosa C, Kogevinas M, Guerra S, Castro-Giner F, Jarvis D, Cazzoletti L, Pin I, Siroux V, Wjst M, Antò JM, de Marco R, Estivill X, Corsico AG, Nielsen R, Janson C. ADRB2 Gly16Arg polymorphism, asthma control and lung function decline. Eur Respir J 2011 Mar 24. [Epub ahead of print]

4. + Bousquet J, Antó J, Auffray C, Akdis M, Cambon-Thomsen A, Keil T, Haahtela T, Lambrecht BN, Postma DS, Sunyer J, Valenta R, Akdis CA, Annesi-Maesano I, Arno A, Bachert C, Ballester F, Basagaña X, Baumgartner U, Bindslev-Jensen C, Brunekreef B, Carlsen KH, Chatzi L, Crameri R, Eveno E, Forastiere F, Garcia-Aymerich J, Guerra S, Hammad H, Heinrich J, Hirsch D, Jacquemin B, Kauffmann F, Kerkhof M, Kogevinas M, Koppelman GH, Kowalski ML, Lau S, Lodrup-Carlsen KC, Lopez-Botet M, Lotvall J, Lupinek C, Maier D, Makela MJ, Martinez FD, Mestres J, Momas I, Nawijn MC, Neubauer A, Oddie S, Palkonen S, Pin I, Pison C, Rancé F, Reitamo S, Rial-Sebbag E, Salapatas M, Siroux V, Smagghe D, Torrent M, Toskala E, van Cauwenberge P, van Oosterhout AJ, Varraso R, von Hertzen L, Wickman M, Wijmenga C, Worm M, Wright J, Zuberbier T. MeDALL (Mechanisms of the Development of ALLergy): an integrated approach from phenotypes to systems medicine. Allergy 2011 Jan 24. doi: 10.1111/j.1398-9995.2010.02534.x. [Epub ahead of print]

5. + Siroux V, Basagaña X, Boudier A, Pin I, Garcia-Aymerich J, Vésin A, Slama R, Jarvis D, Antó JM, Kauffmann F, Sunyer J. Identifying clinical phenotypes of asthma using clustering approach. Eur Respir J 2011 Jan 13. [Epub ahead of print]

6. Moffatt MF, Gut IG, Demenais F, Strachan DP, Bouzigon E, Heath S, von Mutius E, Farrall M, Lathrop M, Cookson WOCM, for the GABRIEL consortium*. *Members of the GABRIEL consortium Moffatt MF, Gut IG, Demenais F, Strachan DP, Bouzigon E, Heath S, Kumar A, Burney P, Jarvis D, Wjst M, Kogevinas M, Jogi R, Janson C, Franklin K, Omenaas E, Leynaert B, Pin I, Heinrich J, Kuenzli N, Probst-Hensch NM, Antó JM, Sunyer J, Maldonado JA, Martinez-Moratalla J, Urritia I, Payo F, Kauffmann F, Dizier MH, Siroux V, Boznanski A, Braun-Fahrländer C, Genuneit J, Glas J, Horak E, Kabesch M, Pillai SG, Helms PJ, Carlsen K, Carlsen KH, Gerritsen J, Silverman M, Sly S, Tsanakas J, Von Berg A, Whyte M, Blumenthal M, Imboden M, Rochat T, Thun GA, Gerbase MW, Curjuric I, Gaspoz JM, Liu LJ, Wouters IM, Sigsgaard T, Heederik D, Basinas I, Schlunssen V, Omland Ø, Cullinan P, Vermeulen R, Henderson J, Granell R, McArdle WL, Davey Smith G, James AL, Hui J, Palmer LJ, Beilby J, Musk AW, Laprise C, Hudson TJ, Lemire M, Daley D, Becker A, Chan-Yeung M, Sandford A, Kozyrskyj AL, Paré P, Ferguson A, Dimich-Ward H, Watson WT, Freidin MB, Bragina EL, Deev IA, Deeva EV, Kobyakova OS, Puzyrev VP, Ogorodova LM, Khusnutdinova EK, Karunas S, Fedorova YY, Hall IP, Sayers I, Tobin MD, Wan YI, Heaney LG, Al-Momani BAH, Mansur AH, Manney S, Thomson NC, Chaudhuri R, Brightling CE, Bafadhel M, Singapuri A, Niven R, Simpson A, Holloway JW, Howarth PH, Polonikov AV, Ivanov VP, Solodilova MA, Melén E, Pershagen G, Bergström A, Kull I, Nyberg F, Wickman M, Söderhäll C, Kere J, Postma DS, Kerkhof M, Brunekreef B, Smit HA, de Jongste JC, Wijga A, Aalberse RC, Hoekstra MO, Koppelman GH, Binia A, Chung KF, Bhavsar P, Chow F, Macedo P, Menzies-Gow A, Stiphout N, Bush A, Lee YA, Esparza-Gordillo J, Nickel R, Wahn U, Lau S, Marenholz I, Haahtela T, von Hertzen L, Jousilahti P, Laatikainen T, Mäkelä MJ, Vartiainen E, Laitinen T, Balding DJ, Peden JF, Corda E, Lechner D, Besse C, Zelenika C, Boland A, Bacq D, Demonchy S, Blanche H, Kamatani Y, von Mutius E, Farrall M, Lathrop M, Cookson WOCM. A Large-Scale, consortium-based Genomewide Association study of asthma. N Engl J Med 2010; 363 : 1211-21.

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7. Voll-Aanerud M, Eagan TM, Plana E, Omenaas ER, Bakke PS, Svanes C, Siroux V, Pin I, Antó JM, Leynaert B. Respiratory symptoms in adults are related to impaired quality of life, regardless of asthma and COPD: results from the European community respiratory health survey. Health Qual Life Outcomes 2010 ;8:107.

8. + Cantero-Recasens G, Gonzalez JR, Fandos C, Duran-Tauleria E, Smit LA, Kauffmann F, Antó JM, Valverde MA. Loss of function of transient receptor potential vanilloid 1 (TRPV1) genetic variant is associated with lower risk of active childhood asthma. J Biol Chem 2010 ;285:27532-5.

9. + Zock JP, Vizcaya D, Le Moual N. Update on asthma and cleaners. Curr Opinion Allergy Clin Immunol 2010 ;10 : 114-120

10. + Kauffmann F, Castro-Giner F, Smit LAM, Nadif R, Kogevinas M. Gene-environment interactions in occupational asthma. In : Occupational asthma. Sigsgaard T & Heederik D eds. Birkhäuser Verlag AG, Basel 2010 pp 205-228

11. Castro-Giner F, de Cid R, Gonzalez JR, Jarvis D, Heinrich J, Janson C, Omenaas ER, Matheson MC, Pin I, Antó JM, Wjst M, Estivill X, Kogevinas M. Positionally cloned genes and age-specific effects in asthma and atopy: an international population-based cohort study (ECRHS). Thorax 2010 Feb;65(2):124-31.

12. Bousquet J, Burney PG, Zuberbier T, Cauwenberge PV, Akdis CA, Bindslev-Jensen C, Bonini S, Fokkens WJ, Kauffmann F, Kowalski ML, Lodrup-Carlsen K, Mullol J,Nizankowska-Mogilnicka E, Papadopoulos N, Toskala E, Wickman M, Antó J, Auvergne N, Bachert C, Bousquet PJ, Brunekreef B, Canonica GW, Carlsen KH, Gjomarkaj M,Haahtela T, Howarth P, Lenzen G, Lotvall J, Radon K, Ring J, Salapatas M, Schünemann HJ, Szczecklik A, Todo-Bom A, Valovirta E, von Mutius E, Zock JP. GA2LEN (Global Allergy and Asthma European Network) addresses the allergy and asthma 'epidemic'. Allergy 2009 Jul;64(7):969-77.

13. + Garcia-Aymerich J, Varraso R, Antó JM, Camargo CA Jr. Prospective study of physical activity and risk of asthma exacerbations in older women. Am J Respir Crit Care Med 2009 Jun 1;179(11):999-1003.

14. Castro-Giner F, Kogevinas M, Imboden M, de Cid R, Jarvis D, Mächler M, Berger W, Burney P, Franklin KA, Gonzalez JR, Heinrich J, Janson C, Omenaas E, Pin I, Rochat T, Sunyer J, Wjst M, Antó JM, Estivill X, Probst-Hensch NM. Joint effect of obesity and TNFA variability on asthma: two international cohort studies. Eur Respir J 2009 May;33(5):1003-9.

15. + Rage E, Siroux V, Künzli N, Pin I, Kauffmann F; Epidemiological Study on the Genetics and Environment of Asthma. Air pollution and asthma severity in adults. Occup Environ Med 2009 Mar;66(3):182-8.

16. + Rage E, Jacquemin, Nadif R, Oryszczyn MP, Siroux V, Aguilera I, Kauffmann F, Künzli N on behalf of the Epidemiological Study on the Genetics and Environment of Asthma (EGEA). Total serum IgE levels are associated with ambient ozone concentration in asthmatic adults. Allergy 2009 ;64(1):40-6.

17. Jacquemin B∗*, Sunyer J, Forsberg B, Aguilera I, Briggs D, García-Esteban R, Götschi T,

Heinrich J, Järvholm B, Jarvis D, Vienneau D, Künzli N. Home outdoor NO2 and new onset of self-reported asthma in adults. Epidemiology 2009 Jan;20(1):119-26.

18. Castro-Giner F, Künzli N, Jacquemin B*, Forsberg B, de Cid R, Sunyer J, Jarvis D, Briggs D, Vienneau D, Norback D, González JR, Guerra S, Janson C, Antó JM, Wjst M, Heinrich J, Estivill X, Kogevinas M.Traffic-related air pollution, oxidative stress genes, and asthma (ECHRS). Environ Health Perspect 2009 Dec;117(12):1919-24.

19. Sunyer J, Forastiere F, Pekkanen J, Plana E, Kolz M, Pistelli R, Jacquemin B*, Brüske-Hohlfeld I, Pitsavos Ch, Bellander T, Koenig W, Peters A; AIRGENE Study Group. Interaction between smoking and the interleukin-6 gene affects systemic levels of inflammatory biomarkers. Nicotine Tob Res 2009 Nov;11(11):1347-53.

20. Jacquemin B*, Sunyer J, Forsberg B, Aguilera I, Bouso L, Briggs D, de Marco R, García-Esteban R, Heinrich J, Jarvis D, Maldonado JA, Payo F, Rage E, Vienneau D, Künzli N. Association

∗* Work started at Creal during PhD, finalised during post doc at Inserm

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between modelled traffic-related air pollution and asthma score in the ECRHS. Eur Respir J 2009 Oct;34(4):834-42.

21. Peters A, Greven S, Heid IM, Baldari F, Breitner S, Bellander T, Chrysohoou C, Illig T, Jacquemin B*, Koenig W, Lanki T, Nyberg F, Pekkanen J, Pistelli R, Rückerl R, Stefanadis C, Schneider A, Sunyer J, Wichmann HE; AIRGENE Study Group. Fibrinogen genes modify the fibrinogen response to ambient particulate matter. Am J Respir Crit Care Med 2009 ;179(6):484-91.

22. Shaaban R, Zureik M, Soussan D, Neukirch C, Heinrich J, Sunyer J, Wjst M, Cerveri I, Pin I, Bousquet J, Jarvis D, Burney PG, Neukirch F, Leynaert B. Rhinitis and onset of asthma: a longitudinal population-based study. Lancet 2008 Sep 20;372(9643):1049-57.

23. + Siroux V, Boudier A, Antó JM, Cazzoletti L, Accordini S, Alonso J, Cerveri I, Corsico A, Gulsvik A, Jarvis D, de Marco R, Marcon A, Almar-Marques E, Bugniani M, Janson C, Leynaert B, Pin I. Quality of life and asthma severity in general population asthmatics: results of the ECRHS II study. Allergy 2008; 63: 547-554

Submitted papers

1. + Kim JM, Blanc PD, Villani S, Oliveri M, Urrutia I, van Sprundel M, Torgeir S, Le Moual N, Zock JP, Torén K. Predictors for respiratory-related sickness absence: an international population-based study.

2. Imboden M*, Bouzigon E*, Curjuric I, Ramasamy A, Kumar A, Hancock DB, Wilk JB, Vonk J, Thun GA, Siroux V, Nadif R, Monier F, González JR, Wjst M, Heinrich J, Loehr L, Franceschini N, North KE, Koppelman GH, Guerra S, Kronenberg F, Lathrop, Moffatt MF, O'Connor GT, Strachan DP, Postma D, London SJ, Schindler C, Kogevinas M, Kauffmann F, Jarvis DL, Demenais F, Probst-Hensch. Genome wide association study of lung function decline in adults with and without asthma.

3. + Siroux V, Boudier A, Vignoud L, Bousquet J, Gormand F, Just J, Le Moual N, Leynaert B, Nadif R, Pison C, Scheinmann P, Vervloet D, Antó JM, Kauffmann F, Pin I. Asthma control assessed in the EGEA epidemiological survey was related to health-related quality of life.

4. Melén E , Granell R, Kogevinas M, Strachan D, Gonzalez JR, Wjst M, Jarvis D, Ege M, Braun-Fahrländer C, Genuneit J, Horak E, Bouzigon E, Demenais F, Kauffmann F, Siroux V, Michel S, von Berg A, Heinzmann A, Kabesch M, Probst-Hensch NM, Curjuric I, Imboden M, Rochat T, Henderson J, Sterne JAC, McArdle WL, Hui J, James AL, Musk AW, Palmer LJ, Becker A, Kozyrskyj AL, Chan-Yeung M, Park JE, Leung A, Daley D, Freidin MB, Deev IA, Ogorodova LM, Puzyrev VP, Celedón J, Soto-Quiros M, Avila L, Bergström A, Söderhäll C, Kull I, Scholtens S, Boezen HM, Koppelman GH, Wijga AH, Marenholz I, Esparza-Gordillo J, Lau S, Lee YA, Farrall M, Kumar A, Moffatt MF, Cookson WOCM, Weiss ST, Lasky-Su J. DENND1B variants link asthma to body mass index in children – results from genome wide analyses

5. + Bousquet J, Abdelhak S, Adcock I, Agusti A, Antó JM, Antonorakis S, Avignon A, Ballabio A, Balling R, Baraldi E, Baranov A, Bieber T, Bockaert J, Brahmachari S, Brambilla C, Brightling C, Bringer J, Brookes A, Cambon-Thomsen A, Cesario A, Charron D, Chen Z, Chung KF, Dauzat M, Ernberg I, Fabbri L, Froguel P, Galas D, Gojobori T, Hood L, Hunter P, Jorgensen C, Kauffmann F, Kourilsky P, Kowalski M, Lancet D, Le Pen C, Mallet J, Mayosi B, Mercier J, Metspalu A, Nadeau J, Ninot G, Noble D, Öztürk M, Palkonen S, Pison C, Préfaut C, Rabe K, Roberts RG, Roca J, Samolinski B, Schünemann HJ, Simon HU , Soares MB, Sterk PJ, Superti-Furga G, Tegner J, Verjovski-Almeida S, Wellstead P, Wolkenhauer O, Wouters E, Auffray C. Systems medicine and integrated care to combat chronic noncommunicable diseases

In preparation (submission planned in the next 3 months)

6. + Smit L, Kogevinas M, Antó JM, Bouzigon E, González JR, Le Moual N, Kromhout H, Carsin AE, Pin I, Jarvis D, Vermeulen R, Janson C, Heinrich J, Gut I, Lathrop M, Valverde MA, Demenais D, Kauffmann F. Transient receptor potential (TRP) genes, smoking, occupational exposures and cough in adults.

7. + Varraso R, Garcia-Aymerich J, Monier F, Miranda G, Pison C, Romieu I, Kauffmann F, Maccario J. Using structural equation modeling to assess dietary patterns: a new approach approach in nutritional epidemiology.

8. + Le Moual N, Varraso R, Siroux V, Dumas O, Nadif R, Pin I, Zock JP, Kauffmann F. The use of household cleaning sprays and asthma in women.

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Joint seminars

ERS/Ga2len Post Genome Respiratory Epidemiology November 2008 (Paris)

Statistical aspects (Barcelona, 2008)

Egea scientific seminars (2 days once a year) (France)

Escape meeting in Barelona – September 2010

IAGO kick off meeting January 2011 (Paris)

Kick-off MedAll scientific seminar in phenotypes January 2011 (CREAL)

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C) Collaborative scientific project (between 5 and 10 pages)

Project

State of the art of the scientific question

For the last 4 years the EAL has developed a substantial amount of collaborative research on three main topics: respiratory phenotypes, environmental determinants of respiratory diseases and gene by environment interactions in asthma. These topics, covering a broad rang of scientific questions, will continue being the mainstream of the scientific work during the next period.

Phenotypes

Both for asthma and chronic obstructive pulmonary disease (COPD) there is a wide interest in reviewing the current phenotypes. In asthma there is a need to improve its characterization by integrating multiple aspects of the disease and at the same time to assess the redistribution of asthma in different entities. During the last years we have started to apply unsupervised methods to this problem. The aim was to identify distinct asthma phenotypes by applying Latent Class Analysis (LCA), a model-based clustering method, to two large epidemiological studies. Adults with asthma who participated in the follow-up of the Epidemiological study on Genetics and Environment of Asthma and the European Community Respiratory Health Survey were included. Four asthma phenotypes were distinguished by the LCA in each sample1. Research is in progress to search genetic determinants of asthma phenotypes based on such clustering approach through a larger collaboration, from that work initiated through the EAL. The same approach is being followed in MeDALL where both classical (expert based) and novel (unsupervised) phenotypes will be extensively compared by means of several omic strategies in a large network of birth cohorts in Europe2. The work on COPD phenotypes has followed a similar approach with a recent publication showing the existence of different sub phenotypes one of them closely resembling the so called metabolic syndrome3. The redefinition of the current respiratory phenotypes is now receiving increasing attention, with a number of papers recently published4,5,6,7

Environmental determinants

Among the environmental determinants of respiratory diseases our EAL has given particular attention to occupation and air pollution.

Exposure to cleaning products both in specific occupational settings and in the general populations has been linked to an increased risk of asthma. In the context of EAL, a state of the art review on cleaning related asthma has been conducted and identified current knowledge gaps8. Recent studies have strengthened the existing evidence of an increased risk of asthma and other adverse respiratory effects in cleaning workers. Similar effects are seen in other settings in which cleaning products are used such as healthcare professionals and homemakers9,10. The predominant effect mechanisms remain largely unclear and may include both specific sensitization and irritant-related features. New research is in progress in the area and in particular a new project with the USA on American Nurses (collaboration with Nurses Health study).

1 Siroux V, Basagana X, Boudier A, et al. Identifying adult asthma phenotypes using a clustering approach. Eur Respir J 2011 Jan 13. [in press] 2 Bousquet J, Antó J, Auffray C et al. MeDALL (Mechanisms of the Development of ALLergy): an integrated approach from phenotypes to systems medicine. Allergy 2011 Jan 24 [in press] 3 Garcia-Aymerich J, Gómez FP, Benet M, et al. Identification and prospective validation of clinically relevant chronic obstructive pulmonary disease (COPD) subtypes. Thorax 2010 Dec 21. [in press] 4 Weatherall M, Travers J, Shirtcliffe PM, et al. Distinct clinical phenotypes of airways disease defined by cluster analysis. Eur Respir J 2009: 34: 812-818. 5 Spycher BD, Silverman M, Brooke AM, et al. Distinguishing phenotypes of childhood wheeze and cough using latent class analysis. Eur Respir J 2008: 31: 974-981. 6 Haldar P, Pavord ID, Shaw DE, et al. Cluster analysis and clinical asthma phenotypes. Am J Respir Crit Care Med 2008: 178: 218-224. 7 Moore WC, Meyers DA, Wenzel SE, et al. Identification of Asthma Phenotypes using Cluster Analysis in the Severe Asthma Research Program. Am J Respir Crit Care Med 2010: 181: 315-323. 8 Zock JP, Vizcaya D, Le Moual N. Update on asthma and cleaners. Curr Opinion Allergy Clin Immunol 2010 ;10 : 114-120 9 Delclos GL, Gimeno D, Arif AA, et al. Occupational risk factors and asthma among health care professionals. Am J Respir Crit Care Med 2007;175:667-75. 10 Arif AA, Delclos GL, Serra C. Occupational exposures and asthma among nursing professionals. Occup Environ Med 2009;66:274-8.

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Acute respiratory effects of air pollution are well established and there is increasing evidence of long term effects11. Epidemiologic studies have now shed light on the long-term effects on chronic pathologies and on the health benefit of air quality improvements12,13,14. The evidence of systemic effects of air pollution has supported its causal role on a variety of health effects at low levels and suggested the role of various pathways15,16. A major challenge is the assessement of traffic related pollution at a fine level to assess long-term effects. That area of research will markedly progressed in the context of the European Escape project which will provide refined assessment of exposure and by studying the associations of other traits with air pollution.

Though not environmental sensu strictu physical activity and diet are, beyond their relevance per se, important both as effect modifiers of environmental exposures as well as potential confounders in many of the EAL studies. Associations of physical activity with asthma characteristics have been studied in the NHS and E3N studies17,18 and currently being studied in the EGEA study. Methodological aspects regarding the assessement of physical activity and diet are a challenge19. Regarding diet, emphasis at the current stage is on the epidemiological methods like the use of confirmatory analysis to derive dietary patterns, especially in the case of small studies and the use of structural models. A diet questionnaire has been included in the ECRHS III

Genetics and gene environment interactions

Current challenges in gene environment interactions concern the improvement of phenotypic and environmental characterization and setting up interdisciplinary research to understand the determinants of asthma, and setting collaborations at sufficient scale. Several research programs are being developed in genetics and gene environment interactions, in particular on gene occupational hazards interaction involving EGEA and ECRHS and others to increase power, taking advantage of GWAS genotyping already performed for these studies20. The evidence of genetic heterogeneity of asthma according to age of onset shows the relevance of genetic approaches to disentangle the phenotypic heterogeneity of such complex disease21. Although gene environment interactions attract a lot of attention, there are yet few demonstrated interactions. Interactions of genes with farming environment have been studied for candidate genes of innate immunity and recently by agnostic approaches22,23. Enhanced associations of early respiratory infections with early-onset asthma was demonstrated for individuals with17q21 genetic variants24. Gene environment interactions studies regarding air pollution and occupational hazards in relation to respiratory phenotypes are increasing, but few interactions can be considered as established.15,25,26. Studies considering several genes from the same pathway or for which gene-gene interaction has been suggested are emerging in the area of gene environment interactions, but proper pathways analyses, considering systematically various 11Perez L, Rapp R, Künzli N. The Year of the Lung: outdoor air pollution and lung health. Swiss Med Wkly. 2010 ;140:w13129 12 Downs SH, Schindler C, Liu LJ, et al. Reduced exposure to PM10 and attenuated age-related decline in lung function. N Engl J Med 2007 ;357:2338-47. 13 Jacquemin B, Sunyer J, Forsberg B, et al. Home outdoor NO2 and new onset of self-reported asthma in adults. Epidemiology 2009 ;20:119-26. 14 Rage E, Siroux V, Künzli N, et al. Air pollution and asthma severity in adults. Occup Environ Med 2009 ;66:182-8. 15 Castro-Giner F, Künzli N, Jacquemin B, et al. Traffic-related air pollution, oxidative stress genes, and asthma (ECHRS). Environ Health Perspect 2009 ;117:1919-24. 16 Jacquemin B, Lanki T, Yli-Tuomi T, et al. Source category-specific PM2.5 and urinary levels of Clara cell protein CC16. The ULTRA study. Inhal Toxicol 2009 Nov;21(13):1068-76. 17 Garcia-Aymerich J, Varraso R, Antó JM, et al. Prospective study of physical activity and risk of asthma exacerbations in older women. Am J Respir Crit Care Med 2009 ;179:999-1003. 18 Benet M, Varraso R, Kauffmann F, et al. The effects of regular physical activity on adult asthma incidence in women. Respir Med 2011 [in press]. 19 Lo Siou G, Yasui Y, Csizmadi I, McGregor SE, Robson PJ. Exploring Statistical Approaches to Diminish Subjectivity of Cluster Analysis to Derive Dietary Patterns: The Tomorrow Project. Am J Epidemiol 2011 Mar 18. [in press] 20 Moffatt MF, Gut IG, Demenais F, et al. A Large-Scale, consortium-based Genomewide Association study of asthma. N Engl J Med 2010; 363 : 1211-21. 21 Bouzigon E, Corda E, Aschard H, et al. Effect of 17q21 Variants and Smoking Exposure in Early-Onset Asthma. N Engl J Med 2008 ; 359 :1985-94 22 Smit LAM, Siroux V, Bouzigon E, et al. CD14 and Toll-like receptor gene polymorphisms, country living, and asthma in adults. Am J Respir Crit Care Med 2009; 179: 363-368 23 Ege MJ, Strachan DP, Cookson WO, et al. Gene-environment interaction for childhood asthma and exposure to farming in Central Europe. J Allergy Clin Immunol 2011;127:138-44, 144.e1-4. 24 Smit LAM, Bouzigon E, Pin I, et al. 17q21 variants modify the association between early respiratory infections and asthma. Eur Respir J 2010; 36:57-64 25 Kauffmann F, Castro-Giner F, Smit LAM, et al. Gene-environment interactions in occupational asthma. In : Occupational asthma. Sigsgaard T & Heederik D eds. Birkhäuser Verlag AG, Basel 2010 pp 205-228 26 Wenten M, Gauderman WJ, Berhane K, et al. Functional variants in the catalase and myeloperoxidase genes, ambient air pollution, and respiratory-related school absences: an example of epistasis in gene-environment interactions. Am J Epidemiol. 2009;170:1494-501.

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pathways have not yet been conducted26,27 The development of large-scale genetic studies of asthma will likely change the situation. Two types of approaches may be developed based on testing hypotheses (candidate interactions) at the gene or pathway level, or in searching interactions with genes of yet unknown function which may be evidenced through genome-wide associations, but such approaches are challenging.23,28,29,30

The working hypothesis

The scientific plan of the EAL for the new period (2011-2014) will continue the research lines that are currently active, while exploring new areas of interest. As explained in the section on strategies, the scientific program of the LEA pays now greater attention to research on childhood health as well as to the environmental determinants of health. Phenotypes Asthma is a term that includes different phenotypes. Comparative assessments of classical and novel phenotypes, based on unsupervised methods, will provide new opportunities for the definition and diagnosis of asthma related entities. This will be done through the EU FP7 MedALL. In adults, studies involving EGEA and ECRHS will continue. (JM Antó, X Basagaña, J Bousquet, J Garcia-Aymerich, B Jacquemin, F Kauffmann, I Pin, R Varraso, V Siroux). COPD is a heterogeneous disease involving different subphenotypes –It is anticipated that with the development of a respiratory program in E3N, the ageing of EGEA and ECRHS cohorts, the continuation of PAC-COPD, the recognition of COPD as a major research topic by WHO, there will be opportunities for development of common research program. (JM Antó, J Bousquet, J Garcia-Aymerich, S Guerra, F Kauffmann, R Nadif, R Varraso). Environmental determinants Occupation and indoor exposure to cleaning products are significant risk factors for asthma development and morbidity - Research will focus on the assessment of exposures in various settings, studies on the associations with asthma phenotypes are in progress and in planning phase in France (EGEA, E3N), Europe (ECRHS), USA (Nurses Health study); two grants have been obtained (NETA, IAGO) (JM Antó, F Kauffmann, M Kogevinas, N Le Moual, R Nadif, R Varraso, JP Zock).

Research on air pollution will be markedly developed through the improvement of exposures in progress thanks to the Escape consortium (FP7 funding). It is planned to strengthen collaborative work in this area between CREAL and both Inserm teams (in the context of the recruitment of B Jacquemin as CR1 in Villejuif and the participation of R Slama from Grenoble in the EAL) by further developing studies in asthma, lung function, enlarging collaborations to other phenotypes such as rhinitis and biomarkers, and to children health. As a first step, research of air pollution effects on respiratory health in early life is going on in Eden (France) and Inma (Spain) cohorts (M. Pedersen post-doctoral position, with V Siroux, R Slama M Kogevinas and J Sunyer). Strengthening international collaboration in this area is planned in the context of two European projects Escape and MedAll, whose possibilities have to be fully exploited, in particular through a long term visit of B Jacquemin planned in CREAL. (B Jacquemin, F Kauffmann, M Nieuwenhuijsen, V Siroux, R Slama, J Sunyer).

Physical activity and diet do not belong to standard data collected in respiratory epidemiology. It is therefore of great interest to further develop mutual access to data sets with such information. Researchers from Inserm and CREAL with interest in these two related lifestyle determinants will further develop collaborations . Developments will take place by analyses on EGEA, E3N, NHS, PAC-COPD and new data collection which will take place in ECRHS III. (J Garcia-Aymerich, M Mendez, R Varraso).

27 Smit LAM, Bouzigon E, Bousquet J, et al Mold allergen sensitization in adult asthma according to ITGB3 polymorphisms and TLR2/+596 genotype. J Allergy Clin Immunol 2011 (in press) 28Kauffmann F, Nadif R. Candidate gene-environment interactions. J Epidemiol Community Health. 2010;6:188-9. 29 Murcray CE, Lewinger JP, Gauderman WJ. Gene-environment interaction in genome-wide association studies. Am J Epidemiol 2009 ;169:219-26. 30 Breitling LP, Steyerberg EW, Brenner H. The novel "genomic pathway approach" to complex diseases: a reason for (over-) optimism? Epidemiology 2009 ;20:500-7.

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Other environmental risk factors. Beyond the environmental determinants already studied in relation to respiratory outcomes, increasing collaborations with environmental epidemiologists, both in CREAL, and Grenoble will open avenues for improving exposure assessment methods (using environmental models or exposure biomarkers) and for integration of understudied environmental characteristics in the respiratory and child health areas. Among others, endocrine disruptors will be considered (E Cardis, B Jacquemin, MJ Nieuwenhuijsen, R Slama, M Vrijheld, C Villanueva, JP Zock). Genetics and gene environment interactions We have now set up conditions for collaborative work in genetics, following in particular our participation to the Gabriel Consortium on asthma (EU-FP6) which provided GWAS information for several cohorts, including EGEA and ECRHS and collaborations with specific genetic epidemiology groups will continue. Developments will include the analyses on both classical (such as asthma severity) and novel phenotypes (derived from our previous work on latent class analyses (see above). Gene environment interactions analyses will be developped at a larger scale than previously, with a focus on occupation in the short term, then with projects on air pollution, always in the context of European and international collaborations. Various approaches are planned including candidate approaches at the gene or pathway level as well as pangenomic analyses. Development of epigenetic approaches is planned in particular in children, through collaborations, within FP7 EU MedAll and in a new birth cohort set-up in Grenoble (JR Gonzales, F Kauffmann, M Kogevinas, R Nadif, V Siroux) Other areas of interest Biomarkers - Inclusion of biomarkers as markers of exposure and of early biological effect or disease are increasingly used in epidemiology and will offer opportunities for translational research. The area is challenging at various levels, but is a developing area between the parties, with exchange of biological samples and mutual access to infrastructure in the context of studies set up in both institutions with biobanks associated with epidemiological surveys. Further development towards system biology is planned in the interdisciplinary frame of the MedAll project. (S Guerra, R Nadif, R Slama).

Child health - Although studies on children were conducted in CREAL and although the EGEA study (Inserm) recruited children, the EAL program of the first period was focused on adults. This will be changed because of the increasing recognition of the importance of early life events in respiratory diseases and beyond, pushing to expand the understanding of that critical period in the context of the DoHAD (Developmental Origins of Health and Diseases) hypothesis. This orientation also relates to the development of high profile research in the area both in Grenoble and CREAL. An epidemiologist with specific competence in the area has arrived in Grenoble (Avenir Inserm grant, now the director of the team), the obtention at CREAL of an ERC senior research grant in children epidemiology and the starting of MedALL a major EU-FP7 project cocoordinated by Inserm and CREAL is based on birth cohorts. (JM Antó, J Bousquet, I Pin, V Siroux, R Slama, J Sunyer, M Vrijheld) Statistical methods - Building on existing new developments (latent class analysis, structural modelling) of collaborations between both institutions, it is planned to explore more systematically areas of applications of up-to-date methods. There is a scientific need to refine statistical methods in epidemiology in areas such as unsupervised methods to defined novel phenotypes, issues of causality between environmental and lifestyle determinants, intermediate phenotypes and clinical phenotypes (structural modelling, ..) or pathway analyses in the field of genetics and gene environment interactions to take a few examples of research in progress by the various teams. Mastering efficiently a variety of new methods is a typical beneficial aspect of achieving a critical mass of researchers of a structure such as a EAL. (JM Antó, X Basagaña, J Garcia-Aymerich, JR Gonzales, N Le Moual, R Nadif, V Siroux, R Slama, R Varraso). Social aspects. Health inequalities (and, symmetrically, the study of social inequalities in environmental exposures, related to the concept of environmental justice) is an area of major public health importance and of increasing recognition in the scientific arena. In the context of our EAL, inequalities in environmental health and interactions between environmental and social factors are topics which deserved particular attention. These topics are seen as topics of large interest in CREAL

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and in Villejuif, without major focus till now. The topic is related to the heterogeneous level of exposure regarding occupational and other environmental hazards, but also to other aspects of more recent interest in the respiratory field such as obesity. It has been listed as an area to be developped both at CREAL and recommended by AERES for Inserm Villejuif. There is an interest of various researchers and already available data in the cohorts constituted. Developing this area appears of public health relevance and well connected with developments in environmental epidemiology. It is planned to develop a collaborative program based on these aspects, with a first step based on a more systematic analysis of the data already collected in existing surveys. CREAL will host as visiting researcher Bruna Galobardes a well known social epidemiologist currently in Bristol. (JM Antó, F Kauffmann, N Le Moual, R Varraso, M Vrijheld).

The strategy

For the next period, the name of the EAL will be changed in International laboratory in respiratory and environmental epidemiology to underline the increasing importance of environmental epidemiology in the Inserm part, since the last application (and successful evaluation by AERES with A+ in both cases) of the two teams in their respective research centers (team 5 at U1018 and team 12 at U823 – see appendix). A broader focus on environmental exposures will also allow to better capitalize the expertise of other scientists in CREAL and Grenoble. Environment is considered as before in its broad sense, i.e. classical environmental factors such as occupational hazards, indoor exposures, and outdoor air pollution, as well as lifestyle factors such as smoking, nutrition or physical activity. No aspect included in the first application will be removed, but as shown above, extensions are considered at various levels, based on the current status of integrated research between institutions, the international evolution of research questions and the extended interest of the greater number of scientists involved in the EAL for the next period. After having developed in the previous period a global collaborative approach going beyond the usual project by project initiative, the current strategy is at aiming to reach a critical mass. Increasing the number of scientists and a better integration of the capabilities of the involved teams will results in better capacity of developing long-term longitudinal projects and in a higher capacity of bringing new hypotheses and improved methods. The later will be achieved both by concentration of the mutual strengths as well as through complementary initiatives. Such global approach will strengthen our common research priorities on which the complementarity of the different groups can be exploited in contribution to the development of respiratory and environmental epidemiology in Europe. The renewed LEA will increase the visibility of the associated laboratories. Respiratory and environmental epidemiology are facing new challenges, which requires a major development at the international level. The EAL is now well-known internationally and has attracted several post docs. It is essential that respiratory epidemiology becomes an attractive area of research for young epidemiological scientists in Europe and elsewhere. Environmental epidemiology is a driving force in CREAL in Barcelona, an essential part of the Grenoble team and the “environment and health” axis of the Villejuif research center is coordinated by the Villejuif team leader. The EAL already appears an incentive for networking at a larger level and three specific collaborations illustrate such growing networking, with a major epidemiological research center in Switzerland (SWTH, N Künzli), and two in United States (Arizona Respiratory Center, F Martinez and Harvard, C Camargo). In the three instances, there are already close collaborations with both Inserm and CREAL including junior and senior researchers exchanges, publications and common grants applications.

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The potential impact for knowledge in the field of life sciences

The advancement of knowledge in the field of life sciences is at a crucial stage of transformation. On the one hand the explosion of "omics" technologies has been a marked advance in the understanding of the mechanisms of chronic diseases at the molecular and cellular level. However, at the same time, it has become apparent a greater need for translation of such knowledge in the understanding of the clinical expression and population health problems. Our research program is able to make significant contributions in this field. Regarding the research on the respiratory phenotypes our results should be useful to redefine the current paradigms of disease classification and diagnosis. New knowledge in this area is likely to have a major impact in both research and practice. In research it may open new avenues for etiological and mechanistic research, which may latter have a translation into new molecular and therapeutically targets. Our research on gene by environment interaction will benefit of high expertise on the crucial aspect of the assessment of environment, a too often neglected aspect31. Understanding the burden of the diseases in the societies and strengthening the scientific basis of prevention and protection policies is an important part of our program. Regarding environmental determinants both cleaning exposures and air pollution are largely disseminated exposures in the community. A closer understanding of their effects and mechanisms of action is crucial for the improvement of the current health protection strategies. A better undertanding of the influence of water contamination, endocrine disruptors, on respiratory morbidity and other outcomes is likely to have an important public health impact.

31 Wild CP. Complementing the genome with an "exposome": the outstanding challenge of environmental exposure measurement in molecular epidemiology. Cancer Epidemiol Biomarkers Prev 2005;14:1847-50.

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Methods and experiments planned (original aspects)

The program will be set up through the following projects :

Bio2Nea (BIOmarkers in Oxidative and Nitrosative pathways related to Environment and Asthma),

BioLung (Molecular epidemiology on lung function)

E3N (Etude épidémiologique auprès des femmes de la MGEN),

ECRHS (European Community respiratory Health Survey)

ECRHS III (European Community Respiratory Health Survey, third survey)

EDEN (Etude des Déterminants pré et post natals précoces du développement et de la santé de

l'enfant)

EGEA (Epidemiological study on the Genetics and Environment of Asthma),

ESCAPE (European study of Cohorts for air pollution effects)

ESE (EGEA-Sapaldia- ECRHS) consortium

GEDA (Genes and Environment in Asthma),

IAGO (Gene Occupation interactions in asthma),

MedALL (Mechanisms of the development of allergy, birth cohorts, European-wide),

NETA (Rôle des expositions professionnelles et domestiques aux produits de nettoyage et de

désinfection dans l’asthme)

NHS (Nurses Health study, Harvard), ongoing projects on diet and occupation in relation to asthma

and COPD

PAC-COPD (Phenotype characterization and course COPD)

Means (humans and materials) required for the proposal, expected timing and researchers exchanges = 1/2page The number of researchers involved in the EAL has expanded from 13 to 22 with a harmonious development in all topics. The number of environmental epidemiologists has increased, coherent with the change in the EAL title, in parallel with the number of respiratory epidemiologists and of chest physicians (two in 2007, one in Inserm and one in Creal ; now four, with two in Inserm and two in Creal). Frequent short-term travel exchanges are key to maintain a dynamic collaboration and should be facilitated by an appropriate funding dedicated to the EAL functionning. Long visits of researchers are starting to take place. Are planned in particular of Nicole Le Moual in CREAL to work on the occupation theme and Bénédicte Jacquemin to CREAL to develop further collaboration on air pollution. Visits of researchers from CREAL at Inserm will be promoted as well. The exchange of post-doc is an essential aspect of the EAL and should be developped. In the previous period, there has been exchange based on one position both ways. To be noticed the first concerned have been recruited at Inserm as CR1, showing the excellence of the candidates and of the framework of the EAL. The current post docs are developing programs explicitely based on combined projects (one on Villejuif and CREAL and one on CREAL and Grenoble). It is of crucial importance that the funding for postdocs is allocated up to a larger scale (2 x centers) in consistence with the wider focus of the EAL in the next period. Grant applications are increasingly applied by Inserm and CREAL researchers with the participation of the other institution. For now, besides EU (successful) funding, only ANSES in France allows that

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the foreign partner can benefit of the budget and increasing such possibilities from national fundings would be useful. Nevertheless, even without funding, the actual participation on the scientific project is likely to increase the success rate in national fundings, in particular in the current era where large collaborations are increasingly searched, not only on genetics, but also on phenotypic and environmental issues. Ethical issues raised by the project and the way they will be treated

Ethical issues are of great interest for both institutions. A specific program is planned in the context of MedAll and a paper on “Ethical challenges in gene environment interactions” is in preparation by F Kauffmann and Anne Cambon (WP leader of ethics in MedAll), a topic relevant for EAL work in progress in the IAGO project.

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D) Added value of the EAL/IAL (1 page)

To what extend the EAL/IAL and its resources will be of any added value for the research proposal and to the career development of researchers involved in the project.

1) Access to cohorts/infrastructures. Access to cohorts/infrastructures will remain as an important asset of the EAL during the next period. CREAL has brought access to data from ECRHS and a stable platform for integrative and pooled analysis of ECRHS, EGEA and SAPALDIA studies is now well established. This will be an important source of analysis and publications during the next period. Analysis on gene by environment interaction and pathway analysis will be made possible through this collaboration. Inserm has facilitated for CREAL access to E3N cohort which is planning a respiratory module including spirometry in the context of E4N (cohorts from the program “Investissements d’avenir”), a major extension over several generations of the population of women ascertained through E3N. Both labs will benefit by extending current studies on this unique population. MeDALL project (FP7; coordinators J Bousquet and Josep M Antó) has made possible to include the largest pool of birth cohorts focusing on respiratory and allergy in Europe and will facilitate the access of the Inserm teams to the cohorts. Research on biomarkers will be taken to a step forward with the ongoing collaboration of Inserm with CREAL for several adult studies (EGEA, ECRHS II and III) as well as in the context of WP6 in MeDALL. In all these initiatives Inserm will be benefited of CREAL access to infrastructures of PRBB including the Laboratory of Human Genetic Diseases, a multiplex platform for the assessment of targeted proteomics and the Laboratory of Immunology. 2) Grants. The strategy applying new research proposal in collaboration will be strengthened in the next period. A new application to the FP7 EU environment call, lead by the Inserm team (J Bousquet) with the participation of CREAL is now under evaluation (ClimALL, Climate change and allergy: Science to Policy) 3) Visibility and attractiveness. The EAL visibility and attractiveness will be reinforced with its extension for a new period. The EAL research programs will be increasingly known from the Inserm research centers (in particular in the context of the Environment and Health axis of the CESP/U1018 in Villejuif) and in the Inserm respiratory epidemiology community, in the context of the biannual French-speaking (usually) respiratory epidemiology seminar coorganized by respiratory epidemiology teams from Inserm at Villejuif with Inserm U700 for more than 20 years. CREAL will host the world congress in environmental epidemiology in September 2011 (ISEE 2011) making this a unique opportunity to make the EAL better known and attractive to new postdoctoral researchers. CREAL is a partner of a proposal to have PRBB centres recognized as an integrated health research centre by the ISC III (Ministry of Science and Innovation of Spain) and F Kauffmann has been invited to integrate its Scientific Advisory Board. 4) Decrease in research fragmentation. Decrease in research fragmentation during the next period will be a consequence of the strategies alluded to above. Future work on several EAL programs, like phenotypes, biomarkers, genetics, among others, will substantially benefit of the EAL integrative structure and research being conducted by the researchers in both labs will be less isolated. The scale of research fragmentation will also be reduced at the institutional level as EAL provides a unique opportunity to share strategic plans for the future, something that has occurred in the past and that will be strengthened in the future. Following what has been initiated in the previous period, during the next EAL the decrease in research fragmentation will continue through both new international research applications and networks. ClimALL application (under evaluation) is an important example of propagating existing collaboration in childhood health research in CREAL (ENRIECO and CHICOS FP7 projects) into a new project (MeDALL) and form here to a new field like climate change (ClimALL). A closer collaboration of the EAL with two other centres in Basel and Tucson is already taking place. The development of EAL is therefore an important node in the context of a wider networking in research in respiratory and environmental epidemiology.

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Appendix

Section des Unités de recherche

Report from the visiting committee - January 2009

Research unit : Centre for Research in Epidemiology and Population Health

University Paris 11

The research unit : Name of the research unit : Centre for research in Epidemiology and Population

Health (CREPH) / Centre de Recherche en Epidémiologie et Santé des Populations (CESP)

Requested label : UMR_S INSERM N° in case of renewal : Head of the research unit : M. Denis HEMON

University or school : Université Paris 11 Université Saint Quentin en Yvelines (UVSQ)

Other institutions and research organization: INSERM INED

Members of the visiting committee Chairman of the committee : Mr Roger SALAMON, Université Bordeaux 2 (and also chairman of sub-committee A) Mrs Claire JULIAN-REYNIER, Institut Paoli-Calmettes de Marseille (chairwoman of sub-committee B)

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Report from the visiting committee (extract)

4 Specific appreciation team by team and/or project by project

Team 5 : Respiratory And Environmental Epidemiology

Team leader: Francine Kauffmann

Overall, the visiting committee assessed the past activity and the research project of this team as EXCELLENT.

This is a small, focused and structured group, with a strong leader in an international arena, with a long and successful track record of respiratory epidemiology that fits coherently with the well planned project for the new period (on respiratory effects of cleaning products, nursing, air pollution, dietary products and genes). The group research lies in either international collaborative projects or the French EGEA case-control that they lead. EGEA incorporates clinical, environmental, molecular and genetic epidemiology, collaborating with other INSERM units. The group is evolving successfully with young researchers.

Weaknesses: The group has limited teaching activity and a short record of PhD students; it is too small to face the high specialized technical challenges in the statistical analysis (spatial statistics, genetic analysis) that probably would require external technical support, and does not take advantage of the life-course studies carried out at INSERM.

Recommendations: The group needs to plan the new incorporation of new researcher, a senior with a long career, to fit successfully in their well structured project; the panel advise to incorporate psychosocial determinants; even though their record of publications is in the upper decile, they should plan how to capitalize in a more efficient way their production; a final recommendation refers to increase the number of PhD incorporations. Overall Evaluation score : A+

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Section des Unités de recherche

AERES report on the research unit - January 2010

Albert Bonniot Institute From the

University Grenoble 1

INSERM

CNRS Research Unit

Name of the research unit : Albert Bonniot Institute Requested label : UMR_S INSERM, UMR CNRS N° in case of renewal : 823 Head of the research unit : M. Christian Brambilla

Members of the visiting committee Chairperson : M. Laszlo Tora

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Report from the visiting committee (extract) Team 12 (Department 2) : Environmental epidemiology applied to reproduction and respiratory health Team leader: M. Rémy Slama Staff members (on the basis of the application file submitted to the AERES) Past Future N1 : Number of researchers with teaching duties (Form 2.1 of the application file) 0 0 N2 : Number of full time researchers from research organizations (Form 2.3 of the application file) 1 2 N3 : Number of other researchers including postdoctoral fellows (Form 2.2 and 2.4 of the application file) 1 3 N4 : Number of engineers, technicians and administrative staff with a tenured position (Form 2.5 of the application file) 0 0,4 N5 : Number of other engineers, technicians and adminsitrative staff (Form 2.6 of the application file) 1,8 2 N6 : Number of Ph.D. students (Form 2.7 of the application file) 0 1 N7 : Number of staff members with a HDR or a similar grade 0 2 • Appreciation on the results

The group was created in 2008 as an « Avenir » team by INSERM within the Albert Bonniot Institute (originally Team 14). The research activities of the group on environmental epidemiology applied to fecundity and reproduction had a main focus on air pollution. Because of widespread exposure and high burden carried by adverse reproductive outcomes, this topic is of major importance for public health. The group had the responsibility of a unique data collection on fertility in France, obtained important results on adverse effects of air pollution on fetal growth, and also proposed important methodological improvements for assessing exposure to air pollutants. This junior Team published in top journals in environmental health (9 publications since the creation of the group in 2008). The team is also strongly implicated with other groups for conducting large cohort studies that allow investigating birth outcomes in relation to environmental pollution.

• Appreciation on the impact, the attractiveness of the research unit and of the quality of its links with international, national and local partners

The group has strong potential in terms of attractiveness. The team leader is involved in teaching and training of students in national and international courses. He is a wellrecognized expert in environmental epidemiology and actively participates to scientific and non-scientific committees (organization of international workshop on air pollution and reproduction, president of the Programme National de Recherche sur les Perturbateurs Endocriniens). The group has attracted one post-doc and a PhD student.

• Appreciation on the strategy, governance and life of the research unit

The team has a clear strategy of developing activities on environmental epidemiology within the IAB, and will extend its focus to respiratory diseases by the arrival of the asthma group, which was formerly part of Team 11 (results of the asthma group are evaluated separately).

• Appreciation on the project

The new group will conduct important studies for the understanding of the relationships between environmental exposures and health, with focus on exposure assessment methodology, and the study of genetic or epigenetic pathways to characterize the role of environment on reproductive function and respiratory health. Projects on epigenetic markers will be developed in collaboration with Team 6. The project of the team is based on solid experience of the team members in the field and strong partnerships with other groups at a national and international level.

• Conclusion

• Overall appreciation

Overall, the appreciation of the visiting committee is excellent. The emergence of this research group may have a strong impact on the development of environmental epidemiology at a local and national

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level, and may rapidly constitute a pole of attraction for new researchers in the field.

• Strengths and opportunities

The group is very dynamic, focused, well-known at the national and international level, able to attract important national and international funding.

• Weaknesses and threats

The main weakness of the group is the absence of senior scientists with an HDR which prevents the possibilities of development. The group may be a bit isolated in its field of expertise at the IAB. The suggested link between epidemiology and cancer was not clear to the committee.

• Recommendations

Attract more foreign post-docs and students with experience in epidemiology.

Overall Evaluation score : A+

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Inserm

Here agreement signed by the ITMO’s director

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Creal :

For the foreign Partner: Formal letter of commitment signed by the Institution to which the partner belongs.