allergen workshop, vancouver march 2009 - fk -1 the egea study francine kauffmann respiratory and...

AllerGen Workshop, Vancouver March 2009 - FK -1

The Egea studyFrancine Kauffmann

Respiratory and Environmental Epidemiology

Inserm, U780 - Epidemiology and Biostatistics

Villejuif, France

Genes and the Environment: The Genesis of Asthma and Allergy Workshop

March 1-3, 2009 - Vancouver


General objectives1) To determine genetic factors of asthma and related traits (atopy

and bronchial responsiveness)

2) To determine environmental factors

and the interactions of these 2 types of factors

3) To clarify the heterogenetiy of asthma


Question => Design

Genetics

Environment

Heterogeneity

Families of asthmatic cases

Segregation

LinkageAssociation

Detailed data on phenotypes => Asthmas

Large nb of « usual » asthma nuclear familiesPrevalence => hospital recruitment

Detailed data on environment(personal, familial, general, childhood, adulthood)

Controls. Further, interest to estimate the allelic frequency of genetic markers and for association studies

Clin Experim Allergy 1995


Egea - A multicentric study

Marseille

Grenoble

Lyon

Montpellier

Paris 65

68

58 60

42

36

11

48

70

83

43

10 97

36

37

+

+

Cases (families ≥ 2 asthmatics)

Adult cases (families ≥ 1 asthma) Pediatric cases (families ≥ 1 asthma) Adult controls

Pediatric controls

4 9

27


415 controls

348 families (1431 subjects)

40 families (189 subjects)

With ≥ 2 relatives 335 families (1415 subjects)

17 16 7

2

1

4

348 cas

18 4

119 65 19 5

48 50

Families ascertained by one asthmatic

Families ascertained by 2 affected sibs

Controls

+58 new relatives examined 12 yrs later (Egea2)

Case-control study - 5 cities in France + Family study of asthmatic probands + families with affected sibs

=>In total 2105 subjects


A longitudinal studySurvey 1 2 New at Egea2

Brief self-completed Q (step 1) and full questionnaire by an interviewer (step 2)

Respiratory and allergic symptoms (ECRHS-like + complements)

+ + New aspects ECRHS 2

Drug consumption + + 3 and 12 last months; dose of steroids

Quality of life (SF36, AQLQ) - +

Skin prick tests 11 ag (ECRHS+2) + + + cypress

LFT, methacholine challenge (4mg), WBC, IgE + +

Exhaled NO, Exhaled breath condensate - + FeNO (3 centers), EBC

Blood (serum, plasma, DNA, cell lines) + + Strict conditions + RNA + erythrocytes

Now DNA for 97% - RNA for 66%

Environment

Smoking, occupational exposures, indoor exposures, pets, air pollution

+ + Complete ccupational and residential histories, cleaning products, window of exposures for pets

Country living + Detailed egea2

Diet, physical activity, - + Silhouettes, FFQ (118 items)

Hormone-related events - + ECRHS questionnaire


First survey Egea1 N = 2047

DeadN = 45 (2.2%)

Only short questionnaire (step1) N = 302 (15.1%)

Long questionnaire (step 2) N = 1543 (77.1 %)

AliveN = 2002

Refusals and lost N= 157 (7.8%) Overall follow-up N = 1845 (92.2%)

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sont requis pour visionner cette image.

FEV1 N=1970 Metha choline test N=1466 pos t BD FEV1 N=1111 Skin pr ick te s ts N=1977 IgE N=1941 Eosinophils N=1910 DNA N=1962 Serum N=1953 Plasma N=1953

FEV1 N=1361 Metha choline test N= 855 pos t BD FEV1 N=1333 Fe NO N= 781 Skin pr ick te s ts N=1284 IgE N=1368 Eosinophils N=1368 DNA N=1512 RNA N=1357 Serum N=1374 Plasma N=1373 Exhaled breat h cond N=1292 FFQ N=1420

..with a good follow-up


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)

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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%]


Among potential areas of international collaborations

Environment

Genetics


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.


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


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, ..


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Age of Onset of Asthma & Env Tobacco Smoke Exposure

Bouzigon et al, New Engl J Med, 2008

risk of early-onset asthma with ETS exposure

17q21 locus associated with early-onset asthma ( 4 yrs)

Asthma onset 4 yrs

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


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:Proposal: GWAS to investigate imprinting in pooled family data sets


GENES WITH PLEIOTROPIC EFFECTSPrevious EGEA linkage scans have characterized regions of linkage common toseveral 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…)


Strengths - Egea

• Families and population-based controls• Phenotypic characterisation (detailed and

longitudinal)• Environment• Biological collection


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


Coordination : F Kauffmann; F Demenais (genetics); I Pin (clinical aspects).

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

Egea cooperative group


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 thatAll 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

http://ifr69.vjf.inserm.fr/~egeanet/

allergen workshop, vancouver march 2009 - fk -1 the egea study francine kauffmann respiratory and...

Documents

serum egea2

lost n

eosinophils n

asthmatic families

asthma rhinitis

genesis of asthma

asthma jem

serum egea1