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290. Genetic risk factors for asthma and COPD

2756 Asthma, obesity and TNFA: two international population-based cohort studies Manolis Kogevinas 1 , Francesc Castro 1 , Deborah Jarvis 2 , Rafael de Cid 3 , Matthias Wjst 4 , Xavier Esivill 3 , Josep-Maria Anto 1 , Marlys Machler 5 , Medea Imboden 5 , Wolfgang Berger 6 , Thierry Rochat 7 , Nicole Margot Probst-Hensch 5 . 1 Centre for Research in Environmental Epidemiology, CREAL, Barcelona, Spain; 2 Respiratory Epidemiology and Public Health Group, Imperial College, London, United Kingdom; 3 Genes & Disease Program, Center for Genomic Regulation (CRG), Barcelona, Spain; 4 Molecular Pulmonology, Institut for Inhalation Biology, Munich, Germany; 5 Molecular Epidemiology/Cancer Registry Zürich, University Hospital Zürich, Zurich, Switzerland; 6 Institute of Medical Genetics, University of Zurich, Zurich, Switzerland; 7 Division of Pulmonary Medicine, University Hospitals of Geneva, Geneva, Switzerland Introduction: There is evidence that obesity is a risk factor for asthma in chlidren and adults. Obesity and asthma may have a common etiology such as fetal environment factors and genetic factors. The TNFA gene is among the few genes associated with both asthma and obesity. Polymorphisms in TNFA may affect the levels of tumor necrosis factor (TNF). In addition, adipose tissue expresses a number of proinflammatory molecules, including TNF. Aims: We evaluated the joint effect of obesity and the TNFA gene in asthma, bronchial hyper-responsiveness and atopy in adults, by combining the results from two large population-based studies. Methods: The European Community Respiratory Health Survey (ECRHS) and the Swiss Cohort Study on Air Pollution and Lung and Heart Disease in Adults (SAPALDIA) used comparable protocols, questionnaires and measures of lung function and atopy. DNA samples from 11,136 participants were genotyped for TNFA-308 and LTA+252. Results: The TNFA-308 polymorphism was associated with increased asthma prevalence and only moderately associated with obesity. Obesity was associated with asthma, and subjects who became obese during the follow-up had an increased incidence of asthma compared to those that remained non-obese (RR=2.6, p-value=0.03). The association of asthma with obesity tended to be stronger for the G/A and A/A TNFA-308 genotypes (OR=3.2, p<0.001) compared to the G/G genotype (OR=2.4, p<0.001). When mutually adjusting, both obesity and TNFA had independent effects on asthma. Associations were more pronounced among non-atopics. Conclusions: Obesity and TNFA are associated with asthma in a complex pattern that involves both independent and combined effects.

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2757 Effect of traffic related air-pollution and oxidative stress genes on asthma (ECRHS) Francesc Castro-Giner 1 , Manolis Kogevinas 1 , Deborah Jarvis 2 , Bertil Fosberg 3 , Benedicte Jacquemin 1 , Inmaculada Aguilera 1 , Danielle Vienneau 2 , Joachim Heinrich 4 , Jordi Sunyer 1 , Rafael de Cid 5 , Juan Ramon Gonzalez 1 , Matthias Wjst 4 , Xavier Estivill 5 , Josep Maria Antó 1 , Nino Künzli 1 . 1 Centre for Research in Environmental Epidemiology, CREAL, Barcelona, Spain; 2 Respiratory Epidemiology and Public Health Group, Imperial College, London, United Kingdom; 3 Occupational and Environmental Medicine, Umea University, Umea, Sweden; 4 Institute of Epidemiology, Helmholtz Zentrum München, Munich, Germany; 5 Genes and Disease Program, Centre for Genomic Regulation (CRG), Barcelona, Spain Aim: Traffic related air-pollution has been related with asthma. Genetic factors may influence response to pollutants. We examined the interaction of the association between traffic-related pollution and specifically modelled outdoor levels of NO2 with genetic variants, and asthma. Methods: Adults from 14 cities of the European Community Respiratory Health Survey (ECRHS II) were included (N= 2401) for whom both DNA and outdoor NO2 estimates were available. Subjectshome addresses were geocoded and linked to outdoor NO2 estimates using the 1-km grid NO2 surface modelled by APMoSPHERE (Air Pollution Modelling for Support to Policy on Health and Environmental Risk in Europe) as a marker of local traffic related pollution. We examined asthma prevalence at follow-up and asthma incidence between baseline and follow-up. We examined polymorphisms in 4 genes involved in oxidative stress pathways. Results: We have previously reported positive associations between NO2 and asthma, e.g. a 30% higher risk (OR=1.3, p=0.05) for asthma incidence per 10 ug/m3 increase in home outdoor NO2. No significant main effects of the genes were observed for any of the asthma outcomes. However, higher asthma was associated with NO2 exposure in subjects with GSTT1 null, GSTP1 Val105Val or NQO1 Pro187Pro polymorphisms. In subjects with both GSTT1 null and NQO1 Pro187Pro polymorphisms, the increase of risk due to NO2 exposure was stronger (OR=5.0, p=0.007). Significant but less pronounced results were found for GSTM1 null. Conclusion: Genetic variability of oxidative stress may modulate the effects of air-pollution on asthma. 2759 The association of bronchial reactivity with use of gas for cooking is modified by GSTM1 homozygous deletion Adaikalavan Ramasamy 1 , Francesc Castro-Giner 2 , Joachim Heinrich 3 , Nino Kunzli 2 , Cosetta Minelli 1 , Manolis Kogevinas 2 , Debbie Jarvis 1 . 1 Respiratory Epidemiology and Public Health Group, Imperial College London, London, United Kingdom; 2 Centre for Research in Environmental Epidemiology, Municipal Institute of Medical Research, Barcelona, Spain; 3 GSF, National Research Center for Environment and Health, Institute of Epidemiology, Neuherberg, Germany Background: Glutathione S-transferase M1 (GSTM1) has detoxifying properties critical in protecting against oxidative stress. Homozygous deletion of GSTM1 (null genotype) is common, found in about half the European population, and has been shown to modify response to smoking. Since cooking with gas also produces oxidative pollutants, we hypothesized that GSTM1 may similarly modify the association between bronchial reactivity (BR) and cooking with gas. Objective: To determine whether the association of BR and cooking with gas (vs. electricity) is modified by GSTM1 in the randomly selected adults (n= 1835 from 7 countries) taking part in the European Community Respiratory Health Survey (ECRHS). Methods: The interaction term between cooking with gas and GSTM1 was estimated using a multiple linear regression for BR slope adjusting for a priori risk factors (including age, sex, smoking in pack years, height, specific IgE titre to 4 common allergens, total IgE, baseline FEV1 and smoking/GSTM1 interaction) for each country and pooled in a random effects model. Results: Individuals with the null genotype who cooked with gas (vs. electricity) had a significantly lower slope (i.e. more severe BR) compared to the non-null genotype [interaction term is -0.57, 95% CI (-1.07,-0.07), p=0.026].

2758 CD14 and toll-like receptor gene polymorphisms, country living during childhood, and asthma in adults of the French EGEA study Lidwien A.M. Smit 1,2 , Valerie Siroux 1,3 , Emmanuelle Bouzigon 4 , Marie-Pierre Oryszczyn 1 , Florence Demenais 4 , Francine Kauffmann 1 . 1 U780, INSERM, Villejuif, France; 2 Division of Environmental Epidemiology, Institute for Risk Assessment Sciences, Utrecht, Netherlands; 3 U823, INSERM, Grenoble, France; 4 U794, INSERM, Paris, France It has been shown that country living protects against asthma, which may be explained by microbial exposures. The aim was to study whether single nucleotide polymorphisms (SNPs) in CD14 and Toll-like receptor (TLR) 2, TLR4 and TLR9 genes are associated with asthma in adults, and whether these SNPs modify associations between country living and asthma. Twenty-five SNPs in CD14, TLR2, TLR4, and TLR9 genes were genotyped in adult subjects from the French Epidemiological study on the Genetics and Environment of Asthma, Bronchial Hyperresponsiveness, and Atopy (EGEA). We conducted a case-control analysis on unrelated subjects (239 asthmatics and 596 non asthmatics), and a family based analysis in 192 families ascertained through asthmatic probands (FBAT). The TLR2/+596 C allele was associated with an increased risk for asthma in both case-control and family-based analyses (under a dominant model, OR [95%CI]=1.91 [1.34-2.72], p=0.0003; z statistics from FBAT=2.48, p=0.01). In skin prick test (SPT) positive subjects, the CD14/-260 C allele was negatively associated with asthma (additive model, OR[95%CI]=0.66 [0.48-0.91]). In SPT negative subjects, the protective effect of country living during childhood on asthma was restricted to subjects carrying TLR2/+596C (gene-environment interaction p=0.03). Significant gene-environment interactions between variation in CD14 and TLR genes and country living were found for eight other SNPs including CD14/-260. Our results suggest an important role for TLR2 and CD14 SNPs in asthma. In addition, CD14, TLR2, TLR4, and TLR9 SNPs may modify associations between country living and asthma. Funded by ANR-SEST, AFSSET.

Conclusion: Individuals with GSTM1 null genotype may be at increased risk of respiratory problems when using gas for cooking.

2760 MRP1 polymorphisms contribute to level and decline of lung function in two general population cohorts Mateusz Siedlinski 1 , Marike Boezen 1 , Jolanda Boer 2 , Henriette Smit 3 , Dirkje Postma 4 . 1 Epidemiology, University Medical Center Groningen, University of Groningen, Groningen, Netherlands; 2 Centre for Nutrition and Health, National Institute for Public Health and the Environment, Bilthoven, Netherlands; 3 Centre for Prevention and Health Services Research, National Institute for Public Health and the Environment, Bilthoven, Netherlands; 4 Pulmonology, University Medical Center Groningen, University of Groningen, Groningen, Netherlands Background: The metabolism of xenobiotics plays an important role in the development of Chronic Obstructive Pulmonary Disease (COPD). The Multidrug Resistance Protein 1 (MRP1) is a membrane pump excreting a variety of xenobiotics from the cell. Aim: To assess effects of MRP1 single nucleotide polymorphisms (SNPs) on the level and longitudinal course of lung function in general population. Methods: All 51 MRP1 tagging SNPs (minor allele frequency>5% and r2 <0.8) were analyzed in two independent, prospective, population-based cohorts, i.e. Doetinchem (n=1,152) and Vlagtwedde-Vlaardingen (n=1,390). Results: SNPs rs212093 and rs4148382 in the 3' untranslated region of MRP1 were significantly associated with a lower Forced Expiratory Volume in one second (FEV1 ) in both cohorts. Four moderately correlated SNPs (0.5<r2 <0.8; rs4148330, rs4781699, rs8045000, and rs7190484) in the MRP1 promoter and intron 1 had significant effects in both cohorts in the same, negative direction, but on different lung function outcomes (i.e. FEV1 or FEV1 /VC (Vital Capacity) ratio). SNP rs35621 (intron 14) was significantly associated with an excessive FEV1 decline in both cohorts (figure).

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Oral Presentation

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M ONDAY, O CTOBER 6 TH 2008

Methods: We collected spirometry from 157 subjects with a doctor's diagnosed COPD from the Genetic Research in Isolated Population study. We analyzed 32 SNPs in 13 candidate genes: ADAM33, TGFB1, MMP1, MMP2, MMP9, MMP12, TIMP1, SFTPA1, SFTPA2, SFTPB, SFTPD, GSTP1 and HMOX1. We analyzed FEV1, FVC, and FEV1/FVC levels in COPD patients using restricted maximum likelihood linear mixed modeling, accounting for pedigree structure. We replicated significant associations in 351 COPD patients selected from the general Vlagtwedde/Vlaardingen study. Results: We studied 106 spirometry confirmed COPD GOLD stage I subjects, members of an extended pedigree including 6,175 people. SNPs in ADAM33, TGFB1, SFTPA1, SFTPA2 and SFTPD were significantly associated with FEV1/FVC level. The ADAM33 and TGFB1 associations with FEV1/FVC were replicated in the Vlagtwedde/Vlaardingen population, with similar effect sizes. Allele frequencies were similar in both populations. Conclusion: This is the first study showing that a genetic isolate can be used to determine genetic risk factors for lung function level, which can be replicated in COPD patients from an independent population.

Conclusions: This is the first study showing a significant relation between MRP1 SNPs and lung function in two independent cohorts. These SNPs are therefore putative candidates for studies to prevent COPD development and pharmacogenetics in established COPD.

2761 C-reactive protein serum levels, genotypes and the risk of COPD. The Rotterdam study Yannick van Durme 1 , Katia Verhamme 2 , Geert Van Pottelberge 1 , Jacqueline Witteman 2 , Andre Uitterlinden 2 , Guy Joos 1 , Albert Hofman 2 , Guy Brusselle 1 , Bruno Stricker 2 . 1 Department of Respiratory Diseases, Ghent University Hospital, Ghent, Belgium; 2 Department of Epidemiology & Biostatistics, Erasmus University Medical Center, Rotterdam, Netherlands Introduction: Chronic obstructive pulmonary disease (COPD) is characterized by chronic inflammation in the pulmonary compartment, as well as in the systemic circulation. Objective: The aim of this study was to examine the association between serum levels of high-sensitivity C-reactive protein (hsCRP), variation in the CRP gene and the risk of developing COPD. Methods: This study was part of the Rotterdam Study, a prospective populationbased cohort study among elderly ( 55 years), that includes 7983 participants with a total follow-up time of 15.5 years (Hofman et al. Eur J epidemiol 2007). COPD cases were identified by spirometry and validation of medical reports from hospitals and general practitioners. Cox proportional hazard models were used to study the association between serum levels of hsCRP, CRP gene SNPs and haplotypes, and incident COPD. Results: Elevated levels of serum hsCRP were associated with a 1.7 increased risk of future COPD (95% CI, 1.16 to 2.49), even after adjustment for smoking and cardiovascular comorbidity. Subgroup analyses showed a similar risk for men and women and the highest risk for the former smokers. There was no evidence for an association between CRP gene SNPs or haplotypes, and the risk of developing COPD. Conclusion: Although elevated levels of serum CRP were associated with an increased risk of future COPD, no association was found between variation in the CRP gene and the risk of developing COPD, suggesting that other determinants may play a role in the observed association between systemic inflammation and COPD. Supported by the Belgian Thoracic Society, the Fund for Scientific Research Flanders and the Netherlands Organization for Scientific Research.

2762 Novel strategy to identify genetic risk factors for COPD severity: genetically isolated populations C.C. van Diemen 1 , D.S. Postma 2 , Y.S. Aulchenko 3 , P.J.L.M. Snijders 3 , B.A. Oostra 3 , C.M. van Duijn 3 , H.M. Boezen 1 . 1 Epidemiology, University Medical Center Groningen, Groningen, Netherlands; 2 Pulmonology, University Medical Center Groningen, Groningen, Netherlands; 3 Epidemiology and Biostatistics, Erasmus Medical Center Rotterdam, Rotterdam, Netherlands Background: Genetic determinants for Chronic Obstructive Pulmonary Disease (COPD) are difficult to study, since COPD develops at later ages and involves multiple genetic and environmental factors. Studies using genetically isolated populations with limited genetic variation may be useful, but are thus far lacking. Aim: To study the associations between Single Nucleotide Polymorphisms (SNPs) in candidate genes and severity of airway obstruction in COPD in a genetically isolated population, and to replicate results in the general population.

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