Genes Interacting with Occupational Exposures to Low Molecular Weight Agents and Irritants on Adult-Onset Asthma in Three European Studies

Background: The biological mechanisms by which cleaning products and disinfectants—an emerging risk factor—affect respiratory health remain incompletely evaluated. Studying genes by environment interactions (G × E) may help identify new genes related to adult-onset asthma. Objectives: We identified interactions between genetic polymorphisms of a large set of genes involved in the response to oxidative stress and occupational exposures to low molecular weight (LMW) agents or irritants on adult-onset asthma. Methods: Our data came from three large European cohorts: Epidemiological Family-based Study of the Genetics and Environment of Asthma (EGEA), Swiss Cohort Study on Air Pollution and Lung and Heart Disease in Adults (SAPALDIA), and European Community Respiratory Health Survey in Adults (ECRHS). A candidate pathway–based strategy identified 163 genes involved in the response to oxidative stress and potentially related to exposures to LMW agents/irritants. Occupational exposures were evaluated using an asthma job-exposure matrix and job-specific questionnaires for cleaners and healthcare workers. Logistic regression models were used to detect G × E interactions, adjusted for age, sex, and population ancestry, in 2,599 adults (mean age, 47 years; 60% women, 36% exposed, 18% asthmatics). p-Values were corrected for multiple comparisons. Results: Ever exposure to LMW agents/irritants was associated with current adult-onset asthma [OR = 1.28 (95% CI: 1.04, 1.58)]. Eight single nucleotide polymorphism (SNP) by exposure interactions at five loci were found at p < 0.005: PLA2G4A (rs932476, chromosome 1), near PLA2R1 (rs2667026, chromosome 2), near RELA (rs931127, rs7949980, chromosome 11), PRKD1 (rs1958980, rs11847351, rs1958987, chromosome 14), and PRKCA (rs6504453, chromosome 17). Results were consistent across the three studies and after accounting for smoking. Conclusions: Using a pathway-based selection process, we identified novel genes potentially involved in adult asthma by interaction with occupational exposure. These genes play a role in the NF-κB pathway, which is involved in inflammation. Citation: Rava M, Ahmed I, Kogevinas M, Le Moual N, Bouzigon E, Curjuric I, Dizier MH, Dumas O, Gonzalez JR, Imboden M, Mehta AJ, Tubert-Bitter P, Zock JP, Jarvis D, Probst-Hensch NM, Demenais F, Nadif R. 2017. Genes interacting with occupational exposures to low molecular weight agents and irritants on adult-onset asthma in three European studies. Environ Health Perspect 125:207–214; http://dx.doi.org/10.1289/EHP376

[1]  A. Lowe,et al.  Relationships between adult asthma and oxidative stress markers and pH in exhaled breath condensate: a systematic review , 2016, Allergy.

[2]  Y. Bossé,et al.  Genome-wide interaction study of gene-by-occupational exposure and effects on FEV1 levels. , 2015, The Journal of allergy and clinical immunology.

[3]  Richard Beasley,et al.  Risk factors for asthma: is prevention possible? , 2015, The Lancet.

[4]  C. Leslie,et al.  Cytosolic phospholipase A2: physiological function and role in disease , 2015, Journal of Lipid Research.

[5]  J. Malo,et al.  An official American Thoracic Society Workshop Report: presentations and discussion of the fifth Jack Pepys Workshop on Asthma in the Workplace. Comparisons between asthma in the workplace and non-work-related asthma. , 2015, Annals of the American Thoracic Society.

[6]  M. Schuliga.  NF-kappaB Signaling in Chronic Inflammatory Airway Disease , 2015, Biomolecules.

[7]  G. Gibson.  GTEx detects genetic effects , 2015, Science.

[8]  M. Quinn,et al.  Cleaning and disinfecting environmental surfaces in health care: Toward an integrated framework for infection and occupational illness prevention. , 2015, American journal of infection control.

[9]  Brigitte Decoster,et al.  Occupational exposures and fluorescent oxidation products in 723 adults of the EGEA study , 2015, European Respiratory Journal.

[10]  L. Smit,et al.  Gene–environment interactions in the study of asthma in the postgenomewide association studies era , 2015, Current opinion in allergy and clinical immunology.

[11]  Y. Miki,et al.  Emerging roles of secreted phospholipase A2 enzymes: the 3rd edition. , 2014, Biochimie.

[12]  Thomas C. Wiegers,et al.  The Comparative Toxicogenomics Database's 10th year anniversary: update 2015 , 2014, Nucleic Acids Res..

[13]  Jan Tamminga,et al.  Genetic susceptibility to beryllium: a case–referent study of men and women of working age with sarcoidosis or other chronic lung disease , 2014, Occupational and Environmental Medicine.

[14]  D. Strachan,et al.  Human leukocyte antigen class II variants and adult-onset asthma: does occupational allergen exposure play a role? , 2014, European Respiratory Journal.

[15]  M. Kogevinas.  0430 Individual variability, from candidate G*E to GEWIS , 2014, Occupational and Environmental Medicine.

[16]  S. Reddy,et al.  Reactive oxygen species in inflammation and tissue injury. , 2014, Antioxidants & redox signaling.

[17]  L. Hsiao,et al.  HO-1 Induction by CO-RM2 Attenuates TNF-α-Induced Cytosolic Phospholipase A2 Expression via Inhibition of PKCα-Dependent NADPH Oxidase/ROS and NF-κB , 2014, Mediators of inflammation.

[18]  S. Tarlo,et al.  Asthma and exposure to cleaning products – a European Academy of Allergy and Clinical Immunology task force consensus statement , 2013, Allergy.

[19]  B. Jacquemin,et al.  Environment and asthma in adults. , 2013, Presse medicale.

[20]  Ismaïl Ahmed,et al.  Selection of genes for gene-environment interaction studies: a candidate pathway-based strategy using asthma as an example , 2013, Environmental Health.

[21]  F. Kauffmann,et al.  Asthme et expositions aux produits de nettoyage , 2013 .

[22]  Xihong Lin,et al.  Design and analysis issues in gene and environment studies , 2012, Environmental Health.

[23]  N. Probst-Hensch,et al.  Occupational exposure to dusts, gases, and fumes and incidence of chronic obstructive pulmonary disease in the Swiss Cohort Study on Air Pollution and Lung and Heart Diseases in Adults. , 2012, American journal of respiratory and critical care medicine.

[24]  F. Kauffmann,et al.  Gene-environment interactions in asthma and allergic diseases: challenges and perspectives. , 2012, The Journal of allergy and clinical immunology.

[25]  Rob J Vandebriel,et al.  A review of mammalian toxicity of ZnO nanoparticles. , 2012, Nanotechnology, science and applications.

[26]  Benjamin A. Logsdon,et al.  Simultaneously testing for marginal genetic association and gene-environment interaction. , 2012, American journal of epidemiology.

[27]  F. Kronenberg,et al.  Different Genes Interact with Particulate Matter and Tobacco Smoke Exposure in Affecting Lung Function Decline in the General Population , 2012, PloS one.

[28]  F. Kronenberg,et al.  Genome-wide association study of lung function decline in adults with and without asthma. , 2012, The Journal of allergy and clinical immunology.

[29]  J. González,et al.  Transient receptor potential genes, smoking, occupational exposures and cough in adults , 2012, Respiratory Research.

[30]  R. Fry,et al.  A Toxicogenomic Comparison of Primary and Photochemically Altered Air Pollutant Mixtures , 2011, Environmental health perspectives.

[31]  Meena Jaggi,et al.  Emerging Roles of Protein Kinase D1 in Cancer , 2011, Molecular Cancer Research.

[32]  D. Jarvis,et al.  Human Genome Epidemiology ( HuGE ) Review Interactive Effects of Antioxidant Genes and Air Pollution on Respiratory Function and Airway Disease : A HuGE Review , 2011 .

[33]  Florence Demenais,et al.  A large-scale, consortium-based genomewide association study of asthma. , 2010, The New England journal of medicine.

[34]  J. Marwick,et al.  Molecular mechanisms of oxidative stress in airways and lungs with reference to asthma and chronic obstructive pulmonary disease , 2010, Annals of the New York Academy of Sciences.

[35]  Michael Boehnke,et al.  LocusZoom: regional visualization of genome-wide association scan results , 2010, Bioinform..

[36]  P. Visscher,et al.  A versatile gene-based test for genome-wide association studies. , 2010, American journal of human genetics.

[37]  M. Sokolowska,et al.  Cytosolic phospholipase A2 group IVA is overexpressed in patients with persistent asthma and regulated by the promoter microsatellites. , 2010, The Journal of allergy and clinical immunology.

[38]  S. London,et al.  Gene by environment interaction and ambient air pollution. , 2010, Proceedings of the American Thoracic Society.

[39]  Wolfgang Viechtbauer,et al.  Outlier and influence diagnostics for meta‐analysis , 2010, Research synthesis methods.

[40]  Weidong Wu,et al.  Phosphorylation of p65 Is Required for Zinc Oxide Nanoparticle–Induced Interleukin 8 Expression in Human Bronchial Epithelial Cells , 2010, Environmental health perspectives.

[41]  S. Holgate,et al.  Genetics of allergic disease. , 2010, The Journal of allergy and clinical immunology.

[42]  P. Boschetto,et al.  Mechanisms of occupational asthma. , 2009, The Journal of allergy and clinical immunology.

[43]  C. Hong,et al.  Alpha‐T‐catenin (CTNNA3) gene was identified as a risk variant for toluene diisocyanate‐induced asthma by genome‐wide association analysis , 2009, Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology.

[44]  K. Torén,et al.  Asthma caused by occupational exposures is common – A systematic analysis of estimates of the population-attributable fraction , 2009, BMC pulmonary medicine.

[45]  Jaeil Ahn,et al.  Tests for gene‐environment interaction from case‐control data: a novel study of type I error, power and designs , 2008, Genetic epidemiology.

[46]  N. Probst-Hensch,et al.  Reduced exposure to PM10 and attenuated age-related decline in lung function. , 2007, The New England journal of medicine.

[47]  M. Kogevinas,et al.  Exposure to substances in the workplace and new-onset asthma: an international prospective population-based study (ECRHS-II) , 2007, The Lancet.

[48]  D. Johns,et al.  Biological dust exposure in the workplace is a risk factor for chronic obstructive pulmonary disease , 2005, Thorax.

[49]  M. Imboden,et al.  Follow-up of the Swiss Cohort Study on Air Pollution and Lung Diseases in Adults (SAPALDIA 2) 1991–2003: methods and characterization of participants , 2005, Sozial- und Präventivmedizin/Social and Preventive Medicine.

[50]  Mark Daly,et al.  Haploview: analysis and visualization of LD and haplotype maps , 2005, Bioinform..

[51]  D. Altman,et al.  Measuring inconsistency in meta-analyses , 2003, BMJ : British Medical Journal.

[52]  S. Nakashima.  Protein kinase Cα (PKCα): Regulation and biological function , 2002 .

[53]  D. Jarvis,et al.  The European Community Respiratory Health Survey II , 2002, European Respiratory Journal.

[54]  S. Thompson,et al.  Quantifying heterogeneity in a meta‐analysis , 2002, Statistics in medicine.

[55]  Tom H. Pringle,et al.  The human genome browser at UCSC. , 2002, Genome research.

[56]  A. Draper,et al.  Occupational Asthma , 2002, The Journal of asthma : official journal of the Association for the Care of Asthma.

[57]  F. Kauffmann,et al.  Development of an asthma specific job exposure matrix and its application in the epidemiological study of genetics and environment in asthma (EGEA) , 2000, Occupational and environmental medicine.

[58]  M. Ashburner,et al.  Gene Ontology: tool for the unification of biology , 2000, Nature Genetics.

[59]  J. Bousquet,et al.  Epidemiological study of the genetics and environment of asthma, bronchial hyperresponsiveness, and atopy: phenotype issues. , 1997, American journal of respiratory and critical care medicine.

[60]  F. Kauffmann,et al.  EGEA (Epidemiological study on the Genetics and Environment of Asthma, bronchial hyperresponsiveness and atopy)—design issues , 1995, Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology.

[61]  K Botzenhart,et al.  Reactive Oxygen Species , 2014 .

[62]  H. Griffin,et al.  The European Bioinformatics Institute , 1995 .

[63]  J. Bousquet,et al.  [Genetic and environmental factors of asthma and allergy: Results of the EGEA study]. , 2015, Revue des maladies respiratoires.

[64]  S. Tarlo.  Irritant-Induced Asthma in the Workplace , 2013, Current Allergy and Asthma Reports.

[65]  J. Stockman,et al.  A Large-Scale, Consortium-Based Genomewide Association Study of Asthma , 2012 .

[66]  Ryan Bomgarden,et al.  A Versatile High-Recovery Method for Removing Detergents from Low-Concentration Protein or Peptide Samples for Mass Spectrometry Sample Preparation and Analysis , 2012 .

[67]  M. Kogevinas,et al.  Gene-environment interactions in occupational asthma , 2010 .

[68]  Peter Storz,et al.  Mitochondrial ROS--radical detoxification, mediated by protein kinase D. , 2007, Trends in cell biology.

[69]  S. Nakashima.  Protein kinase C alpha (PKC alpha): regulation and biological function. , 2002, Journal of biochemistry.

[70]  Y. Benjamini,et al.  Controlling the false discovery rate: a practical and powerful approach to multiple testing , 1995 .

[71]  D. Jarvis,et al.  The European Community Respiratory Health Survey. , 1994, The European respiratory journal.

[72]  H GRUNEBERG,et al.  Human genetics. , 1947, The Eugenics review.