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Zhou M, Yang S, Cao L, Dai W, Nie X, Mu G, Zhang X, Wang B, Ma J, Wang D, Shi T, Wang C, Hao X, Chen W. Longitudinal association of polycyclic aromatic hydrocarbons and genetic risk with lung function. ENVIRONMENTAL POLLUTION (BARKING, ESSEX : 1987) 2024; 340:122801. [PMID: 37890693 DOI: 10.1016/j.envpol.2023.122801] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/01/2022] [Revised: 10/21/2023] [Accepted: 10/23/2023] [Indexed: 10/29/2023]
Abstract
To quantify the association of polycyclic aromatic hydrocarbons (PAHs) and the polygenic risk score (PRS) with lung function decline, we developed a repeated-measures study with 4681 observations from baseline and 6-year follow-up of the Wuhan-Zhuhai cohort. Lung function and urinary monohydroxylated PAH metabolites (OH-PAHs) were measured for each observation. The PRS was derived from 246 lung function-associated genetic variants weighted by the effect size of the decreasing ratio of forced expiratory volume in 1 s by forced vital capacity (FEV1/FVC). Linear mixed models were used to estimate the longitudinal exposure-response relationships between OH-PAHs and lung function, and to evaluate the interactions between OH-PAHs and PRS on the longitudinal change of lung function. We found that each 1-unit increase in log-transformed values of 9-hydroxyfluorene, 2-hydroxyfluorene, 4-hydroxyphenanthrene, 9-hydroxyphenanthrene, 2-hydroxyphenanthrene, 1-hydroxyphenanthrene, 1-hydroxypyrene, low molecular weight OH-PAHs (ΣLMW-OH-PAHs), and total OH-PAHs (ΣOH-PAHs) was associated with an annual change in FEV1/FVC of -0.140, -0.112, -0.260, -0.300, -0.159, -0.220, -0.145, -0.156, and -0.177 %/year, respectively. Interactions on the annual decline of FEV1/FVC were detected between ΣLMW-OH-PAHs and PRS (-0.010 %/year, 95% confidence interval -0.018 to -0.001, Pint = 0.0228), and between ΣOH-PAHs and PRS (-0.010 %/year, -0.018 to -0.001, Pint = 0.0203). These results indicated that specific and total urinary OH-PAHs were associated with the longitudinal FEV1/FVC decline, and ΣLMW-OH-PAHs as well as ΣOH-PAHs interacted with PRS on the annual decline of FEV1/FVC.
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Affiliation(s)
- Min Zhou
- Department of Occupational & Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China; Key Laboratory of Environment and Health, Ministry of Education & Ministry of Environmental Protection, And State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China
| | - Shijie Yang
- Department of Occupational & Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China; Key Laboratory of Environment and Health, Ministry of Education & Ministry of Environmental Protection, And State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China; Hubei Provincial Key Laboratory for Applied Toxicology, Hubei Provincial Center for Disease Control and Prevention, Wuhan, Hubei 430079, China
| | - Limin Cao
- Department of Occupational & Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China; Key Laboratory of Environment and Health, Ministry of Education & Ministry of Environmental Protection, And State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China; Tianjin Third Central Hospital, Tianjin 300170, China
| | - Wencan Dai
- Zhuhai Center for Disease Control and Prevention, Zhuhai, Guangdong 519060, China
| | - Xiuquan Nie
- Department of Occupational & Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China; Key Laboratory of Environment and Health, Ministry of Education & Ministry of Environmental Protection, And State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China
| | - Ge Mu
- Department of Occupational & Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China; Key Laboratory of Environment and Health, Ministry of Education & Ministry of Environmental Protection, And State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China
| | - Xiaokang Zhang
- Gannan Medical University, No.1 Harmonious Road, RongJiang District, Ganzhou, Jiangxi 341000, China
| | - Bin Wang
- Department of Occupational & Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China; Key Laboratory of Environment and Health, Ministry of Education & Ministry of Environmental Protection, And State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China
| | - Jixuan Ma
- Department of Occupational & Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China; Key Laboratory of Environment and Health, Ministry of Education & Ministry of Environmental Protection, And State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China
| | - Dongming Wang
- Department of Occupational & Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China; Key Laboratory of Environment and Health, Ministry of Education & Ministry of Environmental Protection, And State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China
| | - Tingming Shi
- Hubei Provincial Key Laboratory for Applied Toxicology, Hubei Provincial Center for Disease Control and Prevention, Wuhan, Hubei 430079, China
| | - Chaolong Wang
- Key Laboratory of Environment and Health, Ministry of Education & Ministry of Environmental Protection, And State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China; Department of Epidemiology and Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China
| | - Xingjie Hao
- Key Laboratory of Environment and Health, Ministry of Education & Ministry of Environmental Protection, And State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China; Department of Epidemiology and Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China
| | - Weihong Chen
- Department of Occupational & Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China; Key Laboratory of Environment and Health, Ministry of Education & Ministry of Environmental Protection, And State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China.
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Fiter RJ, Murphy LJ, Gong MN, Cleven KL. The impact of air pollution on asthma: clinical outcomes, current epidemiology, and health disparities. Expert Rev Respir Med 2023; 17:1237-1247. [PMID: 38247719 DOI: 10.1080/17476348.2024.2307545] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2023] [Accepted: 01/16/2024] [Indexed: 01/23/2024]
Abstract
INTRODUCTION Air pollution has been shown to have a significant impact on morbidity and mortality of respiratory illnesses including asthma. AREAS COVERED Outdoor air pollution consists of a mixture of individual pollutants including vehicle traffic and industrial pollution. Studies have implicated an array of individual components of air pollution, with PM2.5, NO2, SO2, and ozone being the most classically described, and newer literature implicating other pollutants such as black carbon and volatile organic compounds. Epidemiological and cohort studies have described incidence and prevalence of pollution-related asthma and investigated both acute and chronic air pollution exposure as they relate to asthma outcomes. There is an increasing body of literature tying disparities in pollution exposure to clinical outcomes. In this narrative review, we assessed the published research investigating the association of pollution with asthma outcomes, focusing on the adult population and health care disparities. EXPERT OPINION Pollution has multiple deleterious effects on respiratory health but there is a lack of data on individualized pollution monitoring, making it difficult to establish a temporal relationship between exposure and symptoms, thereby limiting our understanding of safe exposure levels. Future research should focus on more personalized monitoring and treatment plans for mitigating exposure.
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Affiliation(s)
- Ryan J Fiter
- Department of Medicine, Montefiore Medical Center, Bronx, NY, USA
| | - Lila J Murphy
- Department of Medicine, Montefiore Medical Center, Bronx, NY, USA
| | - Michelle N Gong
- Department of Medicine, Montefiore Medical Center, Bronx, NY, USA
- Department of Medicine, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Krystal L Cleven
- Department of Medicine, Montefiore Medical Center, Bronx, NY, USA
- Department of Medicine, Albert Einstein College of Medicine, Bronx, NY, USA
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Rushing BR, Thessen AE, Soliman GA, Ramesh A, Sumner SCJ. The Exposome and Nutritional Pharmacology and Toxicology: A New Application for Metabolomics. EXPOSOME 2023; 3:osad008. [PMID: 38766521 PMCID: PMC11101153 DOI: 10.1093/exposome/osad008] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/22/2024]
Abstract
The exposome refers to all of the internal and external life-long exposures that an individual experiences. These exposures, either acute or chronic, are associated with changes in metabolism that will positively or negatively influence the health and well-being of individuals. Nutrients and other dietary compounds modulate similar biochemical processes and have the potential in some cases to counteract the negative effects of exposures or enhance their beneficial effects. We present herein the concept of Nutritional Pharmacology/Toxicology which uses high-information metabolomics workflows to identify metabolic targets associated with exposures. Using this information, nutritional interventions can be designed toward those targets to mitigate adverse effects or enhance positive effects. We also discuss the potential for this approach in precision nutrition where nutrients/diet can be used to target gene-environment interactions and other subpopulation characteristics. Deriving these "nutrient cocktails" presents an opportunity to modify the effects of exposures for more beneficial outcomes in public health.
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Affiliation(s)
- Blake R. Rushing
- Department of Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Anne E Thessen
- Department of Biomedical Informatics, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Ghada A. Soliman
- Department of Environmental, Occupational and Geospatial Health Sciences, City University of New York-Graduate School of Public Health and Health Policy, New York, NY, USA
| | - Aramandla Ramesh
- Department of Biochemistry, Cancer Biology, Neuroscience & Pharmacology, Meharry Medical College, Nashville, TN, USA
| | - Susan CJ Sumner
- Department of Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
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Akhmerova YN, Shpakova TA, Grammatikati KS, Mitrofanov SI, Kazakova PG, Mkrtchian AA, Zemsky PU, Pilipenko MN, Feliz NV, Frolova LV, Frolovskaya AA, Yudin VS, Keskinov AA, Kraevoy SA, Yudin SM, Skvortsova VI. Genetic Variants Associated with Bronchial Asthma Specific to the Population of the Russian Federation. Acta Naturae 2023; 15:31-41. [PMID: 37153512 PMCID: PMC10154776 DOI: 10.32607/actanaturae.11853] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2022] [Accepted: 01/09/2023] [Indexed: 05/09/2023] Open
Abstract
Bronchial asthma (BA) is a disease that still lacks an exhaustive treatment protocol. In this regard, the global medical community pays special attention to the genetic prerequisites for the occurrence of this disease. Therefore, the search for the genetic polymorphisms underlying bronchial asthma has expanded considerably. As the present study progressed, a significant amount of scientific medical literature was analyzed and 167 genes reported to be associated with the development of bronchial asthma were identified. A group of participants (n = 7,303) who had voluntarily provided their biomaterial (venous blood) to be used in the research conducted by the Federal Medical Biological Agency of Russia was formed to subsequently perform a bioinformatic verification of known associations and search for new ones. This group of participants was divided into four cohorts, including two sex-distinct cohorts of individuals with a history of asthma and two sex-distinct cohorts of apparently healthy individuals. A search for polymorphisms was made in each cohort among the selected genes, and genetic variants were identified whose difference in occurrence in the different cohorts was statistically significant (significance level less than 0.0001). The study revealed 11 polymorphisms that affect the development of asthma: four genetic variants (rs869106717, rs1461555098, rs189649077, and rs1199362453), which are more common in men with bronchial asthma compared to apparently healthy men; five genetic variants (rs1923038536, rs181066119, rs143247175, rs140597386, and rs762042586), which are more common in women with bronchial asthma compared to apparently healthy women; and two genetic variants (rs1219244986 and rs2291651) that are rare in women with a history of asthma.
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Affiliation(s)
- Y. N. Akhmerova
- Federal State Budgetary Institution “Center for Strategic Planning and Management of Biomedical Health Risks” of the Federal Medical Biological Agency (Center for Strategic Planning of FMBA of Russia), Moscow, 119121 Russian Federation
| | - T. A. Shpakova
- Federal State Budgetary Institution “Center for Strategic Planning and Management of Biomedical Health Risks” of the Federal Medical Biological Agency (Center for Strategic Planning of FMBA of Russia), Moscow, 119121 Russian Federation
| | - K. S. Grammatikati
- Federal State Budgetary Institution “Center for Strategic Planning and Management of Biomedical Health Risks” of the Federal Medical Biological Agency (Center for Strategic Planning of FMBA of Russia), Moscow, 119121 Russian Federation
| | - S. I. Mitrofanov
- Federal State Budgetary Institution “Center for Strategic Planning and Management of Biomedical Health Risks” of the Federal Medical Biological Agency (Center for Strategic Planning of FMBA of Russia), Moscow, 119121 Russian Federation
| | - P. G. Kazakova
- Federal State Budgetary Institution “Center for Strategic Planning and Management of Biomedical Health Risks” of the Federal Medical Biological Agency (Center for Strategic Planning of FMBA of Russia), Moscow, 119121 Russian Federation
| | - A. A. Mkrtchian
- Federal State Budgetary Institution “Center for Strategic Planning and Management of Biomedical Health Risks” of the Federal Medical Biological Agency (Center for Strategic Planning of FMBA of Russia), Moscow, 119121 Russian Federation
| | - P. U. Zemsky
- Federal State Budgetary Institution “Center for Strategic Planning and Management of Biomedical Health Risks” of the Federal Medical Biological Agency (Center for Strategic Planning of FMBA of Russia), Moscow, 119121 Russian Federation
| | - M. N. Pilipenko
- Federal State Budgetary Institution “Center for Strategic Planning and Management of Biomedical Health Risks” of the Federal Medical Biological Agency (Center for Strategic Planning of FMBA of Russia), Moscow, 119121 Russian Federation
| | - N. V. Feliz
- Federal State Budgetary Institution “Center for Strategic Planning and Management of Biomedical Health Risks” of the Federal Medical Biological Agency (Center for Strategic Planning of FMBA of Russia), Moscow, 119121 Russian Federation
| | - L. V. Frolova
- Federal State Budgetary Institution “Center for Strategic Planning and Management of Biomedical Health Risks” of the Federal Medical Biological Agency (Center for Strategic Planning of FMBA of Russia), Moscow, 119121 Russian Federation
| | - A. A. Frolovskaya
- Federal State Budgetary Institution “Center for Strategic Planning and Management of Biomedical Health Risks” of the Federal Medical Biological Agency (Center for Strategic Planning of FMBA of Russia), Moscow, 119121 Russian Federation
| | - V. S. Yudin
- Federal State Budgetary Institution “Center for Strategic Planning and Management of Biomedical Health Risks” of the Federal Medical Biological Agency (Center for Strategic Planning of FMBA of Russia), Moscow, 119121 Russian Federation
| | - A. A. Keskinov
- Federal State Budgetary Institution “Center for Strategic Planning and Management of Biomedical Health Risks” of the Federal Medical Biological Agency (Center for Strategic Planning of FMBA of Russia), Moscow, 119121 Russian Federation
| | - S. A. Kraevoy
- Federal State Budgetary Institution “Center for Strategic Planning and Management of Biomedical Health Risks” of the Federal Medical Biological Agency (Center for Strategic Planning of FMBA of Russia), Moscow, 119121 Russian Federation
| | - S. M. Yudin
- Federal State Budgetary Institution “Center for Strategic Planning and Management of Biomedical Health Risks” of the Federal Medical Biological Agency (Center for Strategic Planning of FMBA of Russia), Moscow, 119121 Russian Federation
| | - V. I. Skvortsova
- Federal Medical Biological Agency (FMBA of Russia), Moscow, 123182 Russian Federation
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Kelchtermans J, Hakonarson H. The role of gene-ambient air pollution interactions in paediatric asthma. Eur Respir Rev 2022; 31:220094. [PMID: 36384702 PMCID: PMC9724879 DOI: 10.1183/16000617.0094-2022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Accepted: 08/22/2022] [Indexed: 11/18/2022] Open
Abstract
Globally, asthma prevention and treatment remain a challenge. Ambient air pollution (AAP) is an environmental risk factor of special interest in asthma research. AAP is poorly defined and has been subdivided either by the origin of the air pollution or by the specific bioactive compounds. The link between AAP exposure and asthma exacerbations is well established and has been extensively reviewed. In this narrative review, we discuss the specific genetic variants that have been associated with increased AAP sensitivity and impact in paediatric asthma. We highlight the relative importance of variants associated with genes with a role in oxidant defences and the nuclear factor-κB pathway supporting a potential central role for these pathways in AAP sensitivity.
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Affiliation(s)
- Jelte Kelchtermans
- Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
- The Center of Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA
- Division of Pulmonary Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA, USA
| | - Hakon Hakonarson
- Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
- The Center of Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA
- Division of Pulmonary Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA, USA
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Next Generation Exome Sequencing of Pediatric Asthma Identifies Rare and Novel Variants in Candidate Genes. DISEASE MARKERS 2021; 2021:8884229. [PMID: 33628342 PMCID: PMC7888305 DOI: 10.1155/2021/8884229] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Download PDF] [Subscribe] [Scholar Register] [Received: 08/17/2020] [Revised: 01/21/2021] [Accepted: 02/03/2021] [Indexed: 12/16/2022]
Abstract
Multiple genes have been implicated to have a role in asthma predisposition by association studies. Pediatric patients often manifest a more extensive form of this disease and a particularly severe disease course. It is likely that genetic predisposition could play a more substantial role in this group. This study is aimed at identifying the spectrum of rare and novel variation in known pediatric asthma susceptibility genes using whole exome sequencing analysis in nine individual cases of childhood onset allergic asthma. DNA samples from the nine children with a history of bronchial asthma diagnosis underwent whole exome sequencing on Ion Proton. For each patient, the entire complement of rare variation within strongly associated candidate genes was catalogued. The analysis showed 21 variants in the subjects, 13 had been previously identified, and 8 were novel. Also, among of which, nineteen were nonsynonymous and 2 were nonsense. With regard to the novel variants, the 2 nonsynonymous variants in the PRKG1 gene (PRKG1: p.C519W and PRKG1: p.G520W) were presented in 4 cases, and a nonsynonymous variant in the MAVS gene (MAVS: p.A45V) was identified in 3 cases. The variants we found in this study will enrich the variant spectrum and build up the database in the Saudi population. Novel eight variants were identified in the study which provides more evidence in the genetic susceptibility in asthma among Saudi children, providing a genetic screening map for the molecular genetic determinants of allergic disease in Saudi children, with the goal of reducing the impact of chronic diseases on the health and the economy. We believe that the advanced specified statistical filtration/annotation programs used in this study succeeded to release such results in a preliminary study, exploring the genetic map of that disease in Saudi children.
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Helling BA, Sobreira DR, Hansen GT, Sakabe NJ, Luo K, Billstrand C, Laxman B, Nicolae RI, Nicolae DL, Bochkov YA, Gern JE, Nobrega MA, White SR, Ober C. Altered transcriptional and chromatin responses to rhinovirus in bronchial epithelial cells from adults with asthma. Commun Biol 2020; 3:678. [PMID: 33188283 PMCID: PMC7666152 DOI: 10.1038/s42003-020-01411-4] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2020] [Accepted: 10/21/2020] [Indexed: 12/20/2022] Open
Abstract
There is a life-long relationship between rhinovirus (RV) infection and the development and clinical manifestations of asthma. In this study we demonstrate that cultured primary bronchial epithelial cells from adults with asthma (n = 9) show different transcriptional and chromatin responses to RV infection compared to those without asthma (n = 9). Both the number and magnitude of transcriptional and chromatin responses to RV were muted in cells from asthma cases compared to controls. Pathway analysis of the transcriptionally responsive genes revealed enrichments of apoptotic pathways in controls but inflammatory pathways in asthma cases. Using promoter capture Hi-C we tethered regions of RV-responsive chromatin to RV-responsive genes and showed enrichment of these regions and genes at asthma GWAS loci. Taken together, our studies indicate a delayed or prolonged inflammatory state in cells from asthma cases and highlight genes that may contribute to genetic risk for asthma.
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Affiliation(s)
- Britney A Helling
- Department of Human Genetics, University of Chicago, Chicago, IL, 60637, USA.
| | - Débora R Sobreira
- Department of Human Genetics, University of Chicago, Chicago, IL, 60637, USA
| | - Grace T Hansen
- Department of Human Genetics, University of Chicago, Chicago, IL, 60637, USA
| | - Noboru J Sakabe
- Department of Human Genetics, University of Chicago, Chicago, IL, 60637, USA
| | - Kaixuan Luo
- Department of Human Genetics, University of Chicago, Chicago, IL, 60637, USA
| | | | - Bharathi Laxman
- Section of Pulmonary and Critical Care Medicine, Department of Medicine, University of Chicago, Chicago, IL, 60637, USA
| | - Raluca I Nicolae
- Department of Human Genetics, University of Chicago, Chicago, IL, 60637, USA
| | - Dan L Nicolae
- Department of Statistics, University of Chicago, Chicago, IL, 60637, USA
| | - Yury A Bochkov
- Department of Pediatrics, University of Wisconsin, School of Medicine and Public Health, Madison, WI, 53706, USA
| | - James E Gern
- Department of Pediatrics, University of Wisconsin, School of Medicine and Public Health, Madison, WI, 53706, USA
| | - Marcelo A Nobrega
- Department of Human Genetics, University of Chicago, Chicago, IL, 60637, USA
| | - Steven R White
- Section of Pulmonary and Critical Care Medicine, Department of Medicine, University of Chicago, Chicago, IL, 60637, USA
| | - Carole Ober
- Department of Human Genetics, University of Chicago, Chicago, IL, 60637, USA
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Fuertes E, van der Plaat DA, Minelli C. Antioxidant genes and susceptibility to air pollution for respiratory and cardiovascular health. Free Radic Biol Med 2020; 151:88-98. [PMID: 32007521 DOI: 10.1016/j.freeradbiomed.2020.01.181] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/29/2019] [Revised: 01/23/2020] [Accepted: 01/24/2020] [Indexed: 12/25/2022]
Abstract
Oxidative stress occurs when antioxidant defences, which are regulated by a complex network of genes, are insufficient to maintain the level of reactive oxygen species below a toxic threshold. Outdoor air pollution has long been known to adversely affect health and one prominent mechanism of action common to all pollutants is the induction of oxidative stress. An individual's susceptibility to the effects of air pollution partly depends on variation in their antioxidant genes. Thus, understanding antioxidant gene-pollution interactions has significant potential clinical and public health impacts, including the development of targeted and cost-effective preventive measures, such as setting appropriate standards which protect all members of the population. In this review, we aimed to summarize the latest epidemiological evidence on interactions between antioxidant genes and outdoor air pollution, in the context of respiratory and cardiovascular health. The evidence supporting the existence of interactions between antioxidant genes and outdoor air pollution is strongest for childhood asthma and wheeze, especially for interactions with GSTT1, GSTM1 and GSTP1, for lung function in both children and adults for several antioxidant genes (GSTT1, GSTM1, GSTP1, HMOX1, NQO1, and SOD2) and, to a more limited extent, for heart rate variability in adults for GSTM1 and HMOX1. Methodological challenges hampering a clear interpretation of these findings and understanding of true potential heterogeneity are discussed.
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Affiliation(s)
- Elaine Fuertes
- National Heart and Lung Institute, Imperial College London, London, United Kingdom.
| | | | - Cosetta Minelli
- National Heart and Lung Institute, Imperial College London, London, United Kingdom
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Thurston GD, Balmes JR, Garcia E, Gilliland FD, Rice MB, Schikowski T, Van Winkle LS, Annesi-Maesano I, Burchard EG, Carlsten C, Harkema JR, Khreis H, Kleeberger SR, Kodavanti UP, London SJ, McConnell R, Peden DB, Pinkerton KE, Reibman J, White CW. Outdoor Air Pollution and New-Onset Airway Disease. An Official American Thoracic Society Workshop Report. Ann Am Thorac Soc 2020; 17:387-398. [PMID: 32233861 PMCID: PMC7175976 DOI: 10.1513/annalsats.202001-046st] [Citation(s) in RCA: 125] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Although it is well accepted that air pollution exposure exacerbates preexisting airway disease, it has not been firmly established that long-term pollution exposure increases the risk of new-onset asthma or chronic obstruction pulmonary disease (COPD). This Workshop brought together experts on mechanistic, epidemiological, and clinical aspects of airway disease to review current knowledge regarding whether air pollution is a causal factor in the development of asthma and/or COPD. Speakers presented recent evidence in their respective areas of expertise related to air pollution and new airway disease incidence, followed by interactive discussions. A writing committee summarized their collective findings. The Epidemiology Group found that long-term exposure to air pollution, especially metrics of traffic-related air pollution such as nitrogen dioxide and black carbon, is associated with onset of childhood asthma. However, the evidence for a causal role in adult-onset asthma or COPD remains insufficient. The Mechanistic Group concluded that air pollution exposure can cause airway remodeling, which can lead to asthma or COPD, as well as asthma-like phenotypes that worsen with long-term exposure to air pollution, especially fine particulate matter and ozone. The Clinical Group concluded that air pollution is a plausible contributor to the onset of both asthma and COPD. Available evidence indicates that long-term exposure to air pollution is a cause of childhood asthma, but the evidence for a similar determination for adult asthma or COPD remains insufficient. Further research is needed to elucidate the exact biological mechanism underlying incident childhood asthma, and the specific air pollutant that causes it.
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Wang Q, Xu X, Cong X, Zeng Z, Xu L, Huo X. Interactions between polycyclic aromatic hydrocarbons and epoxide hydrolase 1 play roles in asthma. ENVIRONMENTAL GEOCHEMISTRY AND HEALTH 2019; 41:191-210. [PMID: 30293161 DOI: 10.1007/s10653-018-0201-1] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/30/2017] [Accepted: 09/29/2018] [Indexed: 02/05/2023]
Abstract
Asthma, as one of the most common chronic diseases in children and adults, is a consequence of complex gene-environment interactions. Polycyclic aromatic hydrocarbons (PAHs), as a group of widespread environmental organic pollutants, are involved in the development, triggering and pathologic changes of asthma. Various previous studies reported the critical roles of PAHs in immune changes, oxidative stress and environment-gene interactions of asthma. EPHX1 (the gene of epoxide hydrolase 1, an enzyme mediating human PAH metabolism) had a possible association with asthma by influencing PAH metabolism. This review summarized that (1) the roles of PAHs in asthma-work as risk factors; (2) the possible mechanisms involved in PAH-related asthma-through immunologic and oxidative stress changes; (3) the interactions between PAHs and EPHX1 involved in asthma-enzymatic activity of epoxide hydrolase 1, which affected by EPHX1 genotypes/SNPs/diplotypes, could influence human PAH metabolism and people's vulnerability to PAH exposure. This review provided a better understanding of the above interactions and underlying mechanisms for asthma which help to raise public's concern on PAH control and develop strategies for individual asthma primary prevention.
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Affiliation(s)
- Qihua Wang
- Laboratory of Environmental Medicine and Developmental Toxicology, and Provincial Key Laboratory of Infectious Diseases and Molecular Immunopathology, Shantou University Medical College, Shantou, Guangdong, China
| | - Xijin Xu
- Laboratory of Environmental Medicine and Developmental Toxicology, and Provincial Key Laboratory of Infectious Diseases and Molecular Immunopathology, Shantou University Medical College, Shantou, Guangdong, China
- Department of Cell Biology and Genetics, Shantou University Medical College, Shantou, Guangdong, China
| | - Xiaowei Cong
- Laboratory of Environmental Medicine and Developmental Toxicology, and Provincial Key Laboratory of Infectious Diseases and Molecular Immunopathology, Shantou University Medical College, Shantou, Guangdong, China
| | - Zhijun Zeng
- Laboratory of Environmental Medicine and Developmental Toxicology, and Provincial Key Laboratory of Infectious Diseases and Molecular Immunopathology, Shantou University Medical College, Shantou, Guangdong, China
| | - Long Xu
- Laboratory of Environmental Medicine and Developmental Toxicology, and Provincial Key Laboratory of Infectious Diseases and Molecular Immunopathology, Shantou University Medical College, Shantou, Guangdong, China
| | - Xia Huo
- Laboratory of Environmental Medicine and Developmental Toxicology, Guangdong Key Laboratory of Environmental Pollution and Health, School of Environment, Jinan University, 601 Huangpu Avenue West, Guangzhou, 510632, Guangdong, China.
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11
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Naidoo P, Naidoo RN, Ramkaran P, Asharam K, Chuturgoon AA. The Tyr113His T/C rs1051740 and 'very slow' phenotype of the EPHX1 gene alters miR-26b-5p and miR-1207-5p expression in pregnancy. Gene 2017; 633:71-81. [PMID: 28789952 DOI: 10.1016/j.gene.2017.07.080] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2017] [Revised: 06/29/2017] [Accepted: 07/31/2017] [Indexed: 12/11/2022]
Abstract
BACKGROUND Environmental insults and microsomal epoxide hydrolase 1 (EPHX1) single nucleotide polymorphisms (SNPs), Tyr113His T/C rs1051740 and His139Arg A/G rs2234922, aberrantly alters microRNA (miR) expression and are linked to low birthweights (LBW). OBJECTIVES To investigate the interplay between pollution, EPHX1 SNPs and miRs during pregnancy and associated LBW outcomes. METHODS South African pregnant women (n=241) were recruited in the MACE birth cohort study in Durban, a city with high levels of industry and traffic related pollutants. EPHX1 SNPs were genotyped using PCR-RFLP and grouped into their respective phenotypes, i.e. normal (N), slow (S), very slow (VS) and fast (F). EPHX1, miR-26b-5p, miR-193b-3p and miR-1207-5p expression were determined using quantitative PCR. RESULTS Mothers with the Tyr113His SNP had low iron levels [TT vs. TC+CC: mean difference (MD)=0.67g/dl; p=0.0167], LBW [TT vs. TC+CC: MD=189.30g; p=0.0067], and low EPHX1 expression; p<0.0001. miR-26b-5p and miR-1207-5p expression were significantly higher in the CC genotypes compared to TT+TC groups; p<0.0001. The opposite trend occurred for miR-193b-3p; p=0.0045. Mothers with the VS phenotype had low iron levels [N vs. VS and VS vs. F: MD=2.03 and -1.96g/dl; p=0.0021, respectively], decreased gestational age [VS vs. F: MD=-2.14weeks; p=0.0051, respectively], and LBW [N vs. VS, VS vs. F and S vs. VS: MD=1000, -940.30 and 968.80g; p<0.0001, respectively]; F phenotype had the highest EPHX1 expression [N vs. F, VS vs. F and S vs. F: MD=-1.067, -1.854 and -1.379; p=0.0002, respectively]; and N phenotype had low miR-26b-5p [N vs. VS: MD=-0.6100; p=0.0159] and miR-1207-5p [N vs. VS and VS vs. F: MD=-0.834 and 1.103; p=0.0007, respectively] expression. miR-193b-3p expression between phenotypes remained unchanged. CONCLUSION The Tyr113His T/C variant of rs1051740 and VS phenotype alters EPHX1, miR-26b-5p and miR-1207-5p expression, and contributes towards low blood iron levels and LBW.
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Affiliation(s)
- Pragalathan Naidoo
- Discipline of Medical Biochemistry and Chemical Pathology, Howard College Campus, University of KwaZulu-Natal, Durban, South Africa
| | - Rajen N Naidoo
- Discipline of Occupational and Environmental Health, University of KwaZulu-Natal, Durban, South Africa
| | - Prithiksha Ramkaran
- Discipline of Medical Biochemistry and Chemical Pathology, Howard College Campus, University of KwaZulu-Natal, Durban, South Africa
| | - Kareshma Asharam
- Discipline of Occupational and Environmental Health, University of KwaZulu-Natal, Durban, South Africa
| | - Anil A Chuturgoon
- Discipline of Medical Biochemistry and Chemical Pathology, Howard College Campus, University of KwaZulu-Natal, Durban, South Africa.
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12
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Edwards MR, Saglani S, Schwarze J, Skevaki C, Smith JA, Ainsworth B, Almond M, Andreakos E, Belvisi MG, Chung KF, Cookson W, Cullinan P, Hawrylowicz C, Lommatzsch M, Jackson D, Lutter R, Marsland B, Moffatt M, Thomas M, Virchow JC, Xanthou G, Edwards J, Walker S, Johnston SL. Addressing unmet needs in understanding asthma mechanisms: From the European Asthma Research and Innovation Partnership (EARIP) Work Package (WP)2 collaborators. Eur Respir J 2017; 49:49/5/1602448. [PMID: 28461300 DOI: 10.1183/13993003.02448-2016] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2016] [Accepted: 03/13/2017] [Indexed: 12/27/2022]
Abstract
Asthma is a heterogeneous, complex disease with clinical phenotypes that incorporate persistent symptoms and acute exacerbations. It affects many millions of Europeans throughout their education and working lives and puts a heavy cost on European productivity. There is a wide spectrum of disease severity and control. Therapeutic advances have been slow despite greater understanding of basic mechanisms and the lack of satisfactory preventative and disease modifying management for asthma constitutes a significant unmet clinical need. Preventing, treating and ultimately curing asthma requires co-ordinated research and innovation across Europe. The European Asthma Research and Innovation Partnership (EARIP) is an FP7-funded programme which has taken a co-ordinated and integrated approach to analysing the future of asthma research and development. This report aims to identify the mechanistic areas in which investment is required to bring about significant improvements in asthma outcomes.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | - Rene Lutter
- Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - Benjamin Marsland
- University of Lausanne, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland
| | | | | | | | - Georgina Xanthou
- Biomedical Research Foundation, Academy of Athens, Athens, Greece
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13
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Basharat Z, Yasmin A. Energy landscape of a GSTP1 polymorph linked with cytological function decay in response to chemical stressors. Gene 2017; 609:19-27. [PMID: 28153749 DOI: 10.1016/j.gene.2017.01.034] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2016] [Revised: 11/20/2016] [Accepted: 01/27/2017] [Indexed: 12/19/2022]
Abstract
Gene polymorphisms lead to varied structure and functional properties. A single nucleotide polymorphism (SNP) i.e. Ile105Val (rs1695) in glutathione S-transferase P1 (GSTP1) gene influences cytological toxicity and modulates the risk to occupational diseases. Apart from this, cancer, neuropathy, NOx, SOx and ozone mediated respiratory function decline including lung inflammation, asthma, allergy etc., have been reported in people with this missense mutation. Here, the functional properties of rs1695 polymorph are revisited through a computational approach. Changes incurred by GSTP1 antioxidant protein as a result of alteration in its sequence, have been studied through docking followed by Poisson-Boltzmann electrostatic equation interpretation, grid and coulombic energy profile mapping for protein polymorphs with DelPhi. Molecular docking simulation of variant and wild type (WT) protein was carried out with eight FDA approved compounds that target GSTP1 for treatment of various diseases. This was to observe binding pattern variation upon mutation induction. Grid, reaction field and coulombic energy calculation of WT and mutated polymorph, complexed with and without these moieties was then attempted. Alteration in conformation and energy was observed in apo- and holo- form of GSTP1 and their ligand-bound complexes as a result of this mutation. This study is a demo of appraising gene-environment interaction based deleteriousness through molecular docking and dynamics simulation approach.
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Affiliation(s)
- Zarrin Basharat
- Microbiology & Biotechnology Research Lab, Department of Environmental Sciences, Fatima Jinnah Women University, Rawalpindi 46000, Pakistan.
| | - Azra Yasmin
- Microbiology & Biotechnology Research Lab, Department of Environmental Sciences, Fatima Jinnah Women University, Rawalpindi 46000, Pakistan
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14
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An L, Lin Y, Yang T, Hua L. Exploring the interaction among EPHX1, GSTP1, SERPINE2, and TGFB1 contributing to the quantitative traits of chronic obstructive pulmonary disease in Chinese Han population. Hum Genomics 2016; 10:13. [PMID: 27193053 PMCID: PMC4870730 DOI: 10.1186/s40246-016-0076-0] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2016] [Accepted: 05/10/2016] [Indexed: 12/17/2022] Open
Abstract
Background Currently, the majority of genetic association studies on chronic obstructive pulmonary disease (COPD) risk focused on identifying the individual effects of single nucleotide polymorphisms (SNPs) as well as their interaction effects on the disease. However, conventional genetic studies often use binary disease status as the primary phenotype, but for COPD, many quantitative traits have the potential correlation with the disease status and closely reflect pathological changes. Method Here, we genotyped 44 SNPs from four genes (EPHX1, GSTP1, SERPINE2, and TGFB1) in 310 patients and 203 controls which belonged to the Chinese Han population to test the two-way and three-way genetic interactions with COPD-related quantitative traits using recently developed generalized multifactor dimensionality reduction (GMDR) and quantitative multifactor dimensionality reduction (QMDR) algorithms. Results Based on the 310 patients and the whole samples of 513 subjects, the best gene-gene interactions models were detected for four lung-function-related quantitative traits. For the forced expiratory volume in 1 s (FEV1), the best interaction was seen from EPHX1, SERPINE2, and GSTP1. For FEV1%pre, the forced vital capacity (FVC), and FEV1/FVC, the best interactions were seen from SERPINE2 and TGFB1. Conclusion The results of this study provide further evidence for the genotype combinations at risk of developing COPD in Chinese Han population and improve the understanding on the genetic etiology of COPD and COPD-related quantitative traits. Electronic supplementary material The online version of this article (doi:10.1186/s40246-016-0076-0) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Li An
- Beijing Key Laboratory of Respiratory and Pulmonary Circulation Disorders, Beijing Institute of Respiratory Medicine, Department of Respiratory and Critical Care Medicine, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, 100020, China
| | - Yingxiang Lin
- Beijing Key Laboratory of Respiratory and Pulmonary Circulation Disorders, Beijing Institute of Respiratory Medicine, Department of Respiratory and Critical Care Medicine, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, 100020, China
| | - Ting Yang
- Department of Respiratory and Critical Care Medicine, China-Japan Friendship Hospital, Beijing, 100029, China
| | - Lin Hua
- School of Biomedical Engineering, Capital Medical University, Beijing, 100069, China. .,Beijing Key Laboratory of Fundamental Research on Biomechanics in Clinical Application, School of Biomedical Engineering, Capital Medical University, Beijing, 100069, China.
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15
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Hua L, An L, Li L, Zhang Y, Wang C. A bioinformatics strategy for detecting the complexity of Chronic Obstructive Pulmonary Disease in Northern Chinese Han Population. Genes Genet Syst 2016; 87:197-209. [PMID: 22976395 DOI: 10.1266/ggs.87.197] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
Chronic Obstructive Pulmonary Disease (COPD) is a complex human disease which is driven not only by genetic factors, but also by various environmental variables, such as gender, age and smoking. Therefore, there is a demand for investigating the complexity among various risk factors involved in COPD. In this study, 44 tagging SNPs from EPHX1, GSTP1, SERPINE2 and TGFB1 were selected and genotyped in 310 COPD cases and 203 controls, all of which belong to the Han from North China. We integrated functional prediction algorithms of nonsynonymous SNPs (nsSNPs) into Bayesian network to explore the complex regulatory relationships among disease traits and various risk factors. The results showed that three basic variables (age, sex and smoking) were risk factors of COPD-related trait and phenotype. Besides these environmental risk factors, deleterious nsSNPs were found to perform better than those of significant synonymous SNPs when used as variables to make risk prediction of disease outcome. This study provides further evidences for detecting the complexity of COPD in Northern Chinese Han Population.
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Affiliation(s)
- Lin Hua
- Biomedical Engineering Institute of Capital Medical University, Beijing, China.
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16
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Do Variants in GSTs Modify the Association between Traffic Air Pollution and Asthma in Adolescence? Int J Mol Sci 2016; 17:485. [PMID: 27043549 PMCID: PMC4848941 DOI: 10.3390/ijms17040485] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2016] [Revised: 03/24/2016] [Accepted: 03/28/2016] [Indexed: 01/01/2023] Open
Abstract
Polymorphisms in genes involved in the oxidative stress response may partially explain the documented heterogeneous associations between traffic-related air pollution (TRAP) exposure and asthma and allergies in children. We investigated whether the GSTT1, GSTM1 and GSTP1 gene polymorphisms modified the associations between TRAP exposure during the first year of life and asthma, wheeze and hay fever in adolescence. We used a birth cohort of 620 high risk infants from the Melbourne Atopy Cohort Study. TRAP exposure during the first year of life was defined as the cumulative length of major roads within 150 m of each participant’s residence during the first year of life. Wheeze, asthma and hay fever were measured at ages 12 (n = 370) and 18 (n = 434) years. The associations and interactions with glutathione S-transferases (GST s) were investigated using regression models. Overall, there was no relationship between TRAP exposure during the first year of life and current asthma, wheeze and hay fever at ages 12 or 18 years. However, in GSTT1 null carriers, every 100 m increase in cumulative lengths of major road exposure during the first year of life was associated with a 2.31-fold increased risk of wheeze and a 2.15-fold increased risk of asthma at 12 years. TRAP is associated with some respiratory outcomes in carriers of genetic polymorphisms in oxidative stress metabolism genes.
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17
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Tsai CH, Su MW, Lee YL. Interactions between traffic air pollution and glutathione S-transferase genes on childhood asthma. World J Respirol 2016; 6:33-41. [DOI: 10.5320/wjr.v6.i1.33] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/24/2015] [Revised: 11/25/2015] [Accepted: 12/14/2015] [Indexed: 02/06/2023] Open
Abstract
AIM: To evaluate the role of glutathione S-transferase P1 (GSTP1) genetic polymorphisms potentially modifying the association between NO2 and asthma/wheeze in Taiwanese children.
METHODS: We investigated 3714 schoolchildren in Taiwan Children Health Study from 14 communities. Children’s information was measured from questionnaire by parents. The traffic air pollutant was available from Environmental Protection Administration monitoring stations.
RESULTS: A two-stage hierarchical model and a multiple logistic regression model were fitted to estimate the effects of NO2 exposures and GSTs polymorphisms on the prevalence of asthma and wheeze. Among children with GSTP1 Ile/Val or Val/Val genotypes, those residing in high-NO2 communities had significantly increased risks of asthma (OR = 1.76, 95%CI: 1.15-2.70), late-onset asthma (OR = 2.59, 95%CI: 1.24-5.41), active asthma (OR = 1.93, 95%CI: 1.05-3.57), asthma under medication (OR = 2.95, 95%CI: 1.37-6.32) and wheeze (OR = 1.54, 95%CI: 1.09-2.18) when compared with children in low-NO2 communities. Significant interactions were noted between ambient NO2 and GSTP1 on asthma, late-onset asthma, asthma under medication and wheeze (P for interaction < 0.05). However, we did not find any association with polymorphisms in GSTM1 and GSTT1.
CONCLUSION: Children under high traffic air pollution exposure are more susceptible to asthma, especially among those with GSTP1 Val allele.
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18
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Bailey LA, Nascarella MA, Kerper LE, Rhomberg LR. Hypothesis-based weight-of-evidence evaluation and risk assessment for naphthalene carcinogenesis. Crit Rev Toxicol 2015; 46:1-42. [PMID: 26202831 PMCID: PMC4732411 DOI: 10.3109/10408444.2015.1061477] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2015] [Accepted: 06/09/2015] [Indexed: 11/13/2022]
Abstract
Inhalation of naphthalene causes olfactory epithelial nasal tumors in rats (but not in mice) and benign lung adenomas in mice (but not in rats). The limited available human data have not identified an association between naphthalene exposure and increased respiratory cancer risk. Assessing naphthalene's carcinogenicity in humans, therefore, depends entirely on experimental evidence from rodents. We evaluated the respiratory carcinogenicity of naphthalene in rodents, and its potential relevance to humans, using our Hypothesis-Based Weight-of-Evidence (HBWoE) approach. We systematically and comparatively reviewed data relevant to key elements in the hypothesized modes of action (MoA) to determine which is best supported by the available data, allowing all of the data from each realm of investigation to inform interpretation of one another. Our analysis supports a mechanism that involves initial metabolism of naphthalene to the epoxide, followed by GSH depletion, cytotoxicity, chronic inflammation, regenerative hyperplasia, and tumor formation, with possible weak genotoxicity from downstream metabolites occurring only at high cytotoxic doses, strongly supporting a non-mutagenic threshold MoA in the rat nose. We also conducted a dose-response analysis, based on the likely MoA, which suggests that the rat nasal MoA is not relevant in human respiratory tissues at typical environmental exposures. Our analysis illustrates how a thorough WoE evaluation can be used to support a MoA, even when a mechanism of action cannot be fully elucidated. A non-mutagenic threshold MoA for naphthalene-induced rat nasal tumors should be considered as a basis to determine human relevance and to guide regulatory and risk-management decisions.
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19
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Gaffney A, Christiani DC. Gene-environment interaction from international cohorts: impact on development and evolution of occupational and environmental lung and airway disease. Semin Respir Crit Care Med 2015; 36:347-57. [PMID: 26024343 DOI: 10.1055/s-0035-1549450] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Abstract
Environmental and occupational pulmonary diseases impose a substantial burden of morbidity and mortality on the global population. However, it has been long observed that only some of those who are exposed to pulmonary toxicants go on to develop disease; increasingly, it is being recognized that genetic differences may underlie some of this person-to-person variability. Studies performed throughout the globe are demonstrating important gene-environment interactions for diseases as diverse as chronic beryllium disease, coal workers' pneumoconiosis, silicosis, asbestosis, byssinosis, occupational asthma, and pollution-associated asthma. These findings have, in many instances, elucidated the pathogenesis of these highly complex diseases. At the same time, however, translation of this research into clinical practice has, for good reasons, proceeded slowly. No genetic test has yet emerged with sufficiently robust operating characteristics to be clearly useful or practicable in an occupational or environmental setting. In addition, occupational genetic testing raises serious ethical and policy concerns. Therefore, the primary objective must remain ensuring that the workplace and the environment are safe for all.
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Affiliation(s)
- Adam Gaffney
- Pulmonary and Critical Care Division, Department of Medicine, Massachusetts General Hospital/Harvard Medical School, Boston, Massachusetts
| | - David C Christiani
- Pulmonary and Critical Care Division, Department of Medicine, Massachusetts General Hospital/Harvard Medical School, Boston, Massachusetts
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20
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Padula AM, Balmes JR, Eisen EA, Mann J, Noth EM, Lurmann FW, Pratt B, Tager IB, Nadeau K, Hammond SK. Ambient polycyclic aromatic hydrocarbons and pulmonary function in children. JOURNAL OF EXPOSURE SCIENCE & ENVIRONMENTAL EPIDEMIOLOGY 2015; 25:295-302. [PMID: 24938508 PMCID: PMC4270934 DOI: 10.1038/jes.2014.42] [Citation(s) in RCA: 47] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/02/2013] [Accepted: 04/14/2014] [Indexed: 05/17/2023]
Abstract
Few studies have examined the relationship between ambient polycyclic aromatic hydrocarbons (PAHs) and pulmonary function in children. Major sources include vehicular emissions, home heating, wildland fires, agricultural burning, and power plants. PAHs are an important component of fine particulate matter that has been linked to respiratory health. This cross-sectional study examines the relationship between estimated individual exposures to the sum of PAHs with 4, 5, or 6 rings (PAH456) and pulmonary function tests (forced expiratory volume in one second (FEV1) and forced expiratory flow between 25% and 75% of vital capacity) in asthmatic and non-asthmatic children. We applied land-use regression to estimate individual exposures to ambient PAHs for averaging periods ranging from 1 week to 1 year. We used linear regression to estimate the relationship between exposure to PAH456 with pre- and postbronchodilator pulmonary function tests in children in Fresno, California (N=297). Among non-asthmatics, there was a statistically significant association between PAH456 during the previous 3 months, 6 months, and 1 year and postbronchodilator FEV1. The magnitude of the association increased with the length of the averaging period ranging from 60 to 110 ml decrease in FEV1 for each 1 ng/m(3) increase in PAH456. There were no associations with PAH456 observed among asthmatic children. We identified an association between annual PAHs and chronic pulmonary function in children without asthma. Additional studies are needed to further explore the association between exposure to PAHs and pulmonary function, especially with regard to differential effects between asthmatic and non-asthmatic children.
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Affiliation(s)
- Amy M. Padula
- Department of Pediatrics – Neonatology, School of Medicine, Stanford University, Stanford, CA, USA
| | - John R. Balmes
- Division of Environmental Health Sciences, School of Public Health, University of California, Berkeley, Berkeley, CA, USA
- Department of Medicine, University of California, San Francisco, San Francisco, CA, USA
| | - Ellen A. Eisen
- Division of Environmental Health Sciences, School of Public Health, University of California, Berkeley, Berkeley, CA, USA
| | - Jennifer Mann
- Division of Environmental Health Sciences, School of Public Health, University of California, Berkeley, Berkeley, CA, USA
| | - Elizabeth M. Noth
- Division of Environmental Health Sciences, School of Public Health, University of California, Berkeley, Berkeley, CA, USA
| | | | - Boriana Pratt
- Division of Environmental Health Sciences, School of Public Health, University of California, Berkeley, Berkeley, CA, USA
| | - Ira B. Tager
- Division of Environmental Health Sciences, School of Public Health, University of California, Berkeley, Berkeley, CA, USA
| | - Kari Nadeau
- Department of Pediatrics – Neonatology, School of Medicine, Stanford University, Stanford, CA, USA
| | - S. Katharine Hammond
- Division of Environmental Health Sciences, School of Public Health, University of California, Berkeley, Berkeley, CA, USA
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21
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Padula AM, Balmes JR, Eisen EA, Mann J, Noth EM, Lurmann FW, Pratt B, Tager IB, Nadeau K, Hammond SK. Ambient polycyclic aromatic hydrocarbons and pulmonary function in children. JOURNAL OF EXPOSURE SCIENCE & ENVIRONMENTAL EPIDEMIOLOGY 2015. [PMID: 24938508 DOI: 10.1038/jes.2014.42.ambient] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Subscribe] [Scholar Register] [Indexed: 05/04/2023]
Abstract
Few studies have examined the relationship between ambient polycyclic aromatic hydrocarbons (PAHs) and pulmonary function in children. Major sources include vehicular emissions, home heating, wildland fires, agricultural burning, and power plants. PAHs are an important component of fine particulate matter that has been linked to respiratory health. This cross-sectional study examines the relationship between estimated individual exposures to the sum of PAHs with 4, 5, or 6 rings (PAH456) and pulmonary function tests (forced expiratory volume in one second (FEV1) and forced expiratory flow between 25% and 75% of vital capacity) in asthmatic and non-asthmatic children. We applied land-use regression to estimate individual exposures to ambient PAHs for averaging periods ranging from 1 week to 1 year. We used linear regression to estimate the relationship between exposure to PAH456 with pre- and postbronchodilator pulmonary function tests in children in Fresno, California (N=297). Among non-asthmatics, there was a statistically significant association between PAH456 during the previous 3 months, 6 months, and 1 year and postbronchodilator FEV1. The magnitude of the association increased with the length of the averaging period ranging from 60 to 110 ml decrease in FEV1 for each 1 ng/m(3) increase in PAH456. There were no associations with PAH456 observed among asthmatic children. We identified an association between annual PAHs and chronic pulmonary function in children without asthma. Additional studies are needed to further explore the association between exposure to PAHs and pulmonary function, especially with regard to differential effects between asthmatic and non-asthmatic children.
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Affiliation(s)
- Amy M Padula
- Department of Pediatrics - Neonatology, School of Medicine, Stanford University, Stanford, CA, USA
| | - John R Balmes
- 1] Division of Environmental Health Sciences, School of Public Health, University of California, Berkeley, Berkeley, CA, USA [2] Department of Medicine, University of California, San Francisco, San Francisco, CA, USA
| | - Ellen A Eisen
- Division of Environmental Health Sciences, School of Public Health, University of California, Berkeley, Berkeley, CA, USA
| | - Jennifer Mann
- Division of Environmental Health Sciences, School of Public Health, University of California, Berkeley, Berkeley, CA, USA
| | - Elizabeth M Noth
- Division of Environmental Health Sciences, School of Public Health, University of California, Berkeley, Berkeley, CA, USA
| | | | - Boriana Pratt
- Division of Environmental Health Sciences, School of Public Health, University of California, Berkeley, Berkeley, CA, USA
| | - Ira B Tager
- Division of Environmental Health Sciences, School of Public Health, University of California, Berkeley, Berkeley, CA, USA
| | - Kari Nadeau
- Department of Pediatrics - Neonatology, School of Medicine, Stanford University, Stanford, CA, USA
| | - S Katharine Hammond
- Division of Environmental Health Sciences, School of Public Health, University of California, Berkeley, Berkeley, CA, USA
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22
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Chen Z, Salam MT, Eckel SP, Breton CV, Gilliland FD. Chronic effects of air pollution on respiratory health in Southern California children: findings from the Southern California Children's Health Study. J Thorac Dis 2015; 7:46-58. [PMID: 25694817 DOI: 10.3978/j.issn.2072-1439.2014.12.20] [Citation(s) in RCA: 52] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2014] [Accepted: 11/20/2014] [Indexed: 01/05/2023]
Abstract
Outdoor air pollution is one of the leading contributors to adverse respiratory health outcomes in urban areas around the world. Children are highly sensitive to the adverse effects of air pollution due to their rapidly growing lungs, incomplete immune and metabolic functions, patterns of ventilation and high levels of outdoor activity. The Children's Health Study (CHS) is a continuing series of longitudinal studies that first began in 1993 and has focused on demonstrating the chronic impacts of air pollution on respiratory illnesses from early childhood through adolescence. A large body of evidence from the CHS has documented that exposures to both regional ambient air and traffic-related pollutants are associated with increased asthma prevalence, new-onset asthma, risk of bronchitis and wheezing, deficits of lung function growth, and airway inflammation. These associations may be modulated by key genes involved in oxidative-nitrosative stress pathways via gene-environment interactions. Despite successful efforts to reduce pollution over the past 40 years, air pollution at the current levels still brings many challenges to public health. To further ameliorate adverse health effects attributable to air pollution, many more toxic pollutants may require regulation and control of motor vehicle emissions and other combustion sources may need to be strengthened. Individual interventions based on personal susceptibility may be needed to protect children's health while control measures are being implemented.
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Affiliation(s)
- Zhanghua Chen
- 1 Department of Preventive Medicine, Division of Environmental Health, 2 Department of Preventive Medicine, Division of Biostatistics, Keck School of Medicine, University of Southern California, Los Angeles, CA 90032, USA
| | - Muhammad T Salam
- 1 Department of Preventive Medicine, Division of Environmental Health, 2 Department of Preventive Medicine, Division of Biostatistics, Keck School of Medicine, University of Southern California, Los Angeles, CA 90032, USA
| | - Sandrah P Eckel
- 1 Department of Preventive Medicine, Division of Environmental Health, 2 Department of Preventive Medicine, Division of Biostatistics, Keck School of Medicine, University of Southern California, Los Angeles, CA 90032, USA
| | - Carrie V Breton
- 1 Department of Preventive Medicine, Division of Environmental Health, 2 Department of Preventive Medicine, Division of Biostatistics, Keck School of Medicine, University of Southern California, Los Angeles, CA 90032, USA
| | - Frank D Gilliland
- 1 Department of Preventive Medicine, Division of Environmental Health, 2 Department of Preventive Medicine, Division of Biostatistics, Keck School of Medicine, University of Southern California, Los Angeles, CA 90032, USA
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Polonikov AV, Ivanov VP, Bogomazov AD, Freidin MB, Illig T, Solodilova MA. Antioxidant defense enzyme genes and asthma susceptibility: gender-specific effects and heterogeneity in gene-gene interactions between pathogenetic variants of the disease. BIOMED RESEARCH INTERNATIONAL 2014; 2014:708903. [PMID: 24895604 PMCID: PMC4026955 DOI: 10.1155/2014/708903] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/23/2014] [Revised: 04/05/2014] [Accepted: 04/07/2014] [Indexed: 12/15/2022]
Abstract
Oxidative stress resulting from an increased amount of reactive oxygen species and an imbalance between oxidants and antioxidants plays an important role in the pathogenesis of asthma. The present study tested the hypothesis that genetic susceptibility to allergic and nonallergic variants of asthma is determined by complex interactions between genes encoding antioxidant defense enzymes (ADE). We carried out a comprehensive analysis of the associations between adult asthma and 46 single nucleotide polymorphisms of 34 ADE genes and 12 other candidate genes of asthma in Russian population using set association analysis and multifactor dimensionality reduction approaches. We found for the first time epistatic interactions between ADE genes underlying asthma susceptibility and the genetic heterogeneity between allergic and nonallergic variants of the disease. We identified GSR (glutathione reductase) and PON2 (paraoxonase 2) as novel candidate genes for asthma susceptibility. We observed gender-specific effects of ADE genes on the risk of asthma. The results of the study demonstrate complexity and diversity of interactions between genes involved in oxidative stress underlying susceptibility to allergic and nonallergic asthma.
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Affiliation(s)
- Alexey V. Polonikov
- Department of Biology, Medical Genetics and Ecology, Kursk State Medical University, 3 Karl Marx Street, Kursk 305041, Russia
| | - Vladimir P. Ivanov
- Department of Biology, Medical Genetics and Ecology, Kursk State Medical University, 3 Karl Marx Street, Kursk 305041, Russia
| | - Alexey D. Bogomazov
- Department of Pediatrics, Kursk State Medical University, 11a Koltsov Street, Kursk 305035, Russia
| | - Maxim B. Freidin
- Research Institute for Medical Genetics, Siberian Branch of Russian Academy of Medical Sciences, 10 Nabereznaya Ushaiki Tomsk 634050, Russia
| | - Thomas Illig
- Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Ingolstädter Landstraße 1, 85764 Neuherberg, Germany
- Hanover Unified Biobank, Hanover Medical School, Carl-Neuberg-Strasse 1, 30625 Hanover, Germany
| | - Maria A. Solodilova
- Department of Biology, Medical Genetics and Ecology, Kursk State Medical University, 3 Karl Marx Street, Kursk 305041, Russia
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MacIntyre EA, Brauer M, Melén E, Bauer CP, Bauer M, Berdel D, Bergström A, Brunekreef B, Chan-Yeung M, Klümper C, Fuertes E, Gehring U, Gref A, Heinrich J, Herbarth O, Kerkhof M, Koppelman GH, Kozyrskyj AL, Pershagen G, Postma DS, Thiering E, Tiesler CMT, Carlsten C. GSTP1 and TNF Gene variants and associations between air pollution and incident childhood asthma: the traffic, asthma and genetics (TAG) study. ENVIRONMENTAL HEALTH PERSPECTIVES 2014; 122:418-24. [PMID: 24465030 PMCID: PMC3984232 DOI: 10.1289/ehp.1307459] [Citation(s) in RCA: 50] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/02/2013] [Accepted: 01/24/2014] [Indexed: 05/09/2023]
Abstract
BACKGROUND Genetics may partially explain observed heterogeneity in associations between traffic-related air pollution and incident asthma. OBJECTIVE Our aim was to investigate the impact of gene variants associated with oxidative stress and inflammation on associations between air pollution and incident childhood asthma. METHODS Traffic-related air pollution, asthma, wheeze, gene variant, and potential confounder data were pooled across six birth cohorts. Parents reported physician-diagnosed asthma and wheeze from birth to 7-8 years of age (confirmed by pediatric allergist in two cohorts). Individual estimates of annual average air pollution [nitrogen dioxide (NO2), particulate matter ≤ 2.5 μm (PM2.5), PM2.5 absorbance, ozone] were assigned to each child's birth address using land use regression, atmospheric modeling, and ambient monitoring data. Effect modification by variants in GSTP1 (rs1138272/Ala114Val and rs1695/IIe105Val) and TNF (rs1800629/G-308A) was investigated. RESULTS Data on asthma, wheeze, potential confounders, at least one SNP of interest, and NO2 were available for 5,115 children. GSTP1 rs1138272 and TNF rs1800629 SNPs were associated with asthma and wheeze, respectively. In relation to air pollution exposure, children with one or more GSTP1 rs1138272 minor allele were at increased risk of current asthma [odds ratio (OR) = 2.59; 95% CI: 1.43, 4.68 per 10 μg/m3 NO2] and ever asthma (OR = 1.64; 95% CI: 1.06, 2.53) compared with homozygous major allele carriers (OR = 0.95; 95% CI: 0.68, 1.32 for current and OR = 1.20; 95% CI: 0.98, 1.48 for ever asthma; Bonferroni-corrected interaction p = 0.04 and 0.01, respectively). Similarly, for GSTP1 rs1695, associations between NO2 and current and ever asthma had ORs of 1.43 (95% CI: 1.03, 1.98) and 1.36 (95% CI: 1.08, 1.70), respectively, for minor allele carriers compared with ORs of 0.82 (95% CI: 0.52, 1.32) and 1.12 (95% CI: 0.84, 1.49) for homozygous major allele carriers (Bonferroni-corrected interaction p-values 0.48 and 0.09). There were no clear differences by TNF genotype. CONCLUSIONS Children carrying GSTP1 rs1138272 or rs1695 minor alleles may constitute a susceptible population at increased risk of asthma associated with air pollution.
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Affiliation(s)
- Elaina A MacIntyre
- School of Population and Public Health, University of British Columbia, Vancouver, British Columbia, Canada
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25
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Damera G, Panettieri RA. Irreversible airway obstruction in asthma: what we lose, we lose early. Allergy Asthma Proc 2014; 35:111-8. [PMID: 24717787 DOI: 10.2500/aap.2013.34.3724] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Asthma, a syndrome manifested by airway inflammation and obstruction, globally contributes significantly to morbidity and mortality. Although current evidence identifies risk factors that evoke asthma, critical questions concerning susceptibility factors that induce severe persistent disease remain unclear. Early onset of asthma decreases lung function that may be unrecognized until later in adulthood when patients experience dyspnea on exertion and attenuated quality of life. This review highlights current evidence in predicting the onset of asthma and identifying those patients at greatest risk for severe persistent disease.
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Affiliation(s)
- Gautam Damera
- Translational Medicine, Respiratory, Inflammation, and Autoimmunity Group, MedImmune, LLC, Gaithersburg, Maryland, USA
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26
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El Rifai N, Moustafa N, Degheidy N, Wilson M. Glutathione S transferase theta1 and mu1 gene polymorphisms and phenotypic expression of asthma in Egyptian children: a case-control study. Ital J Pediatr 2014; 40:22. [PMID: 24559168 PMCID: PMC3974057 DOI: 10.1186/1824-7288-40-22] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/06/2013] [Accepted: 02/19/2014] [Indexed: 02/07/2023] Open
Abstract
Background Asthma is the result of a complex interaction between environmental factors and genetic variants that confer susceptibility. The glutathione S-transferases (GSTT1 and GSTM1) are phase II enzymes thought to protect the airways from oxidative stress. Few and contradictory data are available on the association between asthma development and GSTT1 and GSTM1 polymorphisms in different ethnic groups. The current study aimed to investigate whether these polymorphisms are associated with asthma development in the Egyptian population. Methods The cross-sectional study was performed on 94 asthmatic children 6 -12 yrs and 90 matched healthy controls. Candidates were subjected to clinical evaluation and measurement of absolute blood eosinophilic count, total serum IgE, and GSTT1 and GSTM1 genotype by multiplex PCR technique. Results The results for GSTT1 null genotype were 87.2% and 97.2% for asthmatic children and controls respectively and showed to be significantly more in controls (P =0.007, OR:0.683, CI: 0.034 -0.715). The results for GSTM1 null genotype were 50% and 61.1% for asthmatic children and controls respectively and showed to be nonsignificant (p = 0.130, OR: 1.000, CI: 0.54- 1.86). Also, no association was detected between GSTT1 and GSTM1 polymorphisms and atopic conditions or asthma severity. Conclusion The significant detection of GSTT1 null genotype more in controls than in asthmatics with no association with other atopic manifestations or asthma severity and the lack of association detected between GSTM1 polymorphism in relation to asthma, atopy or asthma severity confirm the uncertain role of those genes in the development of asthma.
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Affiliation(s)
- Nihal El Rifai
- Department of Pediatrics, Faculty of Medicine, Cairo University, Giza, Egypt.
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27
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Ghosh R, Topinka J, Joad JP, Dostal M, Sram RJ, Hertz-Picciotto I. Air pollutants, genes and early childhood acute bronchitis. Mutat Res 2013; 749:80-6. [DOI: 10.1016/j.mrfmmm.2013.04.001] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2013] [Revised: 04/08/2013] [Accepted: 04/09/2013] [Indexed: 04/10/2023]
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Lee SY, Chang YS, Cho SH. Allergic diseases and air pollution. Asia Pac Allergy 2013; 3:145-54. [PMID: 23956961 PMCID: PMC3736369 DOI: 10.5415/apallergy.2013.3.3.145] [Citation(s) in RCA: 44] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2013] [Accepted: 07/15/2013] [Indexed: 12/12/2022] Open
Abstract
The prevalence of allergic diseases has been increasing rapidly, especially in developing countries. Various adverse health outcomes such as allergic disease can be attributed to rapidly increasing air pollution levels. Rapid urbanization and increased energy consumption worldwide have exposed the human body to not only increased quantities of ambient air pollution, but also a greater variety of pollutants. Many studies clearly demonstrate that air pollutants potently trigger asthma exacerbation. Evidence that transportation-related pollutants contribute to the development of allergies is also emerging. Moreover, exposure to particulate matter, ozone, and nitrogen dioxide contributes to the increased susceptibility to respiratory infections. This article focuses on the current understanding of the detrimental effects of air pollutants on allergic disease including exacerbation to the development of asthma, allergic rhinitis, and eczema as well as epigenetic regulation.
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Affiliation(s)
- Suh-Young Lee
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul 110-799, Korea. ; Institute of Allergy and Clinical Immunology, Seoul National University Medical Research Center, Seoul 110-799, Korea
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MacIntyre EA, Carlsten C, MacNutt M, Fuertes E, Melén E, Tiesler CMT, Gehring U, Krämer U, Klümper C, Kerkhof M, Chan-Yeung M, Kozyrskyj AL, Berdel D, Bauer CP, Herbarth O, Bauer M, Schaaf B, Koletzko S, Pershagen G, Brunekreef B, Heinrich J, Brauer M. Traffic, asthma and genetics: combining international birth cohort data to examine genetics as a mediator of traffic-related air pollution's impact on childhood asthma. Eur J Epidemiol 2013; 28:597-606. [PMID: 23880893 DOI: 10.1007/s10654-013-9828-5] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2012] [Accepted: 07/10/2013] [Indexed: 11/26/2022]
Abstract
Associations between traffic-related air pollution and incident childhood asthma can be strengthened by analysis of gene-environment interactions, but studies have typically been limited by lack of study power. We combined data from six birth cohorts on: asthma, eczema and allergic rhinitis to 7/8 years, and candidate genes. Individual-level assessment of traffic-related air pollution exposure was estimated using land use regression or dispersion modeling. A total of 11,760 children were included in the Traffic, Asthma and Genetics (TAG) Study; 6.3 % reported physician-diagnosed asthma at school-age, 16.0 % had asthma at anytime during childhood, 14.1 % had allergic rhinitis at school-age, 10.0 % had eczema at school-age and 33.1 % were sensitized to any allergen. For GSTP1 rs1138272, the prevalence of heterozygosity was 16 % (range amongst individual cohorts, 11-17 %) and homozygosity for the minor allele was 1 % (0-2 %). For GSTP1 rs1695, the prevalence of heterozygosity was 45 % (40-48 %) and homozygosity for the minor allele, 12 % (10-12 %). For TNF rs1800629, the prevalence of heterozygosity was 29 % (25-32 %) and homozygosity for the minor allele, 3 % (1-3 %). TAG comprises a rich database, the largest of its kind, for investigating the effect of genotype on the association between air pollution and childhood allergic disease.
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Affiliation(s)
- Elaina A MacIntyre
- School of Population and Public Health, University of British Columbia, 2206 East Mall, Vancouver, BC, V6T1Z3, Canada
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30
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Affiliation(s)
- Diane R Gold
- Channing Laboratory, Brigham and Women's Hospital, Department of Medicine, Harvard Medical School, 181 Longwood Ave, Boston MA 02115, USA.
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31
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Ma J, Strub P, Lavori PW, Buist AS, Camargo CA, Nadeau KC, Wilson SR, Xiao L. DASH for asthma: a pilot study of the DASH diet in not-well-controlled adult asthma. Contemp Clin Trials 2013; 35:55-67. [PMID: 23648395 PMCID: PMC4217513 DOI: 10.1016/j.cct.2013.04.008] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2013] [Revised: 04/24/2013] [Accepted: 04/26/2013] [Indexed: 01/03/2023]
Abstract
This pilot study aims to provide effect size confidence intervals, clinical trial and intervention feasibility data, and procedural materials for a full-scale randomized controlled trial that will determine the efficacy of Dietary Approaches to Stop Hypertension (DASH) as adjunct therapy to standard care for adults with uncontrolled asthma. The DASH diet encompasses foods (e.g., fresh fruit, vegetables, and nuts) and antioxidant nutrients (e.g., vitamins A, C, E, and zinc) with potential benefits for persons with asthma, but it is unknown whether the whole diet is beneficial. Participants (n = 90) will be randomized to receive usual care alone or combined with a DASH intervention consisting of 8 group and 3 individual sessions during the first 3 months, followed by at least monthly phone consultations for another 3 months. Follow-up assessments will occur at 3 and 6 months. The primary outcome measure is the 7-item Juniper Asthma Control Questionnaire, a validated composite measure of daytime and nocturnal symptoms, activity limitations, rescue medication use, and percentage predicted forced expiratory volume in 1 second. We will explore changes in inflammatory markers important to asthma pathophysiology (e.g., fractional exhaled nitric oxide) and their potential to mediate the intervention effect on disease control. We will also conduct pre-specified subgroup analyses by genotype (e.g., polymorphisms on the glutathione S transferase gene) and phenotype (e.g., atopy, obesity). By evaluating a dietary pattern approach to improving asthma control, this study could advance the evidence base for refining clinical guidelines and public health recommendations regarding the role of dietary modifications in asthma management.
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Affiliation(s)
- Jun Ma
- Department of Health Services Research, Palo Alto Medical Foundation Research Institute, Palo Alto, CA, USA.
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Persistent recurring wheezing in the fifth year of life after laboratory-confirmed, medically attended respiratory syncytial virus infection in infancy. BMC Pediatr 2013; 13:97. [PMID: 23782528 PMCID: PMC3703269 DOI: 10.1186/1471-2431-13-97] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2013] [Accepted: 06/13/2013] [Indexed: 11/26/2022] Open
Abstract
Background Respiratory syncytial virus (RSV) infection in infancy is associated with subsequent recurrent wheezing. Methods A retrospective cohort study examined children born at ≥32 weeks gestation between 1996–2004. All children were enrolled in an integrated health care delivery system in Northern California and were followed through the fifth year of life. The primary endpoint was recurrent wheezing in the fifth year of life and its association with laboratory-confirmed, medically-attended RSV infection during the first year, prematurity, and supplemental oxygen during birth hospitalization. Other outcomes measured were recurrent wheezing quantified through outpatient visits, inpatient hospital stays, and asthma prescriptions. Results The study sample included 72,602 children. The rate of recurrent wheezing in the second year was 5.6% and fell to 4.7% by the fifth year. Recurrent wheezing rates varied by risk status: the rate was 12.5% among infants with RSV hospitalization, 8% among infants 32–33 weeks gestation, and 18% in infants with bronchopulmonary dysplasia. In multivariate analyses, increasing severity of respiratory syncytial virus infection was significantly associated with recurrent wheezing in year 5; compared with children without RSV infection in infancy, children who only had an outpatient RSV encounter had an adjusted odds ratio of 1.38 (95% CI,1.03–1.85), while children with a prolonged RSV hospitalization had an adjusted odds ratio of 2.59 (95% CI, 1.49–4.50). Conclusions Laboratory-confirmed, medically attended RSV infection, prematurity, and neonatal exposure to supplemental oxygen have independent associations with development of recurrent wheezing in the fifth year of life.
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Fuertes E, Brauer M, MacIntyre E, Bauer M, Bellander T, von Berg A, Berdel D, Brunekreef B, Chan-Yeung M, Gehring U, Herbarth O, Hoffmann B, Kerkhof M, Klümper C, Koletzko S, Kozyrskyj A, Kull I, Heinrich J, Melén E, Pershagen G, Postma D, Tiesler CMT, Carlsten C. Childhood allergic rhinitis, traffic-related air pollution, and variability in the GSTP1, TNF, TLR2, and TLR4 genes: results from the TAG Study. J Allergy Clin Immunol 2013; 132:342-52.e2. [PMID: 23639307 DOI: 10.1016/j.jaci.2013.03.007] [Citation(s) in RCA: 59] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2012] [Revised: 02/05/2013] [Accepted: 03/06/2013] [Indexed: 12/25/2022]
Abstract
BACKGROUND Associations between traffic-related air pollution (TRAP) and allergic rhinitis remain inconsistent, possibly because of unexplored gene-environment interactions. OBJECTIVE In a pooled analysis of 6 birth cohorts (Ntotal = 15,299), we examined whether TRAP and genetic polymorphisms related to inflammation and oxidative stress predict allergic rhinitis and sensitization. METHODS Allergic rhinitis was defined with a doctor diagnosis or reported symptoms at age 7 or 8 years. Associations between nitrogen dioxide, particulate matter 2.5 (PM2.5) mass, PM2.5 absorbance, and ozone, estimated for each child at the year of birth, and single nucleotide polymorphisms within the GSTP1, TNF, TLR2, or TLR4 genes with allergic rhinitis and aeroallergen sensitization were examined with logistic regression. Models were stratified by genotype and interaction terms tested for gene-environment associations. RESULTS Point estimates for associations between nitrogen dioxide, PM2.5 mass, and PM2.5 absorbance with allergic rhinitis were elevated, but only that for PM2.5 mass was statistically significant (1.37 [1.01, 1.86] per 5 μg/m(3)). This result was not robust to single-cohort exclusions. Carriers of at least 1 minor rs1800629 (TNF) or rs1927911 (TLR4) allele were consistently at an increased risk of developing allergic rhinitis (1.19 [1.00, 1.41] and 1.24 [1.01, 1.53], respectively), regardless of TRAP exposure. No evidence of gene-environment interactions was observed. CONCLUSION The generally null effect of TRAP on allergic rhinitis and aeroallergen sensitization was not modified by the studied variants in the GSTP1, TNF, TLR2, or TLR4 genes. Children carrying a minor rs1800629 (TNF) or rs1927911 (TLR4) allele may be at a higher risk of allergic rhinitis.
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Affiliation(s)
- Elaine Fuertes
- School of Population and Public Health, University of British Columbia, Vancouver, British Columbia, Canada
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Plé C, Chang Y, Wallaert B, Tsicopoulos A. [Environmental pollution and allergy: immunological mechanisms]. REVUE DE PNEUMOLOGIE CLINIQUE 2013; 69:18-25. [PMID: 23333049 DOI: 10.1016/j.pneumo.2012.11.007] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/01/2012] [Accepted: 11/06/2012] [Indexed: 06/01/2023]
Abstract
Airborne pollutants, both particulate and gaseous, represent a major environmental factor promoting allergic sensitization and disease expression. These adverse effects of particulate matter are highly dependent upon the nature and size of the particles, their content of chemicals and metals, and the subject's genetic makeup. Diesel exhaust and gases, in particular ozone, have been shown to exacerbate cellular inflammation and to act as mucosal adjuvants to skew the immune response to inhaled antigens toward a Th2-like phenotype. Growing evidence suggests that mechanisms of pollutant-induced amplification of the allergic reaction depend on oxidative stress that is under the control of susceptibility genes, as well as epigenetic mechanisms.
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Affiliation(s)
- C Plé
- Inserm U1019, CNRS UMR 8204, pulmonary immunity, center for infection and immunity of Lille, institut Pasteur de Lille, université Lille Nord de France, 1, rue du Prof.-Calmette, BP 245, 59019 Lille, France
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Li R, Conti DV, Diaz-Sanchez D, Gilliland F, Thomas DC. Joint analysis for integrating two related studies of different data types and different study designs using hierarchical modeling approaches. Hum Hered 2013; 74:83-96. [PMID: 23343600 DOI: 10.1159/000345181] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2012] [Accepted: 10/17/2012] [Indexed: 01/07/2023] Open
Abstract
BACKGROUND A chronic disease such as asthma is the result of a complex sequence of biological interactions involving multiple genes and pathways in response to a multitude of environmental exposures. However, methods to model jointly all factors are still evolving. Some of the current challenges include how to integrate knowledge from different data types and different disciplines, as well as how to utilize relevant external information such as gene annotation to identify novel disease genes and gene-environment inter-actions. METHODS Using a Bayesian hierarchical modeling framework, we developed two alternative methods for joint analysis of an epidemiologic study of a disease endpoint and an experimental study of intermediate phenotypes, while incorporating external information. RESULTS Our simulation studies demonstrated superior performance of the proposed hierarchical models compared to separate analysis with the standard single-level regression modeling approach. The combined analyses of the Southern California Children's Health Study and challenge study data suggest that these joint analytical methods detected more significant genetic main and gene-environment interaction effects than the conventional analysis. CONCLUSION The proposed prior framework is very flexible and can be generalized for an integrative analysis of diverse sources of relevant biological data.
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Affiliation(s)
- Rui Li
- Division of Biostatistics, Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA
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Piacentini S, Polimanti R, Simonelli I, Donno S, Pasqualetti P, Manfellotto D, Fuciarelli M. Glutathione S-transferase polymorphisms, asthma susceptibility and confounding variables: a meta-analysis. Mol Biol Rep 2013; 40:3299-313. [PMID: 23307299 DOI: 10.1007/s11033-012-2405-2] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2012] [Accepted: 12/18/2012] [Indexed: 11/28/2022]
Abstract
Oxidative stress is one of the main risk factors for asthma development. Glutathione S-transferases play an important role in antioxidant defences and may influence asthma susceptibility. In particular, GSTM1 and GSTT1 positive/null genotypes and the GSTP1 Ile105 Val polymorphism have been analyzed in a number of genetic association studies, with conflicting outcomes. Two previous meta-analyses have attempted to clarify the associations between GST genes and asthma, but these studies have also showed contrasting results. Our aim was to perform a meta-analysis that included independent genetic association studies on GSTM1, GSTP1, and GSTT1, evaluating also the effect of potential confounding variables (i.e. ethnicity, population age, and urbanization). Systematic review and meta-analysis of the effects of GST genes on asthma were conducted. The meta-analyses were performed using a fixed or, where appropriate, random effects model. The meta-analysis of the GSTM1 (n = 35), GSTT1 (n = 31) and GSTP1 (n = 28) studies suggests that no significant associations with asthma susceptibility were observed for GSTM1 and GSTP1 gene polymorphisms, whereas a significant outcome was detected for the GSTT1 positive/null genotype (pooled OR = 1.33, 95 %CI = 1.10-1.60). However, high between-study heterogeneity was identified in all the general analyses (p heterogenetity < 0.05). The stratification analysis seems to explain the heterogeneity only in few cases. This picture is probably due to the interactive process of genetics and environment that characterizes disease pathogenesis. Further studies on interactions of GST genes with the potential oxidative stress sources and with other antioxidant genes are needed to explain the role of GST enzymes in asthma.
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Affiliation(s)
- Sara Piacentini
- Department of Biology, University of Rome "Tor Vergata", Via della Ricerca Scientifica 1, 00133 Rome, Italy
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Herbert C, Siegle JS, Shadie AM, Nikolaysen S, Garthwaite L, Hansbro NG, Foster PS, Kumar RK. Development of asthmatic inflammation in mice following early-life exposure to ambient environmental particulates and chronic allergen challenge. Dis Model Mech 2012; 6:479-88. [PMID: 23223614 PMCID: PMC3597029 DOI: 10.1242/dmm.010728] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Childhood exposure to environmental particulates increases the risk of development of asthma. The underlying mechanisms might include oxidant injury to airway epithelial cells (AEC). We investigated the ability of ambient environmental particulates to contribute to sensitization via the airways, and thus to the pathogenesis of childhood asthma. To do so, we devised a novel model in which weanling BALB/c mice were exposed to both ambient particulate pollutants and ovalbumin for sensitization via the respiratory tract, followed by chronic inhalational challenge with a low mass concentration of the antigen. We also examined whether these particulates caused oxidant injury and activation of AEC in vitro. Furthermore, we assessed the potential benefit of minimizing oxidative stress to AEC through the period of sensitization and challenge by dietary intervention. We found that characteristic features of asthmatic inflammation developed only in animals that received particulates at the same time as respiratory sensitization, and were then chronically challenged with allergen. However, these animals did not develop airway hyper-responsiveness. Ambient particulates induced epithelial injury in vitro, with evidence of oxidative stress and production of both pro-inflammatory cytokines and Th2-promoting cytokines such as IL-33. Treatment of AEC with an antioxidant in vitro inhibited the pro-inflammatory cytokine response to these particulates. Ambient particulates also induced pro-inflammatory cytokine expression following administration to weanling mice. However, early-life dietary supplementation with antioxidants did not prevent the development of an asthmatic inflammatory response in animals that were exposed to particulates, sensitized and challenged. We conclude that injury to airway epithelium by ambient environmental particulates in early life is capable of promoting the development of an asthmatic inflammatory response in sensitized and antigen-challenged mice. These findings are likely to be relevant to the induction of childhood asthma.
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Affiliation(s)
- Cristan Herbert
- Inflammation and Infection Research Centre, School of Medical Sciences, University of New South Wales, Sydney, 2052, Australia
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Bauer M, Gräbsch C, Schlink U, Klopp N, Illig T, Krämer U, von Berg A, Schaaf B, Borte M, Heinrich J, Herbarth O, Lehmann I, Röder S. Genetic association between obstructive bronchitis and enzymes of oxidative stress. Metabolism 2012; 61:1771-9. [PMID: 22738861 DOI: 10.1016/j.metabol.2012.05.013] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2012] [Accepted: 05/22/2012] [Indexed: 11/30/2022]
Abstract
OBJECTIVE Obstructive respiratory diseases, mainly the chronic obstructive pulmonary disease (COPD) and asthma, are associated with functional polymorphisms of xenobiotic-metabolizing enzymes (XMEs). To date, association for obstructive bronchitis has not been described. MATERIAL/METHODS In this study, we investigated the genotypes from 26 functional polymorphisms of 20 XMEs in children (n, 1028) at the age of 6 years from the German prospective birth cohort study (LISAplus) and analyzed the associations between genotypes and obstructive bronchitis. RESULTS For the first time, we found noteworthy gene-disease associations for the functional PON1 M55L and EPHX1 H139R polymorphisms and gene-environment associations for the functional COMT V158M and NQO1 P187S polymorphisms after stratification for maternal active smoking behaviour during pregnancy. The noteworthy associations were substantiated by the biological findings that all the risk genotypes belong to genes involved in oxidative stress and code for proteins with a fast enzymatic activity or concomitantly appear in common estrogene-metabolizing pathway (COMT, NQO1). CONCLUSION The oxidative stress has to be taken into account in mechanism of the obstructive bronchitis in early childhood. The risk genotypes may serve as risk factors for respiratory obstruction rather than for signs of COPD or asthma.
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Affiliation(s)
- Mario Bauer
- UFZ-Helmholtz Centre for Environmental Research, Department of Environmental Immunology, Leipzig, Germany.
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Perez L, Lurmann F, Wilson J, Pastor M, Brandt SJ, Künzli N, McConnell R. Near-roadway pollution and childhood asthma: implications for developing "win-win" compact urban development and clean vehicle strategies. ENVIRONMENTAL HEALTH PERSPECTIVES 2012; 120:1619-26. [PMID: 23008270 PMCID: PMC3556611 DOI: 10.1289/ehp.1104785] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/25/2011] [Accepted: 09/05/2012] [Indexed: 05/05/2023]
Abstract
BACKGROUND The emerging consensus that exposure to near-roadway traffic-related pollution causes asthma has implications for compact urban development policies designed to reduce driving and greenhouse gases. OBJECTIVES We estimated the current burden of childhood asthma-related disease attributable to near-roadway and regional air pollution in Los Angeles County (LAC) and the potential health impact of regional pollution reduction associated with changes in population along major traffic corridors. METHODS The burden of asthma attributable to the dual effects of near-roadway and regional air pollution was estimated, using nitrogen dioxide and ozone as markers of urban combustion-related and secondary oxidant pollution, respectively. We also estimated the impact of alternative scenarios that assumed a 20% reduction in regional pollution in combination with a 3.6% reduction or 3.6% increase in the proportion of the total population living near major roads, a proxy for near-roadway exposure. RESULTS We estimated that 27,100 cases of childhood asthma (8% of total) in LAC were at least partly attributable to pollution associated with residential location within 75 m of a major road. As a result, a substantial proportion of asthma-related morbidity is a consequence of near-roadway pollution, even if symptoms are triggered by other factors. Benefits resulting from a 20% regional pollution reduction varied markedly depending on the associated change in near-roadway proximity. CONCLUSIONS Our findings suggest that there are large and previously unappreciated public health consequences of air pollution in LAC and probably in other metropolitan areas with dense traffic corridors. To maximize health benefits, compact urban development strategies should be coupled with policies to reduce near-roadway pollution exposure.
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Affiliation(s)
- Laura Perez
- Swiss Tropical and Public Health Institute, Basel, Switzerland
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40
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Zhao Y, Liu S, Liu Z, Ye Y, Mao M. Significant association between GSTT1 null genotype and risk of asthma during childhood in Caucasians. Mol Biol Rep 2012; 40:1973-8. [PMID: 23076538 DOI: 10.1007/s11033-012-2254-z] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2012] [Accepted: 10/10/2012] [Indexed: 12/21/2022]
Abstract
Asthma is a complex multifactorial disorder and its management requires a better understanding of its various pathogenesis and mechanisms. Previous studies assessing the association between glutathione S-transferase T1 (GSTT1) null genotype and asthma risk during childhood reported conflicting results. To get a more precise estimation of the association between GSTT1 null genotype and risk of asthma during childhood, we performed a meta-analysis of 16 studies with a total of 18,558 subjects. Subgroup analyses were performed by ethnicity. The pooled odds ratio (OR) with corresponding 95 % confidence interval (95 %CI) was used to assess the association. Overall, there was a significant association between GSTT1 null genotype and increased risk of children asthma (OR = 1.25, 95 % CI, 1.02-1.54; P = 0.032). Subgroup analyses showed GSTT1 null genotype was associated with increased risk of children asthma in Caucasians (OR = 1.46, 95 % CI, 1.04-2.03; P = 0.027), but not in Asians (OR = 1.03, 95 % CI, 0.55-1.94; P = 0.928) and Africans (OR = 1.33, 95 % CI, 0.92-1.91; P = 0.127). There was no evidence of publication bias in the subgroup analysis of Caucasians. In conclusion, there is a significant association between GSTT1 null genotype and risk of asthma during childhood in Caucasians. More well-designed epidemiological studies are needed to further assess this association in Asians and Africans.
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Affiliation(s)
- Yongmei Zhao
- Department of Paediatrics, West China Second University Hospital, Sichuan University, Chengdu, 610100, Sichuan, China.
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Wu W, Peden D, Diaz-Sanchez D. Role of GSTM1 in resistance to lung inflammation. Free Radic Biol Med 2012; 53:721-9. [PMID: 22683820 PMCID: PMC3418458 DOI: 10.1016/j.freeradbiomed.2012.05.037] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2012] [Revised: 05/18/2012] [Accepted: 05/23/2012] [Indexed: 01/04/2023]
Abstract
Lung inflammation resulting from oxidant/antioxidant imbalance is a common feature of many lung diseases. In particular, the role of enzymes regulated by the NF-E2-related factor 2 transcription factor has recently received increased attention. Among these antioxidant genes, glutathione S-transferase Mu 1 (GSTM1) has been most extensively characterized because it has a null polymorphism that is highly prevalent in the population and associated with increased risk of inflammatory lung diseases. Present evidence suggests that GSTM1 acts through interactions with other genes and environmental factors, especially air pollutants. Here, we review GSTM1 gene expression and regulation and summarize the findings from epidemiological, clinical, animal, and in vitro studies on the role played by GSTM1 in lung inflammation. We discuss limitations in the existing knowledge base and future perspectives and evaluate the potential of pharmacologic and genetic manipulation of the GSTM1 gene to modulate pulmonary inflammatory responses.
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Affiliation(s)
- Weidong Wu
- Department of Pediatrics, Center for Environmental Medicine, Asthma, and Lung Biology, University of North Carolina, Chapel Hill, NC 7599, USA.
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Holloway JW, Savarimuthu Francis S, Fong KM, Yang IA. Genomics and the respiratory effects of air pollution exposure. Respirology 2012; 17:590-600. [PMID: 22404320 DOI: 10.1111/j.1440-1843.2012.02164.x] [Citation(s) in RCA: 58] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Adverse health effects from air pollutants remain important, despite improvement in air quality in the past few decades. The exact mechanisms of lung injury from exposure to air pollutants are not yet fully understood. Studying the genome (e.g. single-nucleotide polymorphisms (SNP) ), epigenome (e.g. methylation of genes), transcriptome (mRNA expression) and microRNAome (microRNA expression) has the potential to improve our understanding of the adverse effects of air pollutants. Genome-wide association studies of SNP have detected SNP associated with respiratory phenotypes; however, to date, only candidate gene studies of air pollution exposure have been performed. Changes in epigenetic processes, such DNA methylation that leads to gene silencing without altering the DNA sequence, occur with air pollutant exposure, especially global and gene-specific methylation changes. Respiratory cell line and animal models demonstrate distinct gene expression signatures in the transcriptome, arising from exposure to particulate matter or ozone. Particulate matter and other environmental toxins alter expression of microRNA, which are short non-coding RNA that regulate gene expression. While it is clearly important to contain rising levels of air pollution, strategies also need to be developed to minimize the damaging effects of air pollutant exposure on the lung, especially for patients with chronic lung disease and for people at risk of future lung disease. Careful study of genomic responses will improve our understanding of mechanisms of lung injury from air pollution and enable future clinical testing of interventions against the toxic effects of air pollutants.
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Affiliation(s)
- John W Holloway
- Human Development and Health, University of Southampton, Southampton, UK.
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Ji H, Khurana Hershey GK. Genetic and epigenetic influence on the response to environmental particulate matter. J Allergy Clin Immunol 2012; 129:33-41. [PMID: 22196522 DOI: 10.1016/j.jaci.2011.11.008] [Citation(s) in RCA: 68] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2011] [Revised: 11/09/2011] [Accepted: 11/10/2011] [Indexed: 12/29/2022]
Abstract
Ambient air pollution, including particulate matter (PM) and gaseous pollutants, represents important environmental exposures that adversely affect human health. Because of their heritable and reversible nature, epigenetic modifications provide a plausible link between the environment and alterations in gene expression that might lead to disease. Epidemiologic evidence supports that environmental exposures in childhood affect susceptibility to disease later in life, supporting the belief that epigenetic changes can affect ongoing development and promote disease long after the environmental exposure has ceased. Indeed, allergic disorders often have their roots in early childhood, and early exposure to PM has been strongly associated with the subsequent development of asthma. The purpose of this review is to summarize recent findings on the genetic and epigenetic regulation of responses to ambient air pollutants, specifically respirable PM, and their association with the development of allergic disorders. Understanding these epigenetic biomarkers and how they integrate with genetic influences to translate the biologic effect of particulate exposure is critical to developing novel preventative and therapeutic strategies for allergic disorders.
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Affiliation(s)
- Hong Ji
- Division of Asthma Research, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
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Gale SL, Noth EM, Mann J, Balmes J, Hammond SK, Tager IB. Polycyclic aromatic hydrocarbon exposure and wheeze in a cohort of children with asthma in Fresno, CA. JOURNAL OF EXPOSURE SCIENCE & ENVIRONMENTAL EPIDEMIOLOGY 2012; 22:386-92. [PMID: 22549720 PMCID: PMC4219412 DOI: 10.1038/jes.2012.29] [Citation(s) in RCA: 68] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/08/2011] [Accepted: 03/19/2012] [Indexed: 05/17/2023]
Abstract
Polycyclic aromatic hydrocarbons (PAHs) are found widely in the ambient air and result from combustion of various fuels and industrial processes. PAHs have been associated with adverse human health effects such as cognitive development, childhood IQ, and respiratory health. The Fresno Asthmatic Children's Environment Study enrolled 315 children aged 6-11 years with asthma in Fresno, CA and followed the cohort from 2000 to 2008. Subjects were evaluated for asthma symptoms in up to three 14-day panels per year. Detailed ambient pollutant concentrations were collected from a central site and outdoor pollutants were measured at 83 homes for at least one 5-day period. Measurements of particle-bound PAHs were used with land-use regression models to estimate individual exposures to PAHs with 4-, 5-, or 6-member rings (PAH456) and phenanthrene for the cohort (approximately 22,000 individual daily estimates). We used a cross-validation-based algorithm for model fitting and a generalized estimated equation approach to account for repeated measures. Multiple lags and moving averages of PAH exposure were associated with increased wheeze for each of the three types of PAH exposure estimates. The odds ratios for asthmatics exposed to PAHs (ng/m(3)) ranged from 1.01 (95% CI, 1.00-1.02) to 1.10 (95% CI, 1.04-1.17). This trend for increased wheeze persisted among all PAHs measured. Phenanthrene was found to have a higher relative impact on wheeze. These data provide further evidence that PAHs contribute to asthma morbidity.
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Affiliation(s)
- Sara L Gale
- Division of Epidemiology, University of California, Berkeley, CA, USA.
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O’Neill MS, Breton CV, Devlin RB, Utell MJ. Air pollution and health: emerging information on susceptible populations. AIR QUALITY, ATMOSPHERE, & HEALTH 2012; 5:189-201. [PMID: 25741389 PMCID: PMC4345419 DOI: 10.1007/s11869-011-0150-7] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/18/2023]
Abstract
Outdoor air pollution poses risks to human health in communities around the world, and research on populations who are most susceptible continues to reveal new insights. Human susceptibility to adverse health effects from exposure to air pollution can be related to underlying disease; demographic or anthropometric characteristics; genetic profile; race and ethnicity; lifestyle, behaviors, and socioeconomic position; and location of residence or daily activities. In health research, an individual or group may have an enhanced responsiveness to a given, identical level of pollution exposure compared to those who are less susceptible. Or, people in these different groups may experience varying levels of exposure (for example, a theoretically homogeneous population whose members differ only by proximity to a road). Often the information available for health research may relate to both exposure and enhanced response to a given dose of pollution. This paper discusses the general direction of research on susceptibility to air pollution, with a general though not an exclusive focus on particulate matter, with specific examples of research on susceptibility related to cardiovascular disease, diabetes, asthma, and genetic and epigenetic features. We conclude by commenting how emerging knowledge of susceptibility can inform policy for controlling pollution sources and exposures to yield maximal health benefit and discuss two areas of emerging interest: studying air pollution and its connection to perinatal health, as well as land use and urban infrastructure design.
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Affiliation(s)
- Marie S. O’Neill
- School of Public Health, University of Michigan, 6631 SPH Tower, 109 South Observatory, Ann Arbor, MI 48109-2029, USA
| | - Carrie V. Breton
- Department of Preventive Medicine, Keck School of Medicine, University of Southern California, 1540 Alcazar St. CHP 236, Los Angeles, CA 90033, USA
| | - Robert B. Devlin
- Clinical Research Branch, Environmental Public Health Division, U.S. Environmental Protection Agency, 104 Mason Farm Road, Chapel Hill, NC 27599-7315, USA
| | - Mark J. Utell
- Department of Medicine, University of Rochester Medical Center, Box EHSC, 575 Elmwood Avenue, Rochester, NY 14642, USA. Department of Environmental Medicine, University of Rochester Medical Center, Box EHSC, 575 Elmwood Avenue, Rochester, NY 14642, USA
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Yucesoy B, Johnson VJ, Lummus ZL, Kissling GE, Fluharty K, Gautrin D, Malo JL, Cartier A, Boulet LP, Sastre J, Quirce S, Germolec DR, Tarlo SM, Cruz MJ, Munoz X, Luster MI, Bernstein DI. Genetic variants in antioxidant genes are associated with diisocyanate-induced asthma. Toxicol Sci 2012; 129:166-73. [PMID: 22610343 DOI: 10.1093/toxsci/kfs183] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Diisocyanates are a common cause of occupational asthma, but risk factors are not well defined. A case-control study was conducted to investigate whether genetic variants of antioxidant defense genes, glutathione S-transferases (GSTM1, GSTT1, GSTM3, GSTP1), manganese superoxide dismutase (SOD2), and microsomal epoxide hydrolase (EPHX1) are associated with increased susceptibility to diisocyanate-induced asthma (DA). The main study population consisted of 353 Caucasian French-Canadians from among a larger sample of 410 diisocyanate-exposed workers in three groups: workers with specific inhalation challenge (SIC) confirmed DA (DA(+), n = 95); symptomatic diisocyanate workers with a negative SIC (DA(-), n = 116); and asymptomatic exposed workers (AW, n = 142). Genotyping was performed on genomic DNA, using a 5'-nuclease PCR assay. The SOD2 rs4880, GSTP1 rs1695, and EPHX1 rs2740171 variants were significantly associated with DA in both univariate and multivariate analyses. In the first logistic regression model comparing DA(+) and DA(-) groups, SOD2 rs4880, GSTM1 (null), GSTP1 rs762803, and EPHX1 rs2854450 variants were associated with DA (p = 0.004, p = 0.047, p = 0.021, p <0.001, respectively). Genotype combinations GSTT1*GSTP1 rs762803, GSTM1*EPHX1 rs2854450, EPHX1 rs2740168*EPHX1 rs1051741, and GSTP1 rs762803*EPHX1 rs2740168 were also associated with DA in this model (p = 0.027, p = 0.002, p = 0.045, p = 0.044, respectively). The GSTP1 rs1695 and EPHX1 rs1051741 and rs2740171 variants showed an association with DA in the second model comparing DA(+) and AW groups (p = 0.040, p = 0.019, p = 0.002, respectively). The GSTM3 rs110913*EPHX1 rs1051741 genotype combination was also associated with DA under this model (p = 0.042). The results suggest that variations in SOD2, GST, and EPHX1 genes and their interactions contribute to DA susceptibility.
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Affiliation(s)
- Berran Yucesoy
- CDC/National Institute for Occupational Safety and Health, Health Effects Laboratory Division, Morgantown, West Virginia 26505, USA.
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Gene-gene and gene-environmental interactions of childhood asthma: a multifactor dimension reduction approach. PLoS One 2012; 7:e30694. [PMID: 22355322 PMCID: PMC3280263 DOI: 10.1371/journal.pone.0030694] [Citation(s) in RCA: 50] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2011] [Accepted: 12/22/2011] [Indexed: 01/24/2023] Open
Abstract
Background The importance of gene-gene and gene-environment interactions on asthma is well documented in literature, but a systematic analysis on the interaction between various genetic and environmental factors is still lacking. Methodology/Principal Findings We conducted a population-based, case-control study comprised of seventh-grade children from 14 Taiwanese communities. A total of 235 asthmatic cases and 1,310 non-asthmatic controls were selected for DNA collection and genotyping. We examined the gene-gene and gene-environment interactions between 17 single-nucleotide polymorphisms in antioxidative, inflammatory and obesity-related genes, and childhood asthma. Environmental exposures and disease status were obtained from parental questionnaires. The model-free and non-parametrical multifactor dimensionality reduction (MDR) method was used for the analysis. A three-way gene-gene interaction was elucidated between the gene coding glutathione S-transferase P (GSTP1), the gene coding interleukin-4 receptor alpha chain (IL4Ra) and the gene coding insulin induced gene 2 (INSIG2) on the risk of lifetime asthma. The testing-balanced accuracy on asthma was 57.83% with a cross-validation consistency of 10 out of 10. The interaction of preterm birth and indoor dampness had the highest training-balanced accuracy at 59.09%. Indoor dampness also interacted with many genes, including IL13, beta-2 adrenergic receptor (ADRB2), signal transducer and activator of transcription 6 (STAT6). We also used likelihood ratio tests for interaction and chi-square tests to validate our results and all tests showed statistical significance. Conclusions/Significance The results of this study suggest that GSTP1, INSIG2 and IL4Ra may influence the lifetime asthma susceptibility through gene-gene interactions in schoolchildren. Home dampness combined with each one of the genes STAT6, IL13 and ADRB2 could raise the asthma risk.
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Malling TH, Sigsgaard T, Brasch-Andersen C, Frischknecht L, Andersen HR, Kruse TA, Sherson D, Skadhauge LR, Thomsen G, Baelum J, Omland Ø. Genetic polymorphisms in antioxidative enzymes are associated to forced expiratory volume in 1 s (FEV1) in smokers independently of asthma. THE CLINICAL RESPIRATORY JOURNAL 2012; 6:46-55. [PMID: 21595856 DOI: 10.1111/j.1752-699x.2011.00245.x] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
INTRODUCTION In this study, we hypothesised that the genotypes coding for low antioxidative enzyme activity are associated with asthma and reduced lung function. METHODS Using the European Community Respiratory Health Survey protocol, we enlisted 1091 Danish subjects in this cross-sectional study. Asthma phenotypes were defined as asthma symptoms in combination with steroid usage, bronchial hyperresponsiveness and atopy. These phenotypes and lung function were analysed with respect to glutathione peroxidase, GPX1 (Pro198Leu, rs1050450), manganese superoxide dismutase, SOD2 (Ala16Val, rs4880) and three glutathione S-transferases; GSTP1 (Ile105Val, rs1695), GSTT1 (gene copy number) and GSTM1 (gene copy number). RESULTS We found no associations between these genotypes and the asthma phenotypes. For the 201 subjects identified as current smokers and recruited via random sampling, an association was seen between increasing number of genotypes coding for high antioxidative enzyme activity (GPX1 Pro/Pro, SOD2 Val/Val, GSTP1 Ile/Ile, GSTT1 two copies, GSTM1 two copies) and forced expiratory volume in 1 s (FEV1%) predicted. The increase in FEV1% predicted was 2.0% (95% confidence interval 0.3-3.8) per genotype. There was no identified significance for the inverse association between FEV1% predicted and number of genotypes coding for low antioxidative enzyme activity. CONCLUSION The present study does not support the hypothesis that asthma is associated with genotypes of these major antioxidative enzymes. However, we speculate that since we see an impact of these genotypes on lung function in young adult smokers, polymorphisms in antioxidative enzymes may contribute to the range of susceptibility of smokers have to Chronic obstructive lung disease.
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Islam T, Urman R, Gauderman WJ, Milam J, Lurmann F, Shankardass K, Avol E, Gilliland F, McConnell R. Parental stress increases the detrimental effect of traffic exposure on children's lung function. Am J Respir Crit Care Med 2011; 184:822-7. [PMID: 21700914 DOI: 10.1164/rccm.201104-0720oc] [Citation(s) in RCA: 68] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
RATIONALE Emerging evidence indicates that psychosocial stress enhances the effect of traffic exposure on the development of asthma. OBJECTIVES We hypothesized that psychosocial stress would also modify the effect of traffic exposure on lung function deficits. METHODS We studied 1,399 participants in the Southern California Children's Health Study undergoing lung function testing (mean age, 11.2 yr). We used hierarchical mixed models to assess the joint effect of traffic-related air pollution and stress on lung function. MEASUREMENTS AND MAIN RESULTS Psychosocial stress in each child's household was assessed based on parental response to the perceived stress scale (range, 0-16) at study entry. Exposures to nitric oxide, nitrogen dioxide, and total oxides of nitrogen (NOx), surrogates of the traffic-related pollution mixture, were estimated at schools and residences based on a land-use regression model. Among children from high-stress households (parental perceived stress scale > 4) deficits in FEV1 of 4.5 (95% confidence interval, -6.5 to -2.4) and of 2.8% (-5.7 to 0.3) were associated with each 21.8 ppb increase in NOx at homes and schools, respectively. These pollutant effects were significantly larger in the high-stress compared with lower-stress households (interaction P value 0.007 and 0.05 for residential and school NOx, respectively). No significant NOx effects were observed in children from low-stress households. A similar pattern of association was observed for FVC. The observed associations for FEV1 and FVC remained after adjusting for sociodemographic factors and after restricting the analysis to children who do not have asthma. CONCLUSIONS A high-stress home environment is associated with increased susceptibility to lung function effects of air pollution both at home and at school.
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Affiliation(s)
- Talat Islam
- Department of Preventive Medicine, Keck School of Medicine, Los Angeles, CA 90033, USA.
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50
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Kumar RK, Siegle JS, Kaiko GE, Herbert C, Mattes JE, Foster PS. Responses of airway epithelium to environmental injury: role in the induction phase of childhood asthma. J Allergy (Cairo) 2011; 2011:257017. [PMID: 22574070 PMCID: PMC3206385 DOI: 10.1155/2011/257017] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2011] [Accepted: 08/26/2011] [Indexed: 12/21/2022] Open
Abstract
The pathogenesis of allergic asthma in childhood remains poorly understood. Environmental factors which appear to contribute to allergic sensitisation, with development of a Th2-biased immunological response in genetically predisposed individuals, include wheezing lower respiratory viral infections in early life and exposure to airborne environmental pollutants. These may activate pattern recognition receptors and/or cause oxidant injury to airway epithelial cells (AECs). In turn, this may promote Th2 polarisation via a "final common pathway" involving interaction between AEC, dendritic cells, and CD4+ T lymphocytes. Potentially important cytokines produced by AEC include thymic stromal lymphopoietin and interleukin-25. Their role is supported by in vitro studies using human AEC, as well as by experiments in animal models. To date, however, few investigations have employed models of the induction phase of childhood asthma. Further research may help to identify interventions that could reduce the risk of allergic asthma.
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Affiliation(s)
- Rakesh K. Kumar
- Inflammation and Infection Research Centre, School of Medial Sciences, University of New South Wales, Sydney, NSW 2052, Australia
| | - Jessica S. Siegle
- Inflammation and Infection Research Centre, School of Medial Sciences, University of New South Wales, Sydney, NSW 2052, Australia
| | - Gerard E. Kaiko
- Centre for Asthma and Respiratory Disease, School of Biomedical Sciences, University of Newcastle and Hunter Medical Research Institute, Callaghan, NSW 2300, Australia
| | - Cristan Herbert
- Inflammation and Infection Research Centre, School of Medial Sciences, University of New South Wales, Sydney, NSW 2052, Australia
| | - Joerg E. Mattes
- Centre for Asthma and Respiratory Disease, School of Biomedical Sciences, University of Newcastle and Hunter Medical Research Institute, Callaghan, NSW 2300, Australia
| | - Paul S. Foster
- Centre for Asthma and Respiratory Disease, School of Biomedical Sciences, University of Newcastle and Hunter Medical Research Institute, Callaghan, NSW 2300, Australia
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