Journal of Community Genetics

, Volume 3, Issue 1, pp 25–33 | Cite as

Relationship between air pollution, NFE2L2 gene polymorphisms and childhood asthma in a Hungarian population

  • Ildikó Ungvári
  • Éva Hadadi
  • Viktor Virág
  • Adrienne Nagy
  • András Kiss
  • Ágnes Kalmár
  • Györgyi Zsigmond
  • Ágnes F. Semsei
  • András Falus
  • Csaba Szalai
Original Article

Abstract

Air pollution and subsequent increased oxidative stress have long been recognized as contributing factors for asthma phenotypes. Individual susceptibility to oxidative stress is determined by genetic variations of the antioxidant defence system. In this study, we analysed the association between environmental nitrogen dioxide (NO2) exposure and single nucleotide polymorphisms (SNP) in NFE2L2 and KEAP1 genes and their common impact on asthma risk. We genotyped 12 SNPs in a case–control study of 307 patients diagnosed with asthma and 344 controls. NO2 concentration was collected from the period preceding the development of asthma symptoms. Multiple logistic regression was applied to evaluate the effects of the studied genetic variations on asthma outcomes in interaction with NO2 exposure. Our data showed that genotypes of rs2588882 and rs6721961 in the regulatory regions of the NFE2L2 gene were inversely associated with infection-induced asthma (odds ratio (OR) = 0.290, p = 0.0015, and OR = 0.437, p = 0.007, respectively). Furthermore, case-only analyses revealed significant differences for these SNPs between asthma patients that lived in modestly or highly polluted environment (OR = 0.43 (0.23–0.82), p = 0.01, and OR = 0.51, p = 0.02, respectively, in a dominant model). In conclusion, our results throw some new light upon the impact of NFE2L2 polymorphisms on infection-induced asthma risk and their effect in gene–environment interactions.

Keywords

Infection-induced asthma NFE2L2 Nitrogen dioxide Oxidative stress SNP 

Abbreviations

AA

Atopic asthma

HWE

Hardy–Weinberg equilibrium

IIA

Infection-induced asthma

NFE2L2

Nuclear factor erythroid-derived 2-like 2

NO2

Nitrogen dioxide

KEAP1

Kelch-like ECH-associated protein 1

OR

Odds ratio

SNP

Single nucleotide polymorphism

References

  1. Albert PS, Ratnasinghe D, Tangrea J, Wacholder S (2001) Limitations of the case-only design for identifying gene–environment interactions. Am J Epidemiol 154:687PubMedCrossRefGoogle Scholar
  2. Botto LD, Khoury MJ (2001) Commentary: facing the challenge of gene-environment interaction: the two-by-four table and beyond. Am J Epidemiol 153:1016PubMedCrossRefGoogle Scholar
  3. Braback L, Forsberg B (2009) Does traffic exhaust contribute to the development of asthma and allergic sensitization in children: findings from recent cohort studies. Environ Health 8:17. doi:10.1186/1476-069X-8-17 PubMedCrossRefGoogle Scholar
  4. Braman SS (2006) The global burden of asthma. Chest 130(1 Suppl):4S–12S. doi:10.1378/chest.130.1_suppl.4S PubMedCrossRefGoogle Scholar
  5. Castro-Giner F, Kunzli N, Jacquemin B, Forsberg B, de Cid R, Sunyer J, Jarvis D, Briggs D, Vienneau D, Norback D, Gonzalez JR, Guerra S, Janson C, Anto JM, Wjst M, Heinrich J, Estivill X, Kogevinas M (2009) Traffic-related air pollution, oxidative stress genes, and asthma (ECHRS). Environ Health Perspect 117(12):1919–1924. doi:10.1289/ehp.0900589 PubMedGoogle Scholar
  6. Ciencewicki J, Jaspers I (2007) Air pollution and respiratory viral infection. Inhal Toxicol 19(14):1135–1146. doi:10.1080/08958370701665434 PubMedCrossRefGoogle Scholar
  7. Eder W, Klimecki W, Yu L, von Mutius E, Riedler J, Braun-Fahrlander C, Nowak D, Martinez FD (2005) Opposite effects of CD 14/-260 on serum IgE levels in children raised in different environments. J Allergy Clin Immunol 116(3):601–607. doi:10.1016/j.jaci.2005.05.003 PubMedCrossRefGoogle Scholar
  8. Favreau LV, Pickett CB (1995) The rat quinone reductase antioxidant response element. Identification of the nucleotide sequence required for basal and inducible activity and detection of antioxidant response element-binding proteins in hepatoma and non-hepatoma cell lines. J Biol Chem 270(41):24468–24474PubMedCrossRefGoogle Scholar
  9. Fitzpatrick AM, Stephenson ST, Hadley GR, Burwell L, Penugonda M, Simon DM, et al. (2011) Thiol redox disturbances in children with severe asthma are associated with posttranslational modification of the transcription factor nuclear factor (erythroid-derived 2)-like 2. J Allergy Clin Immunol 127:1604–1611Google Scholar
  10. Holroyd KJ, Eleff SM, Zhang LY, Jakab GJ, Kleeberger SR (1997) Genetic modeling of susceptibility to nitrogen dioxide-induced lung injury in mice. Am J Physiol 273(3 Pt 1):L595–L602PubMedGoogle Scholar
  11. Iizuka T, Ishii Y, Itoh K, Kiwamoto T, Kimura T, Matsuno Y, Morishima Y, Hegab AE, Homma S, Nomura A, Sakamoto T, Shimura M, Yoshida A, Yamamoto M, Sekizawa K (2005) Nrf2-deficient mice are highly susceptible to cigarette smoke-induced emphysema. Genes Cells 10(12):1113–1125. doi:10.1111/j.1365-2443.2005.00905.x PubMedCrossRefGoogle Scholar
  12. Kerkhof M, Postma DS, Brunekreef B, Reijmerink NE, Wijga AH, de Jongste JC, Gehring U, Koppelman GH (2010) Toll-like receptor 2 and 4 genes influence susceptibility to adverse effects of traffic-related air pollution on childhood asthma. Thorax 65(8):690–697. doi:10.1136/thx.2009.119636 PubMedCrossRefGoogle Scholar
  13. Kim J, Cha YN, Surh YJ (2010) A protective role of nuclear factor-erythroid 2-related factor-2 (Nrf2) in inflammatory disorders. Mutat Res 690(1–2):12–23. doi:10.1016/j.mrfmmm.2009.09.007 PubMedGoogle Scholar
  14. Kwak MK, Itoh K, Yamamoto M, Kensler TW (2002) Enhanced expression of the transcription factor Nrf2 by cancer chemopreventive agents: role of antioxidant response element-like sequences in the nrf2 promoter. Mol Cell Biol 22(9):2883–2892PubMedCrossRefGoogle Scholar
  15. Kwak MK, Wakabayashi N, Itoh K, Motohashi H, Yamamoto M, Kensler TW (2003) Modulation of gene expression by cancer chemopreventive dithiolethiones through the Keap1–Nrf2 pathway. Identification of novel gene clusters for cell survival. J Biol Chem 278(10):8135–8145. doi:10.1074/jbc.M211898200 PubMedCrossRefGoogle Scholar
  16. Lee YL, Lin YC, Lee YC, Wang JY, Hsiue TR, Guo YL (2004) Glutathione S-transferase P1 gene polymorphism and air pollution as interactive risk factors for childhood asthma. Clin Exp Allergy 34(11):1707–1713. doi:10.1111/j.1365-2222.2004.02099.x PubMedCrossRefGoogle Scholar
  17. Li N, Hao M, Phalen RF, Hinds WC, Nel AE (2003) Particulate air pollutants and asthma. A paradigm for the role of oxidative stress in PM-induced adverse health effects. Clin Immunol 109(3):250–265PubMedCrossRefGoogle Scholar
  18. Linaker CH, Coggon D, Holgate ST, Clough J, Josephs L, Chauhan AJ, Inskip HM (2000) Personal exposure to nitrogen dioxide and risk of airflow obstruction in asthmatic children with upper respiratory infection. Thorax 55(11):930–933PubMedCrossRefGoogle Scholar
  19. Litonjua AA, Silverman EK, Tantisira KG, Sparrow D, Sylvia JS, Weiss ST (2004) Beta 2 adrenergic receptor polymorphisms and haplotypes are associated with airways hyperresponsiveness among nonsmoking men. Chest 126:66–74Google Scholar
  20. Marzec JM, Christie JD, Reddy SP, Jedlicka AE, Vuong H, Lanken PN, Aplenc R, Yamamoto T, Yamamoto M, Cho HY, Kleeberger SR (2007) Functional polymorphisms in the transcription factor NRF2 in humans increase the risk of acute lung injury. FASEB J 21(9):2237–2246. doi:10.1096/fj.06-7759com PubMedCrossRefGoogle Scholar
  21. Melen E, Nyberg F, Lindgren CM, Berglind N, Zucchelli M, Nordling E, Hallberg J, Svartengren M, Morgenstern R, Kere J, Bellander T, Wickman M, Pershagen G (2008) Interactions between glutathione S-transferase P1, tumor necrosis factor, and traffic-related air pollution for development of childhood allergic disease. Environ Health Perspect 116(8):1077–1084. doi:10.1289/ehp.11117 PubMedCrossRefGoogle Scholar
  22. Minelli C, Wei I, Sagoo G, Jarvis D, Shaheen S, Burney P (2011) Interactive effects of antioxidant genes and air pollution on respiratory function and airway disease: a HuGE review. Am J Epidemiol 173(6):603–620. doi:10.1093/aje/kwq403 PubMedCrossRefGoogle Scholar
  23. Poynter ME, Persinger RL, Irvin CG, Butnor KJ, van Hirtum H, Blay W, Heintz NH, Robbins J, Hemenway D, Taatjes DJ, Janssen-Heininger Y (2006) Nitrogen dioxide enhances allergic airway inflammation and hyperresponsiveness in the mouse. Am J Physiol Lung Cell Mol Physiol 290(1):L144–L152. doi:10.1152/ajplung.00131.2005 PubMedCrossRefGoogle Scholar
  24. Rangasamy T, Guo J, Mitzner WA, Roman J, Singh A, Fryer AD, Yamamoto M, Kensler TW, Tuder RM, Georas SN, Biswal S (2005) Disruption of Nrf2 enhances susceptibility to severe airway inflammation and asthma in mice. J Exp Med 202(1):47–59. doi:10.1084/jem.20050538 PubMedCrossRefGoogle Scholar
  25. Reddy NM, Suryanarayana V, Kalvakolanu DV, Yamamoto M, Kensler TW, Hassoun PM, Kleeberger SR, Reddy SP (2009) Innate immunity against bacterial infection following hyperoxia exposure is impaired in NRF2-deficient mice. J Immunol 183(7):4601–4608. doi:10.4049/jimmunol.0901754 PubMedCrossRefGoogle Scholar
  26. Siedlinski M, Postma DS, Boer JM, van der Steege G, Schouten JP, Smit HA, Boezen HM (2009) Level and course of FEV1 in relation to polymorphisms in NFE2L2 and KEAP1 in the general population. Respir Res 10:73. doi:10.1186/1465-9921-10-73 PubMedCrossRefGoogle Scholar
  27. Simpson A, John SL, Jury F, Niven R, Woodcock A, Ollier WE, Custovic A (2006) Endotoxin exposure, CD14, and allergic disease: an interaction between genes and the environment. Am J Respir Crit Care Med 174(4):386–392. doi:10.1164/rccm.200509-1380OC PubMedCrossRefGoogle Scholar
  28. Vercelli D (2003) Learning from discrepancies: CD14 polymorphisms, atopy and the endotoxin switch. Clin Exp Allergy 33(2):153–155PubMedCrossRefGoogle Scholar
  29. von Otter M, Landgren S, Nilsson S, Celojevic D, Bergstrom P, Hakansson A, Nissbrandt H, Drozdzik M, Bialecka M, Kurzawski M, Blennow K, Nilsson M, Hammarsten O, Zetterberg H (2010) Association of Nrf2-encoding NFE2L2 haplotypes with Parkinson’s disease. BMC Med Genet 11:36. doi:10.1186/1471-2350-11-36 CrossRefGoogle Scholar
  30. Wang R, An J, Ji F, Jiao H, Sun H, Zhou D (2008) Hypermethylation of the Keap1 gene in human lung cancer cell lines and lung cancer tissues. Biochem Biophys Res Commun 373(1):151–154. doi:10.1016/j.bbrc.2008.06.004 PubMedCrossRefGoogle Scholar
  31. Zhang LY, Levitt RC, Kleeberger SR (1995) Differential susceptibility to ozone-induced airways hyperreactivity in inbred strains of mice. Exp Lung Res 21(4):503–518PubMedCrossRefGoogle Scholar
  32. Zhang G, Hayden CM, Khoo SK, Candelaria P, Laing IA, Turner S, Franklin P, Stick S, Landau L, Goldblatt J, Le Souef PN (2007) Beta2-Adrenoceptor polymorphisms and asthma phenotypes: interactions with passive smoking. Eur Respir J 30(1):48–55. doi:10.1183/09031936.00123206 PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Ildikó Ungvári
    • 1
  • Éva Hadadi
    • 1
  • Viktor Virág
    • 1
  • Adrienne Nagy
    • 2
  • András Kiss
    • 2
  • Ágnes Kalmár
    • 3
  • Györgyi Zsigmond
    • 4
  • Ágnes F. Semsei
    • 5
  • András Falus
    • 1
    • 5
  • Csaba Szalai
    • 2
    • 5
    • 6
  1. 1.Department of Genetics, Cell- and ImmunobiologySemmelweis UniversityBudapestHungary
  2. 2.Heim Pál Pediatric HospitalBudapestHungary
  3. 3.St János HospitalBudapestHungary
  4. 4.Svábhegy National Clinic for Allergy Immmunology and PulmonologyBudapestHungary
  5. 5.Inflammation Biology and Immunogenomics Research GroupHungarian Academy of Sciences–Semmelweis UniversityBudapestHungary
  6. 6.Csertex Research LaboratoryBudapestHungary

Personalised recommendations