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Glutathione S-Transferase Gene Associations and Gene-Environment Interactions for Asthma

  • Asthma (V Ortega, Section Editor)
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Abstract

Purpose of Review

Asthma is one of the most common chronic inflammatory airway diseases. Airway oxidative stress is defined as an imbalance between oxidative and antioxidative processes in the airways. There is evidence that chronic damage caused by oxidative stress may be involved in asthmatic inflammation and reduced lung function. Given their biological antioxidant function, the antioxidant genes in the glutathione S-transferase (GST) family are believed to be associated with development and progression of asthma. This review aims to summarize evidence on the relationship between GST gene polymorphisms and asthma and interactions with environmental exposures.

Recent Findings

The current evidence on the association between GST genes and asthma is still weak or inconsistent. Failure to account for environmental exposures may explain the lack of consistency. It is highly likely that environmental exposures interact with GST genes involved in the antioxidant pathway. According to current knowledge, carriers of GSTM1(rs366631)/T1(rs17856199) null genotypes and GSTP1 Val105 (rs1695) genotypes are more susceptible to environmental oxidative exposures and have a higher risk of asthma. Some doubt remains regarding the presence or absence of interactions with different environmental exposures in different study scenarios. The GST-environment interaction may depend on exposure type, asthma phenotype or endotype, ethnics, and other complex gene-gene interaction. Future studies could be improved by defining precise asthma endotypes, involving multiple gene-gene interactions, and increasing sample size and power.

Summary

Although there is evidence for an interaction between GST genes, and environmental exposures in relation to asthma, results are not concordant. Further investigations are needed to explore the reasons behind the inconsistency.

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References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Milos J, Maria Z, Eva B. Oxidative stress and bronchial asthma in children—causes or consequences? Front Pediatr. 2017;5:Article 162. https://doi.org/10.3389/fped.2017.00162.

    Article  Google Scholar 

  2. •• Piacentini S, Polimanti R, Simonelli I, Donno S, Pasqualetti P, Manfellotto D, et al. Glutathione S-transferase polymorphisms, asthma susceptibility and confounding variables: a meta-analysis. Mol Biol Rep. 2013;40(4):3299–314 A comprehensive review and meta-analysis reporting the estimated effects of GST genes on asthma, giving evidence for gene-environment interaction.

    Article  CAS  Google Scholar 

  3. Holley SL, Fryer AA, Haycock JW, Grubb SEW, Strange RC, Hoban PR. Differential effects of glutathione S-transferase pi (GSTP1) haplotypes on cell proliferation and apoptosis. Carcinogenesis. 2007;28(11):2268–73. https://doi.org/10.1093/carcin/bgm135.

    Article  CAS  PubMed  Google Scholar 

  4. • Fryer AA, Bianco A, Hepple M, Jones PW, Strange RC, Spiteri MA. Polymorphism at the glutathione S-transferase GSTP1 locus. A new marker for bronchial hyperresponsiveness and asthma. Am J Respir Crit Care Med. 2000;161(5):1437–42 This study provides clear information on GSTP1 and evidence on GSTP1 risk alleles.

    Article  CAS  Google Scholar 

  5. •• Dai X, Bowatte G, Lowe AJ, Matheson MC, Gurrin LC, Burgess JA, et al. Do glutathione S-transferase genes modify the link between indoor air pollution and asthma, allergies, and lung function? A systematic review. Curr Allergy Asthma Rep. 2018;18. https://doi.org/10.1007/s11882-018-0771-0This systematic review synthesized evidence for interactions of GST genes with household air pollution, on asthma and lung function.

  6. Lenney W, Fryer AA. The genetics of asthma: are the glutathione S-transferases serious players? Clin Expl Allergy. 2007;37(8):1124–6.

    Article  CAS  Google Scholar 

  7. • Minelli C, Wei I, Sagoo G, Jarvis D, Shaheen S, Burney P. Interactive effects of antioxidant genes and air pollution on respiratory function and airway disease: a HuGE review. Am J Epidemiol. 2011;173(6):603–21 A HuGE on similar topic summarized the frequency of GST variants in different populations and describes associations of these variants with disease, and their interaction with air pollution.

    Article  Google Scholar 

  8. Martos-Maldonado MC, Casas-Solvas JM, Vargas-Berenguel A, García-Fuentes L. Electrochemical detection of glutathione S-transferase: an important enzyme in the cell protective mechanism against oxidative stress. In: Armstrong D, editor. Advanced protocols in oxidative stress III. New York, NY: Springer New York; 2015. p. 123–38.

    Chapter  Google Scholar 

  9. Dasari S, Ganjayi MS, Yellanurkonda P, Basha S, Meriga B. Role of glutathione S-transferases in detoxification of a polycyclic aromatic hydrocarbon, methylcholanthrene. Chem Biol Interact. 2018;294:81–90. https://doi.org/10.1016/j.cbi.2018.08.023.

    Article  CAS  PubMed  Google Scholar 

  10. Sun N, Sun X, Chen B, Cheng H, Feng J, Cheng L, et al. MRP2 and GSTP1 polymorphisms and chemotherapy response in advanced non-small cell lung cancer. Cancer Chemother Pharmacol. 2010;65(3):437–46. https://doi.org/10.1007/s00280-009-1046-1.

    Article  CAS  PubMed  Google Scholar 

  11. Erik M, Fredrik N, Cecilia ML, Niklas B, Marco Z, Emma N, et al. Interactions between glutathione S-Transferase P1, tumor necrosis factor, and traffic-related air pollution for development of childhood allergic disease. Environ Health Perspect. 2008;116(8):1077–84. https://doi.org/10.1289/ehp.11117.

    Article  Google Scholar 

  12. Schultz EN, Devadason SG, Khoo SK, Zhang G, Bizzintino JA, Martin AC, et al. The role of GSTP1 polymorphisms and tobacco smoke exposure in children with acute asthma. J Asthma. 2010;47(9):1049–56. https://doi.org/10.1080/02770903.2010.508856.

    Article  CAS  PubMed  Google Scholar 

  13. Ishii T, Matsuse T, Teramoto S, Matsui H, Miyao M, Hosoi T, et al. Glutathione S-transferase P1 (GSTP1) polymorphism in patients with chronic obstructive pulmonary disease. Thorax. 1999;54(8):693–6.

    Article  CAS  Google Scholar 

  14. Tamer L, Calikoglu M, Ates NA, Yildirim H, Ercan B, Saritas E, et al. Glutathione-S-transferase gene polymorphisms (GSTT1, GSTM1, GSTP1) as increased risk factors for asthma. Respirology. 2004;9(4):493–8.

    Article  Google Scholar 

  15. •• Minelli C, Granell R, Newson R, Rose-Zerilli MJ, Torrent M, Ring SM, et al. Glutathione-S-transferase genes and asthma phenotypes: a Human Genome Epidemiology (HuGE) systematic review and meta-analysis including unpublished data. Int J Epidemiol. 2010;39(2):539–62. https://doi.org/10.1093/ije/dyp337Another comprehensive review and meta-analysis reporting the estimated effects of GST genes on asthma, giving evidence for gene-environment interaction.

    Article  PubMed  Google Scholar 

  16. Al-Arifa N, Jahan N. Association of glutathione-S-transferase P1 (GSTP1) and group-specific component (GC) polymorphism with the risk of asthma in Pakistani population. Pak J Zool. 2016;48(4):937–42.

    CAS  Google Scholar 

  17. Karam RA, Pasha, Heba F, El-Shal AS, Rahman HMA, Gad DM. Impact of glutathione-S-transferase gene polymorphisms on enzyme activity, lung function and bronchial asthma susceptibility in Egyptian children. Gene. 2012;497(2):314–9. https://doi.org/10.1016/j.gene.2012.01.059.

    Article  CAS  PubMed  Google Scholar 

  18. Imboden M, Rochat T, Brutsche M, Schindler C, Downs SH, Gerbase MW, et al. Glutathione S-transferase genotype increases risk of progression from bronchial hyperresponsiveness to asthma in adults. Thorax. 2008;63(4):322–8.

    Article  CAS  Google Scholar 

  19. Renate N, Assja H, Claudia S, Susanne L, Bodo N, Klaus AD, et al. Association study of glutathione S-transferase P1 (GSTP1) with asthma and bronchial hyper-responsiveness in two German pediatric populations. Pediatr Allergy Immunol. 2005;16(6):539–41.

    Article  Google Scholar 

  20. Palmer CN, Doney AS, Lee SP, Murrie I, Ismail T, Macgregor DF, et al. Glutathione S-transferase M1 and P1 genotype, passive smoking, and peak expiratory flow in asthma. Pediatrics. 2006;118(2):710–6. https://doi.org/10.1542/peds.2005-3030.

    Article  PubMed  Google Scholar 

  21. Malling TH, Sigsgaard T, Brasch-Andersen C, Frischknecht L, Andersen HR, Kruse TA, et al. Genetic polymorphisms in antioxidative enzymes are associated to forced expiratory volume in 1 s (FEV1) in smokers independently of asthma. Clin Respir J. 2012;6(1):46–55. https://doi.org/10.1111/j.1752-699X.2011.00245.x.

    Article  CAS  PubMed  Google Scholar 

  22. Vavilin VA, Makarova SI, Lyakhovich VV, Gavalov SM. Polymorphic genes of xenobiotic-metabolizing enzymes associated with predisposition to bronchial asthma in hereditarily burdened and nonburdened children. Russ J Genet. 2002;38(4):439–45.

    Article  CAS  Google Scholar 

  23. Mostafa S, Iraj S, Zahra S, Ali E. Combination of CC16, GSTM1, and GSTT1 genetic polymorphisms is associated with asthma. J Allergy Clin Immunol. 2004;113(5):996–8.

    Article  Google Scholar 

  24. Zhang Y-Q, Sun B-Y, Dai J-J, Wu S-S, Zhang A-P, Zhao C-F, et al. [Studies on the genetic diathesis of asthma bronchial]. Yi Chuan =. Hereditas. 2004;26(2):147–50.

    CAS  PubMed  Google Scholar 

  25. Frank DG, Yu-Fen L, Louis D, Kiros B, Edward A, Rob M, et al. Effects of glutathione S-transferase M1, maternal smoking during pregnancy, and environmental tobacco smoke on asthma and wheezing in children. Am J Respir Crit Care Med. 2002;166(4):457–63. https://doi.org/10.1164/rccm.2112064.

    Article  Google Scholar 

  26. Kabesch M, Hoefler C, Carr D, Leupold W, Weiland SK, von Mutius E. Glutathione S transferase deficiency and passive smoking increase childhood asthma. Thorax. 2004;59(7):569–73.

    Article  CAS  Google Scholar 

  27. Li YF, Tseng PJ, Lin CC, Hung CL, Lin SC, Su WC, et al. NAD(P)H: Quinone oxidoreductase 1, glutathione S-transferase M1, environmental tobacco smoke exposure, and childhood asthma. Mutat Res. 2009;678(1):53–8. https://doi.org/10.1016/j.mrgentox.2009.06.008.

    Article  CAS  PubMed  Google Scholar 

  28. Li YF, Gauderman WJ, Conti DV, Lin PC, Avol E, Gilliland FD. Glutathione S-transferase P1, maternal smoking, and asthma in children: a haplotype-based analysis. Environ Health Perspect. 2008;116(3):409–15. https://doi.org/10.1289/ehp.10655.

    Article  PubMed  Google Scholar 

  29. Panasevich S, Lindgren C, Kere J, Wickman M, Pershagen G, Nyberg F, et al. Interaction between early maternal smoking and variants in TNF and GSTP1 in childhood wheezing. Clin Exp Allergy. 2010;40(3):458–67. https://doi.org/10.1111/j.1365-2222.2010.03452.x.

    Article  CAS  PubMed  Google Scholar 

  30. Lee YL, Lee YC, Guo YL. Associations of glutathione S-transferase P1, M1, and environmental tobacco smoke with wheezing illness in school children. Allergy. 2007;62(6):641–7. https://doi.org/10.1111/j.1398-9995.2007.01380.x.

    Article  PubMed  Google Scholar 

  31. Wang IJ, Guo YL, Lin TJ, Chen PC, Wu YN. GSTM1, GSTP1, prenatal smoke exposure, and atopic dermatitis. Ann Allergy Asthma Immunol. 2010;105(2):124–9. https://doi.org/10.1016/j.anai.2010.04.017.

    Article  CAS  PubMed  Google Scholar 

  32. Lee S-Y, Kim B-S, Kwon S-O, Oh S-Y, Shin HL, Jung Y-H, et al. Modification of additive effect between vitamins and ETS on childhood asthma risk according to GSTP1 polymorphism: a cross-sectional study. BMC Pulm Med. 2015;15:125. https://doi.org/10.1186/s12890-015-0093-0.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Schroer KT, Biagini Myers JM, Ryan PH, LeMasters GK, Bernstein DI, Villareal M, et al. Associations between multiple environmental exposures and glutathione S-transferase P1 on persistent wheezing in a birth cohort. J Pediatr. 2009;154(3):401–8. https://doi.org/10.1016/j.jpeds.2008.08.040.

    Article  CAS  PubMed  Google Scholar 

  34. Munoz B, Magana JJ, Romero-Toledo I, Juarez-Perez E, Lopez-Moya A, Leyva-Garcia N, et al. The relationship among IL-13, GSTP1, and CYP1A1 polymorphisms and environmental tobacco smoke in a population of children with asthma in Northern Mexico. Environ Toxicol Pharmacol. 2012;33(2):226–32. https://doi.org/10.1016/j.etap.2011.12.007.

    Article  CAS  PubMed  Google Scholar 

  35. Dai X, Dharmage SC, Bowatte G, Waidyatillake NT, Perret JL, Hui J, et al. Interaction of glutathione S-transferase M1, T1, and P1 genes with early life tobacco smoke exposure on lung function in adolescents. CHEST. 2019;155(1):94–102. https://doi.org/10.1016/j.chest.2018.08.1079.

    Article  PubMed  Google Scholar 

  36. • Bowatte G, Lodge CJ, Perret JL, Matheson MC, Dharmage SC. Interactions of GST polymorphisms in air pollution exposure and respiratory diseases and allergies. Curr Allergy Asthma Rep. 2016;16:85. https://doi.org/10.1007/s11882-016-0664-z 9 pages. This review synthesized evidences on interactions of GST genes on outdoor air pollution and airway diseases.

    Article  CAS  PubMed  Google Scholar 

  37. Bowatte G, Lodge CJ, Lowe AJ, Erbas B, Dennekamp M, Marks GB, et al. Do variants in GSTs modify the association between traffic air pollution and asthma in adolescence? Int J Mol Sci. 2016;17(4):485. https://doi.org/10.3390/ijms17040485.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Bowatte G, Lodge CJ, Knibbs LD, Erbas B, Perret JL, Jalaludin B, et al. Traffic related air pollution and development and persistence of asthma and low lung function. Environ Int. 2018;113:170–6. https://doi.org/10.1016/j.envint.2018.01.028.

    Article  CAS  PubMed  Google Scholar 

  39. MacIntyre EA, Brauer M, Melén E, Bauer CP, Bauer M, Berdel D, et al. GSTP1 and TNF gene variants and associations between air pollution and incident childhood asthma: The Traffic, Asthma and Genetics (TAG) study...glutathione S-transferase pi gene. Environ Health Perspect. 2014;122(4):418–24. https://doi.org/10.1289/ehp.1307459.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Bing-Fang H, Li-Hao Y, Ching-Hui T, Kuan-Yen T, Pei-Chuan W, Ming-Wei S, et al. Fine particle, ozone exposure, and asthma/wheezing: effect modification by glutathione S-transferase P1 polymorphisms. PLoS ONE. 2013;1:e52715. https://doi.org/10.1371/journal.pone.0052715.

    Article  CAS  Google Scholar 

  41. Su MW, Tsai CH, Tung KY, Hwang BF, Liang PH, Chiang BL, et al. GSTP1 is a hub gene for gene-air pollution interactions on childhood asthma. Allergy. 2013;68(12):1614–7. https://doi.org/10.1111/all.12298.

    Article  CAS  PubMed  Google Scholar 

  42. Wang IJ, Tsai CH, Chen CH, Tung KY, Lee YL. Glutathione S-transferase, incense burning and asthma in children. Eur Respir J. 2011;37(6):1371–7. https://doi.org/10.1183/09031936.00137210.

    Article  CAS  PubMed  Google Scholar 

  43. Hersoug L-G, Brasch-Andersen C, Husemoen LLN, Sigsgaard T, Linneberg A. The relationship of glutathione-S-transferases copy number variation and indoor air pollution to symptoms and markers of respiratory disease. Clin Respir J. 2012;6(3):175–85. https://doi.org/10.1111/j.1752-699X.2011.00258.x.

    Article  PubMed  Google Scholar 

  44. Hu X, Xia H, Srivastava SK, Herzog C, Awasthi YC, Ji X, et al. Activity of four allelic forms of glutathione S-transferase hGSTP1-1 for diol epoxides of polycyclic aromatic hydrocarbons. Biochem Biophys Res Commun. 1997;238(2):397–402. https://doi.org/10.1006/bbrc.1997.7311.

    Article  CAS  PubMed  Google Scholar 

  45. Ortega VE, Meyers DA. Pharmacogenetics: implications of race and ethnicity on defining genetic profiles for personalized medicine. J Allergy Clin Immunol. 2014;133(1):16–26. https://doi.org/10.1016/j.jaci.2013.10.040.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Geisler SA, Olshan AF. GSTM1, GSTT1, and the risk of squamous cell carcinoma of the head and neck: a Mini-HuGE review. Am J Epidemiol. 2001;154(2):95–105. https://doi.org/10.1093/aje/154.2.95.

    Article  CAS  PubMed  Google Scholar 

  47. Jaclyn AS, Richard D, Angela S, Ashley W, Andrew P, Adnan C. Dimensions of respiratory symptoms in preschool children: population-based birth cohort study. Am J Respir Crit Care Med. 2008;12:1358–63. https://doi.org/10.1164/rccm.200709-1419OC.

    Article  Google Scholar 

  48. Bønnelykke K, Ober C. Leveraging gene-environment interactions and endotypes for asthma gene discovery. J Allergy Clin Immunol. 2016;137(3):667–79. https://doi.org/10.1016/j.jaci.2016.01.006.

    Article  PubMed  PubMed Central  Google Scholar 

  49. Nissen F, Douglas IJ, Müllerová H, Pearce N, Bloom CI, Smeeth L, et al. Clinical profile of predefined asthma phenotypes in a large cohort of UK primary care patients (Clinical Practice Research Datalink). J Asthma Allergy. 2019;7.

  50. Douglas G, Elward KS. Asthma. Clinician’s desk reference. London: Manson; 2011.

    Google Scholar 

  51. Sandford AJ, Pare PD. The genetics of asthma-the important questions. Am J Respir Crit Care Med. 2000;161(3):S202–S6. https://doi.org/10.1164/ajrccm.161.supplement_2.a1q4-11.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank Prof. Shyamali Dharmage who provided guidance for interpretation of the included studies and provided comments on the manuscript.

Data Transparency

All data and materials support published claims and comply with field standards.

Funding

Dr. Dai has no personal funding relationship to declare. Dr. Caroline Lodge is funded by a Melbourne University Developing Research Momentum (DRM) grant; Dr. Dinh Bui is funded by Centre for Air pollution, energy and health Research (CAR), Australia.

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Dr. Dai, Dr. Lodge, and Dr. Bui all contributed to the study conception and design. Dr. Dai led the analysis and interpretation of data, with the support from Dr. Lodge and Dr. Bui. Dr. Dai wrote the initial draft of the manuscript which was critically revised for important content by all the authors. All authors approved the final version.

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Correspondence to Caroline Lodge.

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Dai, X., Bui, D.S. & Lodge, C. Glutathione S-Transferase Gene Associations and Gene-Environment Interactions for Asthma. Curr Allergy Asthma Rep 21, 31 (2021). https://doi.org/10.1007/s11882-021-01005-y

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