Yonsei Medical Journal

Yonsei Univ College Medicine (연세대학교의과대학)
권호 표지
DOI QR코드

DOI QR Code

Gene-Environment Interactions in Asthma: Genetic and Epigenetic Effects

  • Lee, Jong-Uk (Department of Interdisciplinary Program in Biomedical Science Major, Soonchunhyang Graduate School) ;
  • Kim, Jeong Dong (Department of Interdisciplinary Program in Biomedical Science Major, Soonchunhyang Graduate School) ;
  • Park, Choon-Sik (Genome Research Center and Division of Allergy and Respiratory Medicine, Soonchunhyang University Bucheon Hospital)
  • Received : 2015.03.31
  • Published : 2015.07.01
⟨ Previous Next ⟩

Abstract

Over the past three decades, a large number of genetic studies have been aimed at finding genetic variants associated with the risk of asthma, applying various genetic and genomic approaches including linkage analysis, candidate gene polymorphism studies, and genome-wide association studies (GWAS). However, contrary to general expectation, even single nucleotide polymorphisms (SNPs) discovered by GWAS failed to fully explain the heritability of asthma. Thus, application of rare allele polymorphisms in well defined phenotypes and clarification of environmental factors have been suggested to overcome the problem of 'missing' heritability. Such factors include allergens, cigarette smoke, air pollutants, and infectious agents during pre- and post-natal periods. The first and simplest interaction between a gene and the environment is a candidate interaction of both a well known gene and environmental factor in a direct physical or chemical interaction such as between CD14 and endotoxin or between HLA and allergens. Several GWAS have found environmental interactions with occupational asthma, aspirin exacerbated respiratory disease, tobacco smoke-related airway dysfunction, and farm-related atopic diseases. As one of the mechanisms behind gene-environment interaction is epigenetics, a few studies on DNA CpG methylation have been reported on subphenotypes of asthma, pitching the exciting idea that it may be possible to intervene at the junction between the genome and the environment. Epigenetic studies are starting to include data from clinical samples, which will make them another powerful tool for research on gene-environment interactions in asthma.

Keywords

References

  1. Burrows B, Martinez FD, Halonen M, Barbee RA, Cline MG. Association of asthma with serum IgE levels and skin-test reactivity to allergens. N Engl J Med 1989;320:271-7. https://doi.org/10.1056/NEJM198902023200502
  2. Burrows B, Sears MR, Flannery EM, Herbison GP, Holdaway MD, Silva PA. Relation of the course of bronchial responsiveness from age 9 to age 15 to allergy. Am J Respir Crit Care Med 1995; 152(4 Pt 1):1302-8. https://doi.org/10.1164/ajrccm.152.4.7551386
  3. Bousquet J, Chanez P, Vignola AM, Lacoste JY, Michel FB. Eosinophil inflammation in asthma. Am J Respir Crit Care Med 1994; 150(5 Pt 2):S33-8. https://doi.org/10.1164/ajrccm/150.5_Pt_2.S33
  4. Edfors-Lubs ML. Allergy in 7000 twin pairs. Acta Allergol 1971;26:249-85. https://doi.org/10.1111/j.1398-9995.1971.tb01300.x
  5. Zielenski J, Tsui LC. Cystic fibrosis: genotypic and phenotypic variations. Annu Rev Genet 1995;29:777-807. https://doi.org/10.1146/annurev.ge.29.120195.004021
  6. Van Eerdewegh P, Little RD, Dupuis J, Del Mastro RG, Falls K, Simon J, et al. Association of the ADAM33 gene with asthma and bronchial hyperresponsiveness. Nature 2002;418:426-30. https://doi.org/10.1038/nature00878
  7. Allen M, Heinzmann A, Noguchi E, Abecasis G, Broxholme J, Ponting CP, et al. Positional cloning of a novel gene influencing asthma from chromosome 2q14. Nat Genet 2003;35:258-63. https://doi.org/10.1038/ng1256
  8. Zhang Y, Leaves NI, Anderson GG, Ponting CP, Broxholme J, Holt R, et al. Positional cloning of a quantitative trait locus on chromosome 13q14 that influences immunoglobulin E levels and asthma. Nat Genet 2003;34:181-6. https://doi.org/10.1038/ng1166
  9. Laitinen T, Polvi A, Rydman P, Vendelin J, Pulkkinen V, Salmikangas P, et al. Characterization of a common susceptibility locus for asthma-related traits. Science 2004;304:300-4. https://doi.org/10.1126/science.1090010
  10. Oguma T, Palmer LJ, Birben E, Sonna LA, Asano K, Lilly CM. Role of prostanoid DP receptor variants in susceptibility to asthma. N Engl J Med 2004;351:1752-63. https://doi.org/10.1056/NEJMoa031785
  11. Risch NJ. Searching for genetic determinants in the new millennium. Nature 2000;405:847-56. https://doi.org/10.1038/35015718
  12. Hardy J, Singleton A. Genomewide association studies and human disease. N Engl J Med 2009;360:1759-68. https://doi.org/10.1056/NEJMra0808700
  13. Moffatt MF, Kabesch M, Liang L, Dixon AL, Strachan D, Heath S, et al. Genetic variants regulating ORMDL3 expression contribute to the risk of childhood asthma. Nature 2007;448:470-3. https://doi.org/10.1038/nature06014
  14. Moffatt MF, Gut IG, Demenais F, Strachan DP, Bouzigon E, Heath S, et al. A large-scale, consortium-based genomewide association study of asthma. N Engl J Med 2010;363:1211-21. https://doi.org/10.1056/NEJMoa0906312
  15. Sheehan NA, Didelez V, Burton PR, Tobin MD. Mendelian randomisation and causal inference in observational epidemiology. PLoS Med 2008;5:e177. https://doi.org/10.1371/journal.pmed.0050177
  16. Levin AM, Mathias RA, Huang L, Roth LA, Daley D, Myers RA, et al. A meta-analysis of genome-wide association studies for serum total IgE in diverse study populations. J Allergy Clin Immunol 2013;131:1176-84. https://doi.org/10.1016/j.jaci.2012.10.002
  17. Kim JH, Cheong HS, Park JS, Jang AS, Uh ST, Kim YH, et al. A genome-wide association study of total serum and mite-specific IgEs in asthma patients. PLoS One 2013;8:e71958. https://doi.org/10.1371/journal.pone.0071958
  18. Manolio TA, Collins FS, Cox NJ, Goldstein DB, Hindorff LA, Hunter DJ, et al. Finding the missing heritability of complex diseases. Nature 2009;461:747-53. https://doi.org/10.1038/nature08494
  19. 1000 Genomes Project Consortium, Abecasis GR, Altshuler D, Auton A, Brooks LD, Durbin RM, et al. A map of human genome variation from population-scale sequencing. Nature 2010;467: 1061-73. https://doi.org/10.1038/nature09534
  20. Raska P, Zhu X. Rare variant density across the genome and across populations. BMC Proc 2011;5 Suppl 9:S39. https://doi.org/10.1186/1753-6561-5-S9-S39
  21. Ortega VE, Hawkins GA, Moore WC, Hastie AT, Ampleford EJ, Busse WW, et al. Effect of rare variants in ADRB2 on risk of severe exacerbations and symptom control during longacting $\beta$ agonist treatment in a multiethnic asthma population: a genetic study. Lancet Respir Med 2014;2:204-13. https://doi.org/10.1016/S2213-2600(13)70289-3
  22. Halapi E, Gudbjartsson DF, Jonsdottir GM, Bjornsdottir US, Thorleifsson G, Helgadottir H, et al. A sequence variant on 17q21 is associated with age at onset and severity of asthma. Eur J Hum Genet 2010;18:902-8. https://doi.org/10.1038/ejhg.2010.38
  23. Green RH, Brightling CE, Bradding P. The reclassification of asthma based on subphenotypes. Curr Opin Allergy Clin Immunol 2007;7:43-50. https://doi.org/10.1097/ACI.0b013e3280118a32
  24. Moore WC, Meyers DA, Wenzel SE, Teague WG, Li H, Li X, et al. Identification of asthma phenotypes using cluster analysis in the Severe Asthma Research Program. Am J Respir Crit Care Med 2010;181:315-23. https://doi.org/10.1164/rccm.200906-0896OC
  25. Jang AS, Kwon HS, Cho YS, Bae YJ, Kim TB, Park JS, et al. Identification of subtypes of refractory asthma in Korean patients by cluster analysis. Lung 2013;191:87-93. https://doi.org/10.1007/s00408-012-9430-8
  26. Ho SM. Environmental epigenetics of asthma: an update. J Allergy Clin Immunol 2010;126:453-65. https://doi.org/10.1016/j.jaci.2010.07.030
  27. Thomsen SF, van der Sluis S, Kyvik KO, Skytthe A, Backer V. Estimates of asthma heritability in a large twin sample. Clin Exp Allergy 2010;40:1054-61. https://doi.org/10.1111/j.1365-2222.2010.03525.x
  28. Haldane JBS. Heredity and politics. London: George Allen & Unwin Ltd Pblisher; 1938.
  29. Huiyan W, Yuhe G, Juan W, Junyan Z, Shan W, Xiaojun Z, et al. The Importance of Allergen Avoidance in High Risk Infants and Sensitized Patients: A Meta-analysis Study. Allergy Asthma Immunol Res 2014;6:525-34. https://doi.org/10.4168/aair.2014.6.6.525
  30. Peden D, Reed CE. Environmental and occupational allergies. J Allergy Clin Immunol 2010;125(2 Suppl 2):S150-60. https://doi.org/10.1016/j.jaci.2009.10.073
  31. von Mutius E. Gene-environment interactions in asthma. J Allergy Clin Immunol 2009;123:3-11. https://doi.org/10.1016/j.jaci.2008.10.046
  32. Park HJ, Lim HS, Park KH, Lee JH, Park JW, Hong CS. Changes in allergen sensitization over the last 30 years in Korea respiratory allergic patients: a single-center. Allergy Asthma Immunol Res 2014;6:434-43. https://doi.org/10.4168/aair.2014.6.5.434
  33. Lee JH, Lee HS, Park MR, Lee SW, Kim EH, Cho JB, et al. Relationship between indoor air pollutant levels and residential environment in children with atopic dermatitis. Allergy Asthma Immunol Res 2014;6:517-24. https://doi.org/10.4168/aair.2014.6.6.517
  34. Jeong I, Kim I, Park HJ, Roh J, Park JW, Lee JH. Allergic diseases and multiple chemical sensitivity in Korean adults. Allergy Asthma Immunol Res 2014;6:409-14. https://doi.org/10.4168/aair.2014.6.5.409
  35. Hur GY, Ye YM, Koh DH, Kim SH, Park HS. IL-4 Receptor $\alpha$ Polymorphisms May Be a Susceptible Factor for Work-Related Respiratory Symptoms in Bakery Workers. Allergy Asthma Immunol Res 2013;5:371-6. https://doi.org/10.4168/aair.2013.5.6.371
  36. Yang SN, Hsieh CC, Kuo HF, Lee MS, Huang MY, Kuo CH, et al. The effects of environmental toxins on allergic inflammation. Allergy Asthma Immunol Res 2014;6:478-84. https://doi.org/10.4168/aair.2014.6.6.478
  37. Kim BJ, Lee SY, Kim HB, Lee E, Hong SJ. Environmental changes, microbiota, and allergic diseases. Allergy Asthma Immunol Res 2014;6:389-400. https://doi.org/10.4168/aair.2014.6.5.389
  38. Yang SI, Lee E, Jung YH, Kim HY, Seo JH, Kwon JW, et al. Effect of antibiotic use and mold exposure in infancy on allergic rhinitis in susceptible adolescents. Ann Allergy Asthma Immunol 2014;113: 160-5.e1. https://doi.org/10.1016/j.anai.2014.05.019
  39. Kim SH, Sutherland ER, Gelfand EW. Is there a link between obesity and asthma? Allergy Asthma Immunol Res 2014;6:189-95. https://doi.org/10.4168/aair.2014.6.3.189
  40. Lee SY, Kang MJ, Kwon JW, Park KS, Hong SJ. Breastfeeding Might Have Protective Effects on Atopy in Children With the CD14C-159T CT/CC Genotype. Allergy Asthma Immunol Res 2013;5:239-41. https://doi.org/10.4168/aair.2013.5.4.239
  41. Seo S, Kim D, Paul C, Yoo Y, Choung JT. Exploring Household-level Risk Factors for Self-reported Prevalence of Allergic Diseases Among Low-income Households in Seoul, Korea. Allergy Asthma Immunol Res 2014;6:421-7. https://doi.org/10.4168/aair.2014.6.5.421
  42. Zhang G, Khoo SK, Makela MJ, Candelaria P, Hayden CM, von Hertzen L, et al. Maternal Genetic Variants of IL4/IL13 Pathway Genes on IgE With "Western or Eastern Environments/Lifestyles". Allergy Asthma Immunol Res 2014;6:350-6. https://doi.org/10.4168/aair.2014.6.4.350
  43. Vercelli D. Learning from discrepancies: CD14 polymorphisms, atopy and the endotoxin switch. Clin Exp Allergy 2003;33:153-5. https://doi.org/10.1046/j.1365-2222.2003.01606.x
  44. Martinez FD. CD14, endotoxin, and asthma risk: actions and interactions. Proc Am Thorac Soc 2007;4:221-5. https://doi.org/10.1513/pats.200702-035AW
  45. Aderem A, Ulevitch RJ. Toll-like receptors in the induction of the innate immune response. Nature 2000;406:782-7. https://doi.org/10.1038/35021228
  46. Howell WM, Holgate ST. HLA genetics and allergic disease. Thorax 1995;50:815-8. https://doi.org/10.1136/thx.50.8.815
  47. Kim SH, Cho BY, Park CS, Shin ES, Cho EY, Yang EM, et al. Alpha-T-catenin (CTNNA3) gene was identified as a risk variant for toluene diisocyanate-induced asthma by genome-wide association analysis. Clin Exp Allergy 2009;39:203-12. https://doi.org/10.1111/j.1365-2222.2008.03117.x
  48. Park SM, Park JS, Park HS, Park CS. Unraveling the genetic basis of aspirin hypersensitivity in asthma beyond arachidonate pathways. Allergy Asthma Immunol Res 2013;5:258-76. https://doi.org/10.4168/aair.2013.5.5.258
  49. Park BL, Kim TH, Kim JH, Bae JS, Pasaje CF, Cheong HS, et al. Genome-wide association study of aspirin-exacerbated respiratory disease in a Korean population. Hum Genet 2013;132:313-21. https://doi.org/10.1007/s00439-012-1247-2
  50. Bouzigon E, Corda E, Aschard H, Dizier MH, Boland A, Bousquet J, et al. Effect of 17q21 variants and smoking exposure in early-onset asthma. N Engl J Med 2008;359:1985-94. https://doi.org/10.1056/NEJMoa0806604
  51. Flory JH, Sleiman PM, Christie JD, Annaiah K, Bradfield J, Kim CE, et al. 17q12-21 variants interact with smoke exposure as a risk factor for pediatric asthma but are equally associated with early-onset versus late-onset asthma in North Americans of European ancestry. J Allergy Clin Immunol 2009;124:605-7. https://doi.org/10.1016/j.jaci.2009.05.047
  52. van der Valk RJ, Duijts L, Kerkhof M, Willemsen SP, Hofman A, Moll HA, et al. Interaction of a 17q12 variant with both fetal and infant smoke exposure in the development of childhood asthma-like symptoms. Allergy 2012;67:767-74. https://doi.org/10.1111/j.1398-9995.2012.02819.x
  53. Ege MJ, Strachan DP, Cookson WO, Moffatt MF, Gut I, Lathrop M, et al. Gene-environment interaction for childhood asthma and exposure to farming in Central Europe. J Allergy Clin Immunol 2011;127:138-44, 144.e1-4. https://doi.org/10.1016/j.jaci.2010.09.041
  54. Hamza TH, Chen H, Hill-Burns EM, Rhodes SL, Montimurro J, Kay DM, et al. Genome-wide gene-environment study identifies glutamate receptor gene GRIN2A as a Parkinson's disease modifier gene via interaction with coffee. PLoS Genet 2011;7:e1002237. https://doi.org/10.1371/journal.pgen.1002237
  55. Wild CP. The exposome: from concept to utility. Int J Epidemiol 2012;41:24-32. https://doi.org/10.1093/ije/dyr236
  56. Wenzel SE. Asthma phenotypes: the evolution from clinical to molecular approaches. Nat Med 2012;18:716-25. https://doi.org/10.1038/nm.2678
  57. Bookman EB, McAllister K, Gillanders E, Wanke K, Balshaw D, Rutter J, et al. Gene-environment interplay in common complex diseases: forging an integrative model-recommendations from an NIH workshop. Genet Epidemiol 2011;35:217-25.
  58. Thomas D. Gene--environment-wide association studies: emerging approaches. Nat Rev Genet 2010;11:259-72. https://doi.org/10.1038/nrg2764
  59. Han MK, Huang YJ, Lipuma JJ, Boushey HA, Boucher RC, Cookson WO, et al. Significance of the microbiome in obstructive lung disease. Thorax 2012;67:456-63. https://doi.org/10.1136/thoraxjnl-2011-201183
  60. Goldberg AD, Allis CD, Bernstein E. Epigenetics: a landscape takes shape. Cell 2007;128:635-8. https://doi.org/10.1016/j.cell.2007.02.006
  61. Klose RJ, Bird AP. Genomic DNA methylation: the mark and its mediators. Trends Biochem Sci 2006;31:89-97. https://doi.org/10.1016/j.tibs.2005.12.008
  62. Sato S, Yagi S, Arai Y, Hirabayashi K, Hattori N, Iwatani M, et al. Genome-wide DNA methylation profile of tissue-dependent and differentially methylated regions (T-DMRs) residing in mouse pluripotent stem cells. Genes Cells 2010;15:607-18. https://doi.org/10.1111/j.1365-2443.2010.01404.x
  63. Cheong HS, Park SM, Kim MO, Park JS, Lee JY, Byun JY, et al. Genome-wide methylation profile of nasal polyps: relation to aspirin hypersensitivity in asthmatics. Allergy 2011;66:637-44. https://doi.org/10.1111/j.1398-9995.2010.02514.x
  64. Kim YJ, Park SW, Kim TH, Park JS, Cheong HS, Shin HD, et al. Genome-wide methylation profiling of the bronchial mucosa of asthmatics: relationship to atopy. BMC Med Genet 2013;14:39.
  65. Gudbjartsson DF, Bjornsdottir US, Halapi E, Helgadottir A, Sulem P, Jonsdottir GM, et al. Sequence variants affecting eosinophil numbers associate with asthma and myocardial infarction. Nat Genet 2009;41:342-7. https://doi.org/10.1038/ng.323
  66. Himes BE, Hunninghake GM, Baurley JW, Rafaels NM, Sleiman P, Strachan DP, et al. Genome-wide association analysis identifies PDE4D as an asthma-susceptibility gene. Am J Hum Genet 2009; 84:581-93. https://doi.org/10.1016/j.ajhg.2009.04.006
  67. Mashimo T, Hadjebi O, Amair-Pinedo F, Tsurumi T, Langa F, Serikawa T, et al. Progressive Purkinje cell degeneration in tambaleante mutant mice is a consequence of a missense mutation in HERC1 E3 ubiquitin ligase. PLoS Genet 2009;5:e1000784. https://doi.org/10.1371/journal.pgen.1000784
  68. Sleiman PM, Flory J, Imielinski M, Bradfield JP, Annaiah K, Willis-Owen SA, et al. Variants of DENND1B associated with asthma in children. N Engl J Med 2010;362:36-44. https://doi.org/10.1056/NEJMoa0901867
  69. Li X, Howard TD, Zheng SL, Haselkorn T, Peters SP, Meyers DA, et al. Genome-wide association study of asthma identifies RAD50-IL13 and HLA-DR/DQ regions. J Allergy Clin Immunol 2010;125: 328-35.e11. https://doi.org/10.1016/j.jaci.2009.11.018

Cited by

  1. Current directions in behavioral medicine research on genetic testing for disease susceptibility: introduction to the special section vol.38, pp.5, 2015, https://doi.org/10.1007/s10865-015-9674-x
  2. The Potential Role of 8-Oxoguanine DNA Glycosylase-Driven DNA Base Excision Repair in Exercise-Induced Asthma vol.2016, pp.None, 2015, https://doi.org/10.1155/2016/3762561
  3. Epigenetics: The New Frontier in the Landscape of Asthma vol.2016, pp.None, 2015, https://doi.org/10.1155/2016/4638949
  4. Near-Road Exposure and Impact of Air Pollution on Allergic Diseases in Elementary School Children: A Cross-Sectional Study vol.57, pp.3, 2015, https://doi.org/10.3349/ymj.2016.57.3.698
  5. A Six-Year Study on the Changes in Airborne Pollen Counts and Skin Positivity Rates in Korea: 2008–2013 vol.57, pp.3, 2015, https://doi.org/10.3349/ymj.2016.57.3.714
  6. Immunomodulatory Effects of Adjuvants CPG, MPLA, and BCG on the Derp2-Induced Acute Asthma at Early Life in an Animal Model of BALB/c Mice vol.40, pp.1, 2015, https://doi.org/10.1007/s10753-016-0476-2
  7. B7-H3 participates in the development of Asthma by augmentation of the inflammatory response independent of TLR2 pathway vol.7, pp.None, 2015, https://doi.org/10.1038/srep40398
  8. Genome-Wide Association Study of Polymorphisms Predisposing to Bronchiolitis vol.7, pp.None, 2015, https://doi.org/10.1038/srep41653
  9. The Clinical Significance of Changes in the Expression Levels of MicroRNA-1 and Inflammatory Factors in the Peripheral Blood of Children with Acute-Stage Asthma vol.2018, pp.None, 2015, https://doi.org/10.1155/2018/7632487
  10. Ambient Air Pollution and Asthma-Related Outcomes in Children of Color of the USA: a Scoping Review of Literature Published Between 2013 and 2017 vol.18, pp.5, 2015, https://doi.org/10.1007/s11882-018-0782-x
  11. Tobacco Smoke Induces and Alters Immune Responses in the Lung Triggering Inflammation, Allergy, Asthma and Other Lung Diseases: A Mechanistic Review vol.15, pp.5, 2015, https://doi.org/10.3390/ijerph15051033
  12. Video education versus face-to-face education on inhaler technique for patients with well-controlled or partly-controlled asthma: A phase IV, open-label, non-inferiority, multicenter, randomized, cont vol.13, pp.8, 2015, https://doi.org/10.1371/journal.pone.0197358
  13. Relationship between the Use of Parabens and Allergic Diseases in Japanese Adults-A Cross-Sectional Study vol.1, pp.1, 2015, https://doi.org/10.3390/j1010014
  14. Fibroblast-to-myofibroblast transition in bronchial asthma vol.75, pp.21, 2015, https://doi.org/10.1007/s00018-018-2899-4
  15. Interactions between polycyclic aromatic hydrocarbons and epoxide hydrolase 1 play roles in asthma vol.41, pp.1, 2015, https://doi.org/10.1007/s10653-018-0201-1
  16. Cell-Specific DNA Methylation Signatures in Asthma vol.10, pp.11, 2015, https://doi.org/10.3390/genes10110932
  17. Interweaving Between Genetic and Epigenetic Studies on Childhood Asthma vol.13, pp.None, 2015, https://doi.org/10.1177/2516865720923395
  18. Whole-Genome Sequencing Identifies Novel Functional Loci Associated with Lung Function in Puerto Rican Youth vol.202, pp.7, 2020, https://doi.org/10.1164/rccm.202002-0351oc
  19. Associations of TNF‐α ‐238G/A, TNF‐α ‐308G/A, and IL‐6 ‐174G/C polymorphisms with the risk of asthma: Evidence from a meta‐analysis vol.55, pp.11, 2015, https://doi.org/10.1002/ppul.25043
  20. Comparing DNA methylation profiles across different tissues associated with the diagnosis of pediatric asthma vol.10, pp.None, 2015, https://doi.org/10.1038/s41598-019-56310-4
  21. Association of the Risk of Childhood Asthma at Age 6 With Maternal Allergic or Immune-Mediated Inflammatory Diseases: A Nationwide Population-Based Study vol.8, pp.None, 2015, https://doi.org/10.3389/fmed.2021.713262
  22. Uncovering Evidence for Endocrine-Disrupting Chemicals That Elicit Differential Susceptibility through Gene-Environment Interactions vol.9, pp.4, 2015, https://doi.org/10.3390/toxics9040077
  23. Second‐hand smoke and NFE2L2 genotype interaction increases paediatric asthma risk and severity vol.51, pp.6, 2015, https://doi.org/10.1111/cea.13815