Association of PTGER gene family polymorphisms with aspirin intolerant asthma in Korean asthmatics

  • Park, Byung-Lae (Department of Genetic Epidemiology, SNP Genetics, Inc.) ;
  • Park, Se-Min (Genome Research Center for Allergy and Respiratory Medicine, Soonchunhyang University Hospital) ;
  • Park, Jong-Sook (Genome Research Center for Allergy and Respiratory Medicine, Soonchunhyang University Hospital) ;
  • Uh, Soo-Taek (Genome Research Center for Allergy and Respiratory Medicine, Soonchunhyang University Hospital) ;
  • Choi, Jae-Sung (Genome Research Center for Allergy and Respiratory Medicine, Soonchunhyang University Hospital) ;
  • Kim, Yong-Hoon (Division of Internal Medicine, Chungbuk National University, College of Medicine) ;
  • Kim, Mi-Kyeong (Department of Allergy, Chonnam National University Medical School and Research Institute of Medical Sciences) ;
  • Choi, In-Seon S. (Division of Pulmonology and Allergy, Department of Internal Medicine, Chung-Ang University Yongsan Hospital) ;
  • Choi, Byoung-Whui (Department of Internal Medicine and Institute of Allergy and Clinical Immunology, Seoul National University College of Medicine) ;
  • Cho, Sang-Heon (Division of Allergy and Immunology, Institute of Allergy, Department of Internal Medicine, Yonsei University College of Medicine) ;
  • Hong, Chein-Soo (Pulmonary, Allergy & Critical Care Medicine, Hallym University College of Medicine) ;
  • Lee, Yong-Won (Pulmonary, Allergy & Critical Care Medicine, Hallym University College of Medicine) ;
  • Lee, Jae-Young (Department of Life Science, Sogang University) ;
  • Park, Choon-Sik (Genome Research Center for Allergy and Respiratory Medicine, Soonchunhyang University Hospital) ;
  • Shin, Hyoung-Doo (Department of Genetic Epidemiology, SNP Genetics, Inc.)
  • Received : 2010.02.01
  • Accepted : 2010.05.07
  • Published : 2010.06.30


Aspirin-intolerant asthma (AIA) is characterized by severe asthmatic attack after ingestion of aspirin and/or non-steroidal anti-inflammatory drugs. In this study, we investigated the relationship between Prostaglandin E2 receptor (PTGER) gene family polymorphisms and AIA in 243 AIA patients and 919 aspirin-tolerant asthma (ATA) controls of Korean ethnicity in two separate study cohorts. After genotyping 120 SNPs of the PTGER gene family for the $1^{st}$ cohort study, four SNPs in PTGER1, ten in PTGER3, six in PTGER3, and a haplotype of PTGER2 showed association signals with decreased or increased risk of AIA. Among the positively associated SNPs, one in PTGER1 and four in PTGER3 were analyzed in the $2^{nd}$ cohort study. The results show that rs7543182 and rs959 in PTGER3 retained their effect, although no statistical significance was retained in the $2^{nd}$ cohort study. Our findings provide further evidence that polymorphisms in PTGER3 might play a significant role in aspirin hypersensitivity among Korean asthmatics.


Supported by : Ministry of Health, Welfare and Family Affairs, Korea Science and Engineering Foundation (KOSEF)


  1. Samter, M. and Beers, R. F., Jr. (1967) Concerning the nature of intolerance to aspirin. J. Allergy 40, 281-293.
  2. Szczeklik, A. and Stevenson, D. D. (2003) Aspirin-induced asthma: advances in pathogenesis, diagnosis, and management. J. Allergy Clin. Immunol. 111, 913-921.
  3. Jenkins, C., Costello, J. and Hodge, L. (2004) Systematic review of prevalence of aspirin induced asthma and its implications for clinical practice. BMJ 328, 434.
  4. Loewe, G., Slapke, J. and Kunath, H. (1985) Nasal polyposis, bronchial asthma and analgesic intolerance. Rhinology. 23, 19-26.
  5. Zeitz, H. J. (1988) Bronchial asthma, nasal polyps, and aspirin sensitivity: Samter's syndrome. Clin. Chest. Med. 9, 567-576
  6. Hedman, J., Kaprio, J., Poussa, T. and Nieminen, M. M. (1999) Prevalence of asthma, aspirin intolerance, nasal polyposis and chronic obstructive pulmonary disease in a population-based study. Int. J. Epidemiol. 28, 717-722.
  7. Berges-Gimeno, M. P., Simon, R. A. and Stevenson, D. D. (2002) The natural history and clinical characteristics of aspirin-exacerbated respiratory disease. Ann. Allergy Asthma. Immunol. 89, 474-478.
  8. Szczeklik, A. and Stevenson, D. D. (1999) Aspirin-induced asthma: advances in pathogenesis and management. J. Allergy Clin. Immunol. 104, 5-13.
  9. Picado, C. (2002) Aspirin-intolerant asthma: role of cyclo-oxygenase enzymes. Allergy 57(Suppl 72), 58-60.
  10. Sampson, A., Holgate, S. Austen, K. F. and Szczeklik, A. (1998) Cyclo-oxygenase. Thorax. 53, 719-720.
  11. Pierzchalska, M., Szabo, Z., Sanak, M., Soja, J. and Szczeklik, A. (2003) Deficient prostaglandin E2 production by bronchial fibroblasts of asthmatic patients, with special reference to aspirin-induced asthma. J. Allergy Clin. Immunol. 111, 1041-1048.
  12. Cowburn, A. S., Sladek, K., Soja, J., Adamek, L., Nizankowska, E., Szczeklik, A., Lam, B. K., Penrose, J. F., Austen, F. K., Holgate, S. T. and Sampson, A. P. (1998) Overexpression of leukotriene C4 synthase in bronchial biopsies from patients with aspirin-intolerant asthma. J. Clin. Invest. 101, 834-846.
  13. Lam, B. K. and Frank Austen, K. (2000) Leukotriene C4 synthase. A pivotal enzyme in the biosynthesis of the cysteinyl leukotrienes. Am. J. Respir. Crit. Care. Med. 161, S16-19.
  14. Celik, G., Bavbek, S., Misirligil, Z. and Melli, M. (2001) Release of cysteinyl leukotrienes with aspirin stimulation and the effect of prostaglandin E(2) on this release from peripheral blood leucocytes in aspirin-induced asthmatic patients. Clin. Exp. Allergy 31, 1615-1622.
  15. Szczeklik, A., Sanak, M., Nizankowska-Mogilnicka, E. and Kielbasa, B. (2004) Aspirin intolerance and the cyclooxygenase-leukotriene pathways. Curr. Opin. Pulm. Med. 10, 51-56.
  16. Vane, J. R., Bakhle, Y. S. and Botting, R. M. (1998) Cyclooxygenases 1 and 2. Annu. Rev. Pharmacol. Toxicol. 38, 97-120.
  17. Snijdewint, F. G., Kalinski, P., Wierenga, E. A., Bos, J. D. and Kapsenberg, M. L. (1993) Prostaglandin E2 differentially modulates cytokine secretion profiles of human T helper lymphocytes. J. Immunol. 150, 5321-5329.
  18. Betz, M. and Fox, B. S. (1991) Prostaglandin E2 inhibits production of Th1 lymphokines but not of Th2 lymphokines. J. Immunol. 146, 108-113.
  19. Coleman, R. A., Smith, W. L. and Narumiya, S. (1994) International Union of Pharmacology classification of prostanoid receptors: properties, distribution, and structure of the receptors and their subtypes. Pharmacol. Rev. 46, 205-229.
  20. Negishi, M., Sugimoto, Y. and Ichikawa, A. (1995) Molecular mechanisms of diverse actions of prostanoid receptors. Biochim. Biophys. Acta. 1259, 109-119.
  21. Narumiya, S., Sugimoto, Y. and Ushikubi, F. (1999) Prostanoid receptors: structures, properties, and functions. Physiol. Rev. 79, 1193-1226.
  22. Higashi, N., Taniguchi, M., Mita, H., Osame, M. and Akiyama, K. (2002) A comparative study of eicosanoid concentrations in sputum and urine in patients with aspirin-intolerant asthma. Clin. Exp. Allergy 32, 1484-1490.
  23. Kunikata, T., Yamane, H., Segi, E., Matsuoka, T., Sugimoto, Y., Tanaka, S., Tanaka, H., Nagai, H., Ichikawa, A. and Narumiya, S. (2005) Suppression of allergic inflammation by the prostaglandin E receptor subtype EP3. Nat. Immunol. 6, 524-531.
  24. Kim, S. H., Kim, Y. K., Park, H. W., Jee, Y. K., Kim, S. H., Bahn, J. W., Chang, Y. S., Kim, S. H., Ye, Y. M., Shin, E. S., Lee, J. E., Park, H. S. and Min, K. U. (2007) Association between polymorphisms in prostanoid receptor genes and aspirin-intolerant asthma. Pharmacogenet. Genomics. 17, 295-304.
  25. Jinnai, N., Sakagami, T., Sekigawa, T., Kakihara, M., Nakajima, T., Yoshida, K., Goto, S., Hasegawa, T., Koshino, T., Hasegawa, Y., Inoue, H., Suzuki, N., Sano, Y. and Inoue, I. (2004) Polymorphisms in the prostaglandin E2 receptor subtype 2 gene confer susceptibility to aspirin-intolerant asthma: a candidate gene approach. Hum. Mol. Genet. 13, 3203-3217.
  26. Park, H. W., Shin, E. S., Lee, J. E., Kim, S. H., Kim, S. S., Chang, Y. S., Kim, Y. K., Min, K. U., Kim, Y. Y. and Cho, S. H. (2007) Association between genetic variations in prostaglandin E2 receptor subtype EP3 gene (Ptger3) and asthma in the Korean population. Clin. Exp. Allergy 37, 1609-1615.
  27. Stock, J. L., Shinjo, K., Burkhardt, J., Roach, M., Taniguchi, K., Ishikawa, T., Kim, H. S., Flannery, P. J., Coffman, T. M., McNeish, J. D. and Audoly, L. P. (2001) The prostaglandin E2 EP1 receptor mediates pain perception and regulates blood pressure. J. Clin. Invest. 107, 325-331.
  28. Conklin, D., Jonassen, I., Aasland, R. and Taylor, W. R. (2002) Association of nucleotide patterns with gene function classes: application to human 3' untranslated sequences. Bioinformatics 18, 182-189.
  29. Kim, T. H., Chang, H. S., Park, S. M., Nam, B. Y., Park, J. S., Rhim, T., Park, H. S., Kim, M. K., Choi, I. S., Cho, S. H., Chung, I. Y., Park, B. L., Park, C. S. and Shin, H. D. (2008) Association of angiotensin I-converting enzyme gene polymorphisms with aspirin intolerance in asthmatics. Clin. Exp. Allergy. 38, 1727-1737.
  30. Cormican, L. J., Farooque, S., Altmann, D. R. and Lee, T. H. (2005) Improvements in an oral aspirin challenge protocol for the diagnosis of aspirin hypersensitivity. Clin. Exp. Allergy. 35, 717-722.
  31. Oliphant, A., Barker, D. L., Stuelpnagel, J. R. and Chee, M. S. (2002) BeadArray technology: enabling an accurate, cost-effective approach to high-throughput genotyping. Biotechniques 32, S56-61.
  32. Livak, K. J. (1999) Allelic discrimination using fluorogenic probes and the 5' nuclease assay. Genet. Anal. 14, 143-149.
  33. Hedrick, P. W. (1987) Gametic disequilibrium measures: proceed with caution. Genetics. 117, 331-341.
  34. Stephens, M., Smith, N. J. and Donnelly, P. (2001) A new statistical method for haplotype reconstruction from population data. Am. J. Hum. Genet. 68, 978-989.

Cited by

  1. Copy number variation in ALOX5 and PTGER1 is associated with NSAIDs-induced urticaria and/or angioedema vol.26, pp.6, 2016,
  2. Aspirin-exacerbated respiratory disease vol.23, pp.1, 2017,
  3. Fatty Acid Binding Protein 1 Is Related with Development of Aspirin-Exacerbated Respiratory Disease vol.6, pp.8, 2011,
  4. Hypersensitivity Reactions to Nonsteroidal Anti-Inflammatory Drugs vol.34, pp.3, 2014,
  5. Genetic variants in arachidonic acid pathway genes associated with NSAID-exacerbated respiratory disease vol.16, pp.8, 2015,
  6. Pharmacogenomics and adverse drug reactions: Primetime and not ready for primetime tests vol.138, pp.4, 2016,
  7. Unraveling the Genetic Basis of Aspirin Hypersensitivity in Asthma Beyond Arachidonate Pathways vol.5, pp.5, 2013,
  8. Potential Biomarkers for NSAID-Exacerbated Respiratory Disease vol.2017, 2017,
  9. A Highly Sensitive and Specific Genetic Marker to Diagnose Aspirin-Exacerbated Respiratory Disease Using a Genome-Wide Association Study vol.31, pp.11, 2012,
  10. Diagnostic Value of Clinical Parameters in the Prediction of Aspirin-Exacerbated Respiratory Disease in Asthma vol.3, pp.4, 2011,
  11. What we know about nonsteroidal anti-inflammatory drug hypersensitivity vol.31, pp.3, 2016,
  12. Evaluation of a Partial Genome Screening of Two Asthma Susceptibility Regions Using Bayesian Network Based Bayesian Multilevel Analysis of Relevance vol.7, pp.3, 2012,
  13. Genetic Mechanisms in Aspirin-Exacerbated Respiratory Disease vol.2012, 2012,
  14. Genetic variability of prostaglandin E2 receptor subtype EP4 gene in aspirin-intolerant chronic urticaria vol.57, pp.8, 2012,
  15. Exonic Variants Associated with Development of Aspirin Exacerbated Respiratory Diseases vol.9, pp.11, 2014,
  16. Genetics of Hypersensitivity to Aspirin and Nonsteroidal Anti-inflammatory Drugs vol.33, pp.2, 2013,
  17. Genetic basis of hypersensitivity reactions to nonsteroidal anti-inflammatory drugs vol.15, pp.4, 2015,
  18. Myeloid-derived suppressor cell function is diminished in aspirin-triggered allergic airway hyperresponsiveness in mice vol.134, pp.5, 2014,
  19. Hypersensitivity reactions to nonsteroidal anti-inflammatory drugs: an update on pharmacogenetics studies vol.19, pp.13, 2018,
  20. Multiomics Data Triangulation for Asthma Candidate Biomarkers and Precision Medicine vol.22, pp.6, 2018,
  21. Samter’s Triad: State of the Art vol.11, pp.2, 2018,
  22. Pharmacogenomics as a Tool for Management of Drug Hypersensitivity Reactions pp.2196-3053, 2019,