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Molecular Genetics and Genomics

, Volume 287, Issue 5, pp 361–371 | Cite as

Differential gene expression profile in PBMCs from subjects with AERD and ATA: a gene marker for AERD

  • SeungWoo Shin
  • Jong Sook Park
  • Yoon-Jeong Kim
  • TaeJeong Oh
  • Sungwhan An
  • Choon-Sik Park
Original Paper

Abstract

Aspirin-exacerbated respiratory disease (AERD) is associated with severe asthma and aspirin can cause asthma to worsen, often in the form of a severe and sudden attack. The oral aspirin challenge is the gold standard to confirm the diagnosis of AERD, but it is time consuming and produces serious complications in some cases. Therefore, more efficient and practical method is needed to predict AERD patients. The aim of the present study was to identify AERD-related gene expression in peripheral blood mononuclear cells (PBMCs) and examine the diagnostic potential of these candidate gene(s) for predicting AERD. To do this, RNAs from 24 subjects with AERD and 18 subjects with aspirin-tolerant asthma (ATA) were subjected to microarray analysis of ~34,560 genes. In total, 10 genes were selected as candidate gene markers by applying p ≤ 0.001(t test) and ≥8-fold change, and to correct for multiple comparisons, the false discovery rate analyses were performed. By applying multiple logistic regression analysis, among possible 1,023 models (210–1), a model consisting of CNKSR3, SPTBN2, and IMPACT was selected as candidate set, because this set showed the best AUC (0.98) with 88 % sensitivity and 89 % specificity. For validation, mRNA levels by real-time PCR on PBMCs from two population sets in a gene-chip study and another replication sample, 20 AERD, 20 ATA, and 8 normal controls, were significantly different between groups with 100 % sensitivity and 100 % specificity in each of the two population sets. However, IMPACT gene did not differentiate between AERD and normal controls. The set of the two genes (CNKSR3 and SPTBN2) showed the best AUC (0.96) with 88 % sensitivity and 94 % specificity in a gene-chip study sample. In addition, this set showed perfect discriminative power with AUC (1.0, 100 % sensitivity and 100 % specificity) in each of the two population sets: the gene-chip samples and the replication samples. It also showed perfect discrimination for AERD from NC (AUC: 1.0) and ATA from NC (AUC: 1.0). In conclusion, we developed the two gene markers (CNKSR3 and SPTBN2) of PBMC which differentiate between AERD and ATA with a perfect discriminative power. These gene markers may be an efficient and practical method for predicting AERD.

Keywords

Asthma Respiratory hypersensitivity Aspirin Gene expression profiling Mononuclear ROC curve 

Supplementary material

438_2012_685_MOESM1_ESM.doc (54 kb)
Supplementary material 1 (DOC 53 kb)
438_2012_685_MOESM2_ESM.doc (378 kb)
Supplementary material 2 (DOC 377 kb)
438_2012_685_MOESM3_ESM.doc (1.7 mb)
Supplementary material 3 (DOC 1706 kb)

References

  1. Aoki T, Matsumoto Y, Hirata K, Ochiai K, Okada M, Ichikawa K, Shibasaki M, Arinami T, Sumazaki R, Noguchi E (2009) Expression profiling of genes related to asthma exacerbations. Clin Exp Allergy 39(2):213–221PubMedCrossRefGoogle Scholar
  2. Baines KJ, Wood LG, Gibson PG (2009) The nutrigenomics of asthma: molecular mechanisms of airway neutrophilia following dietary antioxidant withdrawal. OMICS 13(5):355–365PubMedCrossRefGoogle Scholar
  3. Bateman ED, Hurd SS, Barnes PJ, Bousquet J, Drazen JM, FitzGerald M, Gibson P, Ohta K, O’Byrne P, Pedersen SE, Pizzichini E, Sullivan SD, Wenzel SE, Zar HJ (2008) Global strategy for asthma management and prevention: GINA executive summary. Eur Respir J 31:143–178PubMedCrossRefGoogle Scholar
  4. Berges-Gimeno MP, Simon RA, Stevenson DD (2002) The natural history and clinical characteristics of aspirin-exacerbated respiratory disease. Ann Allergy Asthma Immunol 89:474PubMedCrossRefGoogle Scholar
  5. Bradley AP (1997) The use of the area under the ROC curve in the evaluation of machine learning algorithms. Pattern Recogn 30(7):1145–1159CrossRefGoogle Scholar
  6. Chamberland A, Madore AM, Tremblay K, Laviolette M, Laprise C (2009) A comparison of two sets of microarray experiments to define allergic asthma expression pattern. Exp Lung Res 35(5):399–410PubMedCrossRefGoogle Scholar
  7. Choi JH, Lee KW, Oh HB, Lee KJ, Suh YJ, Park CS, Park HS (2004) HLA association in aspirin-intolerant asthma: DPB1*0301 as a strong marker in a Korean population. J Allergy Clin Immunol 113(3):562–564PubMedCrossRefGoogle Scholar
  8. Chong PK, Lee H, Zhou J, Liu SC, Loh MC, Wang TT, Chan SP, Smoot DT, Ashktorab H, So JB, Lim KH, Yeoh KG, Lim YP (2010) ITIH3 is a potential biomarker for early detection of gastric cancer. J Proteome Res 9(7):3671–3679PubMedCrossRefGoogle Scholar
  9. Dekker JW, Nizankowska E, Schmitz-Schumann M, Pile K, Bochenek G, Dyczek A, Cookson WO, Szczeklik A (1997) Aspirin-induced asthma and HLA-DRB1 and HLA-DPB1 genotypes. Clin Exp Allergy 27(5):574–577PubMedCrossRefGoogle Scholar
  10. Fawcett T (2006) An introduction to ROC analysis. Pattern Recogn 27(8):861–874CrossRefGoogle Scholar
  11. Gelb MH, Altemeier WA, Beyer RP, Aitken ML, Henderson WR Jr (2010) Transglutaminase 2, a novel regulator of eicosanoid production in asthma revealed by genome-wide expression profiling of distinct asthma phenotypes. PLoS ONE 55(1):e8583Google Scholar
  12. Gollapudi RR, Teirstein PS, Stevenson DD, Simon RA (2004) Aspirin sensitivity: implications for patients with coronary artery disease. JAMA 292(24):3017–3023PubMedCrossRefGoogle Scholar
  13. Guajardo JR, Schleifer KW, Daines MO, Ruddy RM, Aronow BJ, Wills-Karp M, Hershey GK (2005) Altered gene expression profiles in nasal respiratory epithelium reflect stable versus acute childhood asthma. J Allergy Clin Immunol 115:243–251PubMedCrossRefGoogle Scholar
  14. Hanselb NN, Hilmera SC, Georasb SN, Copece LM, Guob J, Irizarryc RA, Diettebd GB (2005) Oligonucleotide microarray analysis of peripheral-blood lymphocytes in severe asthma. J Lab Clin Med 145:263–274CrossRefGoogle Scholar
  15. Huang DW, Sherman BT, Lempicki RA (2009) Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nature Protoc 4(1):44–57CrossRefGoogle Scholar
  16. Kalady MF, Dejulius K, Church JM, Lavery IC, Fazio VW, Ishwaran H (2010) Gene signature is associated with early stage rectal cancer recurrence. J Am Coll Surg 211(2):187–195PubMedCrossRefGoogle Scholar
  17. Kanehisa M, Goto S (1999) KEGG: Kyoto encyclopedia of genes and genomes. Nucleic Acids Res 27(1):29–34PubMedCrossRefGoogle Scholar
  18. Kavuru MS, Dweik RA, Thomassen MJ (1999) Role of bronchoscopy in asthma research. Clin Chest Med 20:153–189PubMedCrossRefGoogle Scholar
  19. Kim BS, Park SM, Uhm TG, Kang JH, Park JS, Jang AS, Uh ST, Kim MK, Choi IS, Cho SH, Hong CS, Lee YW, Lee JY, Choi BW, Park HS, Park BL, Shin HD, Chung IY, Park CS (2010a) Effect of single nucleotide polymorphisms within the interleukin-4 promoter on aspirin intolerance in asthmatics and interleukin-4 promoter activity. Pharmacogenet Genomics 20(12):748–758PubMedGoogle Scholar
  20. Kim JH, Park BL, Cheong HS, Bae JS, Park JS, Jang AS, Uh ST, Choi JS, Kim YH, Kim MK, Choi IS, Cho SH, Choi BW, Park CS, Shin HD (2010b) Genome-wide and follow-up studies identify CEP68 gene variants associated with risk of aspirin-intolerant asthma. PLoS ONE 5(11):e13818PubMedCrossRefGoogle Scholar
  21. Kim JY, Kim JH, Park BL, Cheong HS, Park JS, Jang AS, Uh ST, Choi JS, Kim YH, Kim MK, Choi IS, Cho SH, Choi BW, Park CS, Shin HD (2010c) Putative association of SMAPIL polymorphisms with risk of aspirin intolerance in asthmatics. J Asthma 47(9):959–965PubMedGoogle Scholar
  22. Kim JH, Cha JY, Cheong HS, Park JS, Jang AS, Uh ST, Kim MK, Choi IS, Cho SH, Park BL, Bae JS, Park CS, Shin HD. KIF3A (2011) A cilia structural gene on chromosome 5q31, and its polymorphisms show an association with aspirin hypersensitivity in asthma. J Clin Immunol 31(1):112–121Google Scholar
  23. Kopp E, Ghosh S (1994) Inhibition of NF-kappa B by sodium salicylate and aspirin. Science 265:956–959PubMedCrossRefGoogle Scholar
  24. Korbinian Strimmer (2008) fdrtool: a versatile R package for estimating local and tail area-based false discovery rates. Bioinformatics 24(12):1461–1462Google Scholar
  25. Kraft P, Wacholder S, Cornelis MC, Hu FB, Hayes RB, Thomas G, Hoover R, Hunter DJ, Chanock S (2009) Beyond odds ratios—communicating disease risk based on genetic profiles. Nat Rev Genet 10:264–269PubMedCrossRefGoogle Scholar
  26. Kruskal WH, Tanur JM (eds) (1978) Linear hypotheses, international encyclopedia of statistics. Colm Macmillan Publishers, LondonGoogle Scholar
  27. Lee RU, Stevenson DD (2011) Aspirin-exacerbated respiratory disease: evaluation and management. Allergy Asthma Immunol Res 3(1):3–10PubMedCrossRefGoogle Scholar
  28. Lee JS, Kim JH, Bae JS, Kim JY, Park TJ, Pasaje CF, Park BL, Cheong HS, Park JS, Uh ST, Kim MK, Choi IS, Cho SH, Choi BW, Park CS, Shin HD (2010a) Association analysis of UBE3C polymorphisms in Korean aspirin-intolerant asthmatic patients. Ann Allergy Asthma Immunol 105(4):307–312PubMedCrossRefGoogle Scholar
  29. Lee JS, Kim JH, Bae JS, Kim JY, Park TJ, Pasaje CF, Park BL, Cheong HS, Uh ST, Park JS, Jang AS, Kim MK, Choi IS, Park CS, Shin HD (2010b) Association of CACNG6 polymorphisms with aspirin-intolerance asthmatics in a Korean population. BMC Med Genet 11:138PubMedCrossRefGoogle Scholar
  30. Leff AR (2001) Regulation of leukotrienes in the management of asthma: biology and clinical therapy. Annu Rev Med 52:1–14PubMedCrossRefGoogle Scholar
  31. Lilly CM, Tateno H, Oguma T, Israel E, Sonna LA (2005) Effects of allergen challenge on airway epithelial cell gene expression. Am J Respir Crit Care Med 171:579–586PubMedCrossRefGoogle Scholar
  32. Oh SH, Park SM, Park JS, Jang AS, Lee YM, Uh ST, Kim YH, Choi IS, Kim MK, Park BL, Shin HD, Park CS (2009) Association analysis of peroxisome proliferator-activated receptors gamma gene polymorphisms with aspirin hypersensitivity in asthmatics. Allergy Asthma Immunol Res 1(1):30–35PubMedCrossRefGoogle Scholar
  33. Pasaje CF, Kim JH, Park BL, Cheong HS, Kim MK, Choi IS, Cho SH, Hong CS, Lee YW, Lee JY, Koh IS, Park TJ, Lee JS, Kim Y, Bae JS, Park CS, Shin HD (2011) A possible association of EMID2 polymorphisms with aspirin hypersensitivity in asthma. Immunogenetics 63(1):13–21PubMedCrossRefGoogle Scholar
  34. Peat G, Thomas E, Duncan R, Wood L (2010) Is “false-positive” clinical diagnosis of knee osteoarthritis just the early diagnosis of pre-radiographic disease? Arthritis Care Res (Hoboken) 62(10):1502–1506CrossRefGoogle Scholar
  35. Perez-G M, Melo M, Keegan AD, Zamorano J (2002) Aspirin and salicylates inhibit the IL-4 and IL-13 induced activation of STAT6. J Immunol 168:1428–1434Google Scholar
  36. Perkins EM, Clarkson YL, Sabatier N, Longhurst DM, Millward CP, Jack J, Toraiwa J, Watanabe M, Rothstein JD, Lyndon AR, Wyllie DJ, Dutia MB, Jackson M (2010) Loss of beta-III spectrin leads to Purkinje cell dysfunction recapitulating the behavior and neuropathology of spinocerebellar ataxia type 5 in humans. J Neurosci 30(14):4857–4867PubMedCrossRefGoogle Scholar
  37. Rom WN, Goldberg JD, Addrizzo-Harris D, Watson HN, Khilkin M, Greenberg AK, Naidich DP, Crawford B, Eylers E, Liu D, Tan EM (2010) Identification of an autoantibody panel to separate lung cancer from smokers and nonsmokers. BMC Cancer 10(1):234PubMedCrossRefGoogle Scholar
  38. Samter M, Beers RF (1967) Concerning the nature of intolerance to aspirin. J Allergy 40:281–293PubMedCrossRefGoogle Scholar
  39. Sousa AR, Parikh A, Scadding G, Corrigan CJ, Lee TH (2002) Leukotriene receptor expression on nasal mucosal inflammatory cells in aspirin-sensitive rhinosinusitis. N Engl J Med 347:1493–1499PubMedCrossRefGoogle Scholar
  40. Subrata LS, Bizzintino J, Mamessier E, Bosco A, McKenna KL, Wikström ME, Goldblatt J, Sly PD, Hales BJ, Thomas WR, Laing IA, LeSouëf PN, Holt PG (2009) Interactions between innate antiviral and atopic immunoinflammatory pathways precipitate and sustain asthma exacerbations in children. J Immunol 15183(4):2793–2800CrossRefGoogle Scholar
  41. Szczeklik A, Nizankowska E (2000) Clinical features and diagnosis of aspirin induced asthma. Thorax 55(Suppl 2):S42–S44PubMedCrossRefGoogle Scholar
  42. Szczeklik A, Nizankowska E, Duplaga M (2000) Natural history of aspirin-induced asthma. AIANE investigators. European network on aspirin-induced asthma Eur Respir J 16(3):432–436Google Scholar
  43. Szefler SJ, Phillips BR, Martinez FD, Chinchilli VM, Lemanske RF Jr, Strunk RC, Zeiger RS, Larsen G, Spahn JD, Bacharier LB, Bloomberg GR, Guilbert TW, Heldt G, Morgan WJ, Moss MH, Sorkness CA, Taussig LM (2005) Characterization of within-subject responses to fluticasone and montelukast in childhood asthma. J Allergy Clin Immunol 115:233–242PubMedCrossRefGoogle Scholar
  44. Thenappan A, Li Y, Kitisin K, Rashid A, Shetty K, Johnson L, Mishra L (2010) Role of transforming growth factor beta signaling and expansion of progenitor cells in regenerating liver. Hepatology 51(4):1373–1382PubMedCrossRefGoogle Scholar
  45. Yang SH, Kim JS, Oh TJ, Kim MS, Lee SW, Woo SK, Cho HS, Choi YH, Kim YH, Rha SY, Chung HC, An SW (2003) Genome-scale analysis of resveratrol-induced gene expression profile in human ovarian cancer cells using a cDNA microarray. Int J Oncol 22:741–750PubMedGoogle Scholar
  46. Zhao H, Shen J, Medico L, Wang D, Ambrosone CB, Liu S (2010) A pilot study of circulating miRNAs as potential biomarkers of early stage breast cancer. PLoS ONE 5(10):e13735PubMedCrossRefGoogle Scholar
  47. Ziera T, Irlbacher H, Fromm A, Latouche C, Krug SM, Fromm M, Jaisser F, Borden SA (2009) Cnksr3 is a direct mineralocorticoid receptor target gene and plays a key role in the regulation of the epithelial sodium channel. FASEB J 23(11):3936–3946PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  • SeungWoo Shin
    • 1
  • Jong Sook Park
    • 1
  • Yoon-Jeong Kim
    • 1
  • TaeJeong Oh
    • 1
    • 2
  • Sungwhan An
    • 2
  • Choon-Sik Park
    • 1
  1. 1.Genome Research Center for Allergy and Respiratory DiseaseSoonchunhyang University Bucheon HospitalBucheonSouth Korea
  2. 2.Genomictree, Inc.DaejeonSouth Korea

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