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Hypersensitivity reactions to nonsteroidal anti-inflammatory drugs: an update on pharmacogenetics studies

    María del Carmen Plaza-Serón

    Research Laboratory-Allergy Unit, Biomedical Institute of Malaga (IBIMA), Regional University Hospital of Malaga (Carlos Haya Hospital), Avda. Hospital Civil s/n, 29009 Malaga, Spain

    ,
    Elena García-Martín

    University Institute of Molecular Pathology Biomarkers, UEx. ARADyAL Instituto de Salud Carlos III, Cáceres, Spain

    ,
    Jose Augusto Agúndez

    University Institute of Molecular Pathology Biomarkers, UEx. ARADyAL Instituto de Salud Carlos III, Cáceres, Spain

    &
    Pedro Ayuso

    *Author for correspondence:

    E-mail Address: payupar@liverpool.ac.uk

    Infection Pharmacology Group, Department of Molecular & Clinical Pharmacology University of Liverpool, L69 3GF, Liverpool, UK

    Published Online:https://doi.org/10.2217/pgs-2018-0079

    Nonsteroidal anti-inflammatory drugs are the medications most frequently involved in hypersensitivity reactions to drugs. These can be induced by specific immunological and nonimmunological mechanisms, being the latter the most frequent. The nonimmunological mechanism is related to an imbalance of inflammatory mediators, which is aggravated by the cyclooxygenase inhibition. Genetic studies suggest that multiples genes and additional mechanisms might be involved. The proposals of this review is summarize the contribution of variations in genes involved in the arachidonic acid, inflammatory and immune pathways as well as the recent genome-wide association studies findings related to cross-intolerant nonsteroidal anti-inflammatory drugs hypersensitivity reactions. In addition, using integration of different genetic studies, we propose new target genes. This will help to understand the underlying mechanism of these reactions.

    References

    • 1 International drug monitoring: the role of national centres. Report of a WHO meeting. World Health Organ. Tech. Rep. Ser. 498, 1–25 (1972).
    • 2 Dona I, Blanca-Lopez N, Torres MJ et al. Drug hypersensitivity reactions: response patterns, drug involved, and temporal variations in a large series of patients. J. Investig. Allergol. Clin. Immunol. 22(5), 363–371 (2012).
    • 3 Kowalski ML, Asero R, Bavbek S et al. Classification and practical approach to the diagnosis and management of hypersensitivity to nonsteroidal anti-inflammatory drugs. Allergy 68(10), 1219–1232 (2013).
    • 4 Vane JR. Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs. Nat. New Biol. 231(25), 232–235 (1971).
    • 5 Harizi H, Corcuff JB, Gualde N. Arachidonic-acid-derived eicosanoids: roles in biology and immunopathology. Trends Mol. Med. 14(10), 461–469 (2008).
    • 6 Sanak M. Eicosanoid mediators in the airway inflammation of asthmatic patients: what is new? Allergy Asthma Immunol. Res. 8(6), 481–490 (2016).
    • 7 Smith WL, Dewitt DL, Garavito RM. Cyclooxygenases: structural, cellular, and molecular biology. Annu. Rev. Biochem. 69, 145–182 (2000).
    • 8 Agundez JA, Gonzalez-Alvarez DL, Vega-Rodriguez MA, Botello E, Garcia-Martin E. Gene variants and haplotypes modifying transcription factor binding sites in the human cyclooxygenase 1 and 2 (PTGS1 and PTGS2) genes. Curr. Drug Metab. 15(2), 182–195 (2014).
    • 9 Agundez JA, Blanca M, Cornejo-Garcia JA, Garcia-Martin E. Pharmacogenomics of cyclooxygenases. Pharmacogenomics 16(5), 501–522 (2015).
    • 10 Ayuso P, Plaza-Seron Mdel C, Blanca-Lopez N et al. Genetic variants in arachidonic acid pathway genes associated with NSAID-exacerbated respiratory disease. Pharmacogenomics 16(8), 825–839 (2015).
    • 11 Cornejo-García Ja JL, Jagemann LR, Blanca-López N et al. Genetic variants of the arachidonic acid pathway in non-steroidal anti-inflammatory drug-induced acute urticaria. Allergy 42(12), 1772–1781 (2012).
    • 12 Szczeklik W, Sanak M, Szczeklik A. Functional effects and gender association of COX-2 gene polymorphism G-765C in bronchial asthma. J. Allergy Clin. Immunol. 114(2), 248–253 (2004).
    • 13 Oh SH, Kim YH, Park SM et al. Association analysis of thromboxane A synthase 1 gene polymorphisms with aspirin intolerance in asthmatic patients. Pharmacogenomics 12(3), 351–363 (2011).
    • 14 Vidal C, Porras-Hurtado L, Cruz R et al. Association of thromboxane A1 synthase (TBXAS1) gene polymorphism with acute urticaria induced by nonsteroidal anti-inflammatory drugs. J. Allergy Clin. Immunol. 132(4), 989–991 (2013).
    • 15 Kim SH, Kim YK, Park HW et al. Association between polymorphisms in prostanoid receptor genes and aspirin-intolerant asthma. Pharmacogenet. Genomics 17(4), 295–304 (2007).
    • 16 Palikhe NS, Kim SH, Lee HY, Kim JH, Ye YM, Park HS. Association of thromboxane A2 receptor (TBXA2R) gene polymorphism in patients with aspirin-intolerant acute urticaria. Clin. Exp. Allergy 41(2), 179–185 (2011).
    • 17 Choi JH, Park HS, Oh HB et al. Leukotriene-related gene polymorphisms in ASA-intolerant asthma: an association with a haplotype of 5-lipoxygenase. Hum. Genet. 114(4), 337–344 (2004).
    • 18 In KH, Asano K, Beier D et al. Naturally occurring mutations in the human 5-lipoxygenase gene promoter that modify transcription factor binding and reporter gene transcription. J. Clin. Invest. 99(5), 1130–1137 (1997).
    • 19 Park JS, Chang HS, Park CS et al. Association analysis of cysteinyl-leukotriene receptor 2 (CYSLTR2) polymorphisms with aspirin intolerance in asthmatics. Pharmacogenet. Genomics 15(7), 483–492 (2005).
    • 20 Kim SH, Choi JH, Holloway JW et al. Leukotriene-related gene polymorphisms in patients with aspirin-intolerant urticaria and aspirin-intolerant asthma: differing contributions of ALOX5 polymorphism in Korean population. J. Korean Med. Sci. 20(6), 926–931 (2005).
    • 21 Plaza-Seron Mdel C, Ayuso P, Perez-Sanchez N et al. Copy number variation in ALOX5 and PTGER1 is associated with NSAIDs-induced urticaria and/or angioedema. Pharmacogenet. Genomics 26(6), 280–287 (2016).
    • 22 Adamjee J, Suh YJ, Park HS et al. Expression of 5-lipoxygenase and cyclooxygenase pathway enzymes in nasal polyps of patients with aspirin-intolerant asthma. J. Pathol. 209(3), 392–399 (2006).
    • 23 Sanak M, Simon HU, Szczeklik A. Leukotriene C4 synthase promoter polymorphism and risk of aspirin-induced asthma. Lancet 350(9091), 1599–1600 (1997).
    • 24 Sanak M, Pierzchalska M, Bazan-Socha S, Szczeklik A. Enhanced expression of the leukotriene C(4) synthase due to overactive transcription of an allelic variant associated with aspirin-intolerant asthma. Am. J. Respir. Cell Mol. Biol. 23(3), 290–296 (2000).
    • 25 Mastalerz L, Setkowicz M, Sanak M, Szczeklik A. Hypersensitivity to aspirin: common eicosanoid alterations in urticaria and asthma. J. Allergy Clin. Immunol. 113(4), 771–775 (2004).
    • 26 Sanchez-Borges M, Acevedo N, Vergara C et al. The A-444C polymorphism in the leukotriene C4 synthase gene is associated with aspirin-induced urticaria. J. Investig. Allergol. Clin. Immunol. 19(5), 375–382 (2009).
    • 27 Kawagishi Y, Mita H, Taniguchi M et al. Leukotriene C4 synthase promoter polymorphism in Japanese patients with aspirin-induced asthma. J. Allergy Clin. Immunol. 109(6), 936–942 (2002).
    • 28 Van Sambeek R, Stevenson DD, Baldasaro M et al. 5′ flanking region polymorphism of the gene encoding leukotriene C4 synthase does not correlate with the aspirin-intolerant asthma phenotype in the United States. J. Allergy Clin. Immunol. 106(1 Pt 1), 72–76 (2000).
    • 29 Lee HY, Kim SH, Ye YM, Choi GS, Park HS. Lack of association of ALOX12 and ALOX15 polymorphisms with aspirin-exacerbated respiratory disease in Korean patients. Ann. Allergy Asthma Immunol. 103(1), 84–86 (2009).
    • 30 Song YS, Yang EM, Kim SH, Jin HJ, Park HS. Effect of genetic polymorphism of ALOX15 on aspirin-exacerbated respiratory disease. Int. Arch. Allergy Immunol. 159(2), 157–161 (2012).
    • 31 Corrigan CJ, Napoli RL, Meng Q et al. Reduced expression of the prostaglandin E2 receptor E-prostanoid 2 on bronchial mucosal leukocytes in patients with aspirin-sensitive asthma. J. Allergy Clin. Immunol. 129(6), 1636–1646 (2012).
    • 32 Jinnai N, Sakagami T, Sekigawa T et al. Polymorphisms in the prostaglandin E2 receptor subtype 2 gene confer susceptibility to aspirin-intolerant asthma: a candidate gene approach. Hum. Mol. Genet. 13(24), 3203–3217 (2004).
    • 33 Park BL, Park SM, Park JS et al. Association of PTGER gene family polymorphisms with aspirin intolerant asthma in Korean asthmatics. BMB Rep. 43(6), 445–449 (2010).
    • 34 Palikhe NS, Sin HJ, Kim SH, Hwang EK, Ye YM, Park HS. Genetic variability of prostaglandin E2 receptor subtype EP4 gene in aspirin-intolerant chronic urticaria. J. Hum. Genet. 57(8), 494–499 (2012).
    • 35 Sousa AR, Parikh A, Scadding G, Corrigan CJ, Lee TH. Leukotriene-receptor expression on nasal mucosal inflammatory cells in aspirin-sensitive rhinosinusitis. N. Engl. J. Med. 347(19), 1493–1499 (2002).
    • 36 Mita H, Hasegawa M, Saito H, Akiyama K. Levels of cysteinyl leukotriene receptor mRNA in human peripheral leucocytes: significantly higher expression of cysteinyl leukotriene receptor 2 mRNA in eosinophils. Clin. Exp. Allergy 31(11), 1714–1723 (2001).
    • 37 Kim SH, Oh JM, Kim YS et al. Cysteinyl leukotriene receptor 1 promoter polymorphism is associated with aspirin-intolerant asthma in males. Clin. Exp. Allergy 36(4), 433–439 (2006).
    • 38 Kim SH, Yang EM, Park HJ, Ye YM, Lee HY, Park HS. Differential contribution of the CysLTR1 gene in patients with aspirin hypersensitivity. J. Clin. Immunol. 27(6), 613–619 (2007).
    • 39 Shin JA, Chang HS, Park SM et al. Genetic effect of CysLTR2 polymorphisms on its mRNA synthesis and stabilization. BMC Med Genet 10, 106 (2009).
    • 40 Kim JM, Park BL, Park SM et al. Association analysis of N-acetyl transferase-2 polymorphisms with aspirin intolerance among asthmatics. Pharmacogenomics 11(7), 951–958 (2010).
    • 41 Martinez C, Andreu I, Amo G et al. Gender and functional CYP2C and NAT2 polymorphisms determine the metabolic profile of metamizole. Biochem. Pharmacol. 92(3), 457–466 (2014).
    • 42 Garcia-Martin E, Esguevillas G, Blanca-Lopez N et al. Genetic determinants of metamizole metabolism modify the risk of developing anaphylaxis. Pharmacogenet. Genomics 25(9), 462–464 (2015).
    • 43 Demoly P, Hellings P, Muraro A et al. Global Atlas of Allergy. In: Global Atlas of Allergy. Akdis AC (Ed.). European Academy of Allergyand Clinical Immunology, Zurich, Switzerland (2014).
    • 44 Garcia-Martin E, Ayuso P, Martinez C, Blanca M, Agundez JA. Histamine pharmacogenomics. Pharmacogenomics 10(5), 867–883 (2009).
    • 45 Kim SH, Kang YM, Cho BY, Ye YM, Hur GY, Park HS. Histamine N-methyltransferase 939A>G polymorphism affects mRNA stability in patients with acetylsalicylic acid-intolerant chronic urticaria. Allergy 64(2), 213–221 (2009).
    • 46 Choi JH, Kim SH, Suh CH, Nahm DH, Park HS. Polymorphisms of high-affinity IgE receptor and histamine-related genes in patients with ASA-induced urticaria/angioedema. J. Korean Med. Sci. 20(3), 367–372 (2005).
    • 47 Ferreira Vasconcelos LM, Rodrigues RO, Albuquerque AA et al. Polymorphism of IL10, IL4, CTLA4, and DAO genes in cross-reactive nonsteroidal anti-inflammatory drug hypersensitivity. J. Clin. Pharmacol. 58(1), 107–113 (2018).
    • 48 Ayuso P, Garcia-Martin E, Martinez C, Agundez JA. Genetic variability of human diamine oxidase: occurrence of three nonsynonymous polymorphisms and study of their effect on serum enzyme activity. Pharmacogenet. Genomics 17(9), 687–693 (2007).
    • 49 Maintz L, Yu CF, Rodriguez E et al. Association of single nucleotide polymorphisms in the diamine oxidase gene with diamine oxidase serum activities. Allergy 66(7), 893–902 (2011).
    • 50 Garcia-Martin E, Ayuso P, Martinez C, Agundez JA. Improved analytical sensitivity reveals the occurrence of gender-related variability in diamine oxidase enzyme activity in healthy individuals. Clin. Biochem. 40(16–17), 1339–1341 (2007).
    • 51 Agundez JA, Ayuso P, Cornejo-Garcia JA et al. The diamine oxidase gene is associated with hypersensitivity response to non-steroidal anti-inflammatory drugs. PLoS ONE 7(11), e47571 (2012).
    • 52 Ayuso P, Blanca M, Cornejo-Garcia JA et al. Variability in histamine receptor genes HRH1, HRH2 and HRH4 in patients with hypersensitivity to NSAIDs. Pharmacogenomics 14(15), 1871–1878 (2013).
    • 53 Kim SH, Kim YK, Park HW, Ye YM, Min KU, Park HS. Adenosine deaminase and adenosine receptor polymorphisms in aspirin-intolerant asthma. Respir. Med. 103(3), 356–363 (2009).
    • 54 Kim SH, Nam EJ, Kim YK, Ye YM, Park HS. Functional variability of the adenosine A3 receptor (ADORA3) gene polymorphism in aspirin-induced urticaria. Br. J. Dermatol. 163(5), 977–985 (2010).
    • 55 Bae JS, Kim SH, Ye YM et al. Significant association of FcepsilonRIalpha promoter polymorphisms with aspirin-intolerant chronic urticaria. J. Allergy Clin. Immunol. 119(2), 449–456 (2007).
    • 56 Palikhe NS, Kim SH, Cho BY, Ye YM, Hur GY, Park HS. Association of three sets of high-affinity IgE receptor (FcepsilonR1) polymorphisms with aspirin-intolerant asthma. Respir. Med. 102(8), 1132–1139 (2008).
    • 57 Palikhe N, Kim SH, Yang EM et al. Analysis of high-affinity IgE receptor (FcepsilonR1) polymorphisms in patients with aspirin-intolerant chronic urticaria. Allergy Asthma Proc. 29(3), 250–257 (2008).
    • 58 Amo G, Cornejo-Garcia JA, Garcia-Menaya JM et al. FCERI and histamine metabolism gene variability in selective responders to NSAIDS. Front. Pharmacol. 7, 353 (2016).
    • 59 Kim SH, Ye YM, Lee SK et al. Association of TNF-alpha genetic polymorphism with HLA DPB1*0301. Clin. Exp. Allergy 36(10), 1247–1253 (2006).
    • 60 Choi JH, Kim SH, Cho BY, Lee SK, Suh CH, Park HS. Association of TNF-alpha promoter polymorphisms with aspirin-induced urticaria. J. Clin. Pharm. Ther. 34(2), 231–238 (2009).
    • 61 Hitomi Y, Ebisawa M, Tomikawa M et al. Associations of functional NLRP3 polymorphisms with susceptibility to food-induced anaphylaxis and aspirin-induced asthma. J. Allergy Clin. Immunol. 124(4), 779–785; e776 (2009).
    • 62 Kim SH, Son JK, Yang EM, Kim JE, Park HS. A functional promoter polymorphism of the human IL18 gene is associated with aspirin-induced urticaria. Br. J. Dermatol. 165(5), 976–984 (2011).
    • 63 Ryan JJ, Kashyap M, Bailey D et al. Mast cell homeostasis: a fundamental aspect of allergic disease. Crit. Rev. Immunol. 27(1), 15–32 (2007).
    • 64 Park HJ, Ye YM, Hur GY, Kim SH, Park HS. Association between a TGFbeta1 promoter polymorphism and the phenotype of aspirin-intolerant chronic urticaria in a Korean population. J. Clin. Pharm. Ther. 33(6), 691–697 (2008).
    • 65 Kim SH, Park HS, Holloway JW, Shin HD, Park CS. Association between a TGFbeta1 promoter polymorphism and rhinosinusitis in aspirin-intolerant asthmatic patients. Respir. Med. 101(3), 490–495 (2007).
    • 66 Steinke JW, Payne SC, Borish L. Interleukin-4 in the generation of the AERD phenotype: implications for molecular mechanisms driving therapeutic benefit of aspirin desensitization. J. Allergy 182090 (2012).
    • 67 Kong SK, Soo Kim B, Gi Uhm T et al. Aspirin induces IL-4 production: augmented IL-4 production in aspirin-exacerbated respiratory disease. Exp. Mol. Med. 48(1), e202 (2016).
    • 68 Kurosawa MYT, Hozawa S, Sutoh E. Single nucleotide polymorphisms in thymic stromal lymphopoietin gene are not associated with aspirin-exacerbated respiratory disease susceptibility – a pilot study in a Japanese population. J. Allergy Ther. 6(3), (2015).
    • 69 Plaza-Seron Mdel C, Blanca-Lopez N, Perez-Sanchez N et al. Genetic variants of thymic stromal lymphopoietin in nonsteroidal anti-inflammatory drug-induced urticaria/angioedema. Int. Arch. Allergy Immunol. 169(4), 249–255 (2016).
    • 70 Kim SH, Yang EM, Lee HN, Choi GS, Ye YM, Park HS. Association of the CCR3 gene polymorphism with aspirin exacerbated respiratory disease. Respir. Med. 104(5), 626–632 (2010).
    • 71 Matsuo H, Yokooji T, Morita H et al. Aspirin augments IgE-mediated histamine release from human peripheral basophils via Syk kinase activation. Allergol. Int. 62(4), 503–511 (2013).
    • 72 Ayuso P, Plaza-Seron MD, Dona I et al. Association study of genetic variants in PLA2G4A, PLCG1, LAT, SYK, and TNFRS11A genes in NSAIDs-induced urticaria and/or angioedema patients. Pharmacogenet. Genomics 25(12), 618–621 (2015).
    • 73 Hartiala J, Gilliam E, Vikman S, Campos H, Allayee H. Association of PLA2G4A with myocardial infarction is modulated by dietary PUFAs. Am. J. Clin. Nutr. 95(4), 959–965 (2012).
    • 74 Lee JS, Kim JH, Bae JS et al. Association analysis of UBE3C polymorphisms in Korean aspirin-intolerant asthmatic patients. Ann. Allergy Asthma Immunol. 105(4), 307–312 (2010).
    • 75 Mullarkey MF, Thomas PS, Hansen JA, Webb DR, Nisperos B. Association of aspirin-sensitive asthma with HLA-DQw2. Am. Rev. Respir. Dis. 133(2), 261–263 (1986).
    • 76 Agundez JA, Esguevillas G, Amo G, Garcia-Martin E. Pharmacogenomics testing for type B adverse drug reactions to anti-infective drugs: the example of hypersensitivity to abacavir. Recent Pat. Antiinfect. Drug Discov. 9(2), 151 (2014).
    • 77 Lympany PA, Welsh KI, Christie PE, Schmitz-Schumann M, Kemeny DM, Lee TH. An analysis with sequence-specific oligonucleotide probes of the association between aspirin-induced asthma and antigens of the HLA system. J. Allergy Clin. Immunol. 92(1 Pt 1), 114–123 (1993).
    • 78 Dekker JW, Nizankowska E, Schmitz-Schumann M et al. Aspirin-induced asthma and HLA-DRB1 and HLA-DPB1 genotypes. Clin. Exp. Allergy 27(5), 574–577 (1997).
    • 79 Choi JH, Lee KW, Oh HB et al. HLA association in aspirin-intolerant asthma: DPB1*0301 as a strong marker in a Korean population. J. Allergy Clin. Immunol. 113(3), 562–564 (2004).
    • 80 Esmaeilzadeh H, Nabavi M, Amirzargar AA et al. HLA-DRB and HLA-DQ genetic variability in patients with aspirin-exacerbated respiratory disease. Am. J. Rhinol. Allergy 29(3), e63–69 (2015).
    • 81 Quiralte J, Sanchez-Garcia F, Torres MJ et al. Association of HLA-DR11 with the anaphylactoid reaction caused by nonsteroidal anti-inflammatory drugs. J. Allergy Clin. Immunol. 103(4), 685–689 (1999).
    • 82 Kim SH, Choi JH, Lee KW et al. The human leucocyte antigen-DRB1*1302-DQB1*0609-DPB1*0201 haplotype may be a strong genetic marker for aspirin-induced urticaria. Clin. Exp. Allergy 35(3), 339–344 (2005).
    • 83 Pacor ML, Di Lorenzo G, Mansueto P et al. Relationship between human leucocyte antigen class I and class II and chronic idiopathic urticaria associated with aspirin and/or NSAIDs hypersensitivity. Mediators Inflamm. 2006(5), 62489 (2006).
    • 84 Pasaje CF, Bae JS, Park BL et al. A possible association between ZNRD1 and aspirin-induced airway bronchoconstriction in a Korean population. J. Investig. Allergol. Clin. Immunol. 22(3), 193–200 (2012).
    • 85 Cho SH, Park JS, Park BL et al. Association analysis of tapasin polymorphisms with aspirin-exacerbated respiratory disease in asthmatics. Pharmacogenet. Genomics 23(7), 341–348 (2013).
    • 86 Kim JH, Park BL, Cheong HS et al. Genome-wide and follow-up studies identify CEP68 gene variants associated with risk of aspirin-intolerant asthma. PLoS ONE 5(11), e13818 (2010).
    • 87 Park BL, Kim TH, Kim JH et al. Genome-wide association study of aspirin-exacerbated respiratory disease in a Korean population. Hum. Genet. 132(3), 313–321 (2013).
    • 88 Cornejo-Garcia JA, Liou LB, Blanca-Lopez N et al. Genome-wide association study in NSAID-induced acute urticaria/angioedema in Spanish and Han Chinese populations. Pharmacogenomics 14(15), 1857–1869 (2013).
    • 89 Cornejo-Garcia JA, Flores C, Plaza-Seron MC et al. Variants of CEP68 gene are associated with acute urticaria/angioedema induced by multiple non-steroidal anti-inflammatory drugs. PLoS ONE 9(3), e90966 (2014).
    • 90 Park JS, Heo JS, Chang HS et al. Association analysis of member RAS oncogene family gene polymorphisms with aspirin intolerance in asthmatic patients. DNA Cell. Bio.l 33(3), 155–161 (2014).
    • 91 Pasaje CF, Kim JH, Park BL et al. A possible association of EMID2 polymorphisms with aspirin hypersensitivity in asthma. Immunogenetics 63(1), 13–21 (2011).
    • 92 Pasaje CF, Bae JS, Park BL et al. Possible role of EMID2 on nasal polyps pathogenesis in Korean asthma patients. BMC Med. Genet. 13, 2 (2012).
    • 93 Park TJ, Kim JH, Park BL et al. Potential association of DCBLD2 polymorphisms with fall rates of FEV(1) by aspirin provocation in Korean asthmatics. J. Korean Med. Sci. 27(4), 343–349 (2012).
    • 94 Pasaje CF, Kim JH, Park BL et al. Association of SLC6A12 variants with aspirin-intolerant asthma in a Korean population. Ann. Hum. Genet. 74(4), 326–334 (2010).
    • 95 Kim SH, Choi H, Yoon MG, Ye YM, Park HS. Dipeptidyl-peptidase 10 as a genetic biomarker for the aspirin-exacerbated respiratory disease phenotype. Ann. Allergy Asthma Immunol. 114(3), 208–213 (2015).
    • 96 Szklarczyk D, Morris JH, Cook H et al. The STRING database in 2017: quality-controlled protein-protein association networks, made broadly accessible. Nucleic Acids Res. 45(D1), D362–D368 (2017).
    • 97 Baratelli F, Lin Y, Zhu L et al. Prostaglandin E2 induces FOXP3 gene expression and T regulatory cell function in human CD4+ T cells. J. Immunol. 175(3), 1483–1490 (2005).
    • 98 Esmaeilzadeh H, Nabavi M, Aryan Z, Amirzargar AA. Pharmacogenetic tests to predict the efficacy of aspirin desensitization in patients with aspirin-exacerbated respiratory diseases; HLA-DQB302. Expert Rev. Respir. Med. 9(5), 511–518 (2015).