Non-steroidal anti-inflammatory drugs (NSAIDs) are the main triggers of drug hypersensitivity reactions. Such reactions can be pharmacologically or immunologically mediated, but in both cases individual susceptibility can be influenced by genetic factors. Polymorphisms in centrosomal protein of 68 kDa (CEP68) have been associated with pharmacologically mediated NSAIDs reactions. Here, we evaluated this gene in immunologically mediated single-NSAID-induced urticaria/angioedema or anaphylaxis (SNIUAA) by analyzing 52 single nucleotide polymorphisms in CEP68 in 176 patients and 363 NSAIDs-tolerant controls. Two intronic variants (rs2241160 and rs2241161) were significantly associated with an increased risk of SNIUAA, suggesting CEP68 to be a key player in both types of NSAIDs hypersensitivity. However, we found no overlap with genetic variants previously associated with pharmacologically mediated hypersensitivity, pointing to a complex role for this gene and its potential use in the development of biomarkers of clinical utility to diagnose patients at risk of these reactions and to differentiate entities.

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  1. 1.

    Conaghan PG. A turbulent decade for NSAIDs: update on current concepts of classification, epidemiology, comparative efficacy, and toxicity. Rheumatol Int. 2012;32:1491–502.

  2. 2.

    Wertli MM, Reich O, Signorell A, Burgstaller JM, Steurer J, Held U. Changes over time in prescription practices of pain medications in Switzerland between 2006 and 2013: an analysis of insurance claims. BMC Health Serv Res. 2017;17:167.

  3. 3.

    Doña I, Blanca-Lopez N, Torres MJ, Garcia-Campos J, Garcia-Nuñez I, Gomez F, et al. Drug hypersensitivity reactions: response patterns, drug involved, and temporal variations in a large series of patients. J Investig Allergol Clin Immunol. 2012;22:363–71.

  4. 4.

    Cornejo-Garcia JA, Blanca-Lopez N, Doña I, Andreu I, Agundez JA, Carballo M, et al. Hypersensitivity reactions to non-steroidal anti-inflammatory drugs. Curr Drug Metab. 2009;10:971–80.

  5. 5.

    Faria E, Rodrigues-Cernadas J, Gaspar A, Botelho C, Castro E, Lopes A, et al. Drug-induced anaphylaxis survey in Portuguese Allergy Departments. J Investig Allergol Clin Immunol. 2014;24:40–48.

  6. 6.

    Aun MV, Blanca M, Garro LS, Ribeiro MR, Kalil J, Motta AA, et al. Nonsteroidal anti-inflammatory drugs are major causes of drug-induced anaphylaxis. J Allergy Clin Immunol Pract. 2014;2:414–20.

  7. 7.

    Ensina LF, de Lacerda AE, de Andrade DM, Machado L, Camelo-Nunes I, Sole D. Drug-induced anaphylaxis in children: nonsteroidal anti-inflammatory drugs and drug provocation test. J Allergy Clin Immunol Pract. 2014;2:825.

  8. 8.

    Kowalski ML, Asero R, Bavbek S, Blanca M, Blanca-Lopez N, Bochenek G, et al. Classification and practical approach to the diagnosis and management of hypersensitivity to nonsteroidal anti-inflammatory drugs. Allergy. 2013;68:1219–32.

  9. 9.

    Doña I, Blanca-Lopez N, Cornejo-Garcia JA, Torres MJ, Laguna JJ, Fernandez J, et al. Characteristics of subjects experiencing hypersensitivity to non-steroidal anti-inflammatory drugs: patterns of response. Clin Exp Allergy. 2011;41:86–95.

  10. 10.

    Demir S, Olgac M, Unal D, Gelincik A, Colakoglu B, Buyukozturk S. Evaluation of hypersensitivity reactions to nonsteroidal anti-inflammatory drugs according to the latest classification. Allergy. 2015;70:1461–7.

  11. 11.

    Himly M, Jahn-Schmid B, Pittertschatscher K, Bohle B, Grubmayr K, Ferreira F, et al. IgE-mediated immediate-type hypersensitivity to the pyrazolone drug propyphenazone. J Allergy Clin Immunol. 2003;111:882–8.

  12. 12.

    Harrer A, Lang R, Grims R, Braitsch M, Hawranek T, Aberer W, et al. Diclofenac hypersensitivity: antibody responses to the parent drug and relevant metabolites. PLoS One. 2010;5:e13707.

  13. 13.

    Kay E, Ben-Shoshan M Anaphylaxis to ibuprofen in a 12-year-old boy. BMJ Case Rep. 2013;1–3 2013.

  14. 14.

    Couto M, Gaspar A, Morais-Almeida M. Selective anaphylaxis to paracetamol in a child. Eur Ann Allergy Clin Immunol. 2012;44:163–6.

  15. 15.

    Cornejo-Garcia JA, Jurado-Escobar R, Doña I, Perkins JR, Agundez JA, Garcia-Martin E, et al. The genetics of drug hypersensitivity reactions. J Investig Allergol Clin Immunol. 2016;26:222–32. quiz next two pages

  16. 16.

    Jurado-Escobar R, Perkins JR, Garcia-Martin E, Isidoro-Garcia M, Doña I, Torres MJ, et al. Update on the genetic basis of drug hypersensitivity reactions. J Investig Allergol Clin Immunol. 2017;27:336–45.

  17. 17.

    Kim JH, Park BL, Cheong HS, Bae JS, Park JS, Jang AS, et al. Genome-wide and follow-up studies identify CEP68 gene variants associated with risk of aspirin-intolerant asthma. PLoS One. 2010;5:e13818.

  18. 18.

    Cornejo-Garcia JA, Flores C, Plaza-Seron MC, Acosta-Herrera M, Blanca-Lopez N, Doña I, et al. Variants of CEP68 gene are associated with acute urticaria/angioedema induced by multiple non-steroidal anti-inflammatory drugs. PLoS One. 2014;9:e90966.

  19. 19.

    Amo G, Cornejo-Garcia JA, Garcia-Menaya JM, Cordobes C, Torres MJ, Esguevillas G, et al. FCERI and histamine metabolism gene variability in selective responders to NSAIDS. Front Pharmacol. 2016;7:353.

  20. 20.

    Blanca-Lopez N, Perez-Sanchez N, Agundez JA, Garcia-Martin E, Torres MJ, Cornejo-Garcia JA, et al. Allergic reactions to metamizole: immediate and delayed responses. Int Arch Allergy Immunol. 2016;169:223–30.

  21. 21.

    Ortega N, Doña I, Moreno E, Audicana MT, Barasona MJ, Berges-Gimeno MP, et al. Practical guidelines for diagnosing hypersensitivity reactions to nonsteroidal anti-inflammatory drugs. J Investig Allergol Clin Immunol. 2014;24:308–23.

  22. 22.

    Weale ME, Depondt C, Macdonald SJ, Smith A, Lai PS, Shorvon SD, et al. Selection and evaluation of tagging SNPs in the neuronal-sodium-channel gene SCN1A: implications for linkage-disequilibrium gene mapping. Am J Hum Genet. 2003;73:551–65.

  23. 23.

    Pruim RJ, Welch RP, Sanna S, Teslovich TM, Chines PS, Gliedt TP, et al. LocusZoom: regional visualization of genome-wide association scan results. Bioinformatics. 2010;26:2336–7.

  24. 24.

    Xu Z, Taylor JA. SNPinfo: integrating GWAS and candidate gene information into functional SNP selection for genetic association studies. Nucleic Acids Res. 2009;37(Web Server issue):W600–605.

  25. 25.

    Yuan HY, Chiou JJ, Tseng WH, Liu CH, Liu CK, Lin YJ, et al. FASTSNP: an always up-to-date and extendable service for SNP function analysis and prioritization. Nucleic Acids Res. 2006;34(Web Server issue):W635–641.

  26. 26.

    Wigginton JE, Cutler DJ, Abecasis GR. A note on exact tests of Hardy-Weinberg equilibrium. Am J Hum Genet. 2005;76:887–93.

  27. 27.

    Pino-Yanes M, Corrales A, Basaldua S, Hernandez A, Guerra L, Villar J, et al. North African influences and potential bias in case-control association studies in the Spanish population. PLoS One. 2011;6:e18389.

  28. 28.

    Li Y, Willer CJ, Ding J, Scheet P, Abecasis GR. MaCH: using sequence and genotype data to estimate haplotypes and unobserved genotypes. Genet Epidemiol. 2010;34:816–34.

  29. 29.

    Genomes Project C, Abecasis GR, Auton A, Brooks LD, DePristo MA, Durbin RM, et al. An integrated map of genetic variation from 1,092 human genomes. Nature. 2012;491:56–65.

  30. 30.

    Garcia-Closas M, Lubin JH. Power and sample size calculations in case-control studies of gene-environment interactions: comments on different approaches. Am J Epidemiol. 1999;149:689–92.

  31. 31.

    Asero R. Single NSAID hypersensitivity is associated with atopic status. Eur Ann Allergy Clin Immunol. 2015;47:48–53.

  32. 32.

    Consortium EP. An integrated encyclopedia of DNA elements in the human genome. Nature. 2012;489:57–74.

  33. 33.

    Hirose T, Steitz JA. Position within the host intron is critical for efficient processing of box C/D snoRNAs in mammalian cells. Proc Natl Acad Sci USA. 2001;98:12914–9.

  34. 34.

    Kim YK, Kim VN. Processing of intronic microRNAs. EMBO J. 2007;26:775–83.

  35. 35.

    Alekseyenko AV, Kim N, Lee CJ. Global analysis of exon creation versus loss and the role of alternative splicing in 17 vertebrate genomes. RNA. 2007;13:661–70.

  36. 36.

    Burgner D, Davila S, Breunis WB, Ng SB, Li Y, Bonnard C, et al. A genome-wide association study identifies novel and functionally related susceptibility Loci for Kawasaki disease. PLoS Genet. 2009;5:e1000319.

  37. 37.

    Low SK, Takahashi A, Ebana Y, Ozaki K, Christophersen IE, Ellinor PT, et al. Identification of six new genetic loci associated with atrial fibrillation in the Japanese population. Nat Genet. 2017;49:953–8.

  38. 38.

    Kumar A, Shetty J, Kumar B, Blanton SH. Confirmation of linkage and refinement of the RP28 locus for autosomal recessive retinitis pigmentosa on chromosome 2p14-p15 in an Indian family. Mol Vis. 2004;10:399–402.

  39. 39.

    Kang X, Liu H, Onaitis MW, Liu Z, Owzar K, Han Y, et al. Polymorphisms of the centrosomal gene (FGFR1OP) and lung cancer risk: a meta-analysis of 14,463 cases and 44,188 controls. Carcinogenesis. 2016;37:280–9.

  40. 40.

    Hussain MS, Baig SM, Neumann S, Nurnberg G, Farooq M, Ahmad I, et al. A truncating mutation of CEP135 causes primary microcephaly and disturbed centrosomal function. Am J Hum Genet. 2012;90:871–8.

  41. 41.

    Lee JE, Silhavy JL, Zaki MS, Schroth J, Bielas SL, Marsh SE, et al. CEP41 is mutated in Joubert syndrome and is required for tubulin glutamylation at the cilium. Nat Genet. 2012;44:193–9.

  42. 42.

    Kumar A, Purohit R. Computational investigation of pathogenic nsSNPs in CEP63 protein. Gene. 2012;503:75–82.

  43. 43.

    Maheshwari R, Dhathathreyan A. Investigation of surface properties of amino acids: polarity scale for amino acids as a means to predict surface exposed residues in films of proteins. J Colloid Interface Sci. 2004;277:79–83.

  44. 44.

    Andersen JS, Wilkinson CJ, Mayor T, Mortensen P, Nigg EA, Mann M. Proteomic characterization of the human centrosome by protein correlation profiling. Nature. 2003;426:570–4.

  45. 45.

    Graser S, Stierhof YD, Nigg EA. Cep68 and Cep215 (Cdk5rap2) are required for centrosome cohesion. J Cell Sci. 2007;120(Pt 24):4321–31.

  46. 46.

    Chen Y, Low TY, Choong LY, Ray RS, Tan YL, Toy W, et al. Phosphoproteomics identified Endofin, DCBLD2, and KIAA0582 as novel tyrosine phosphorylation targets of EGF signaling and Iressa in human cancer cells. Proteomics. 2007;7:2384–97.

  47. 47.

    Kim Y, Kim K, Park D, Eom S, Park H, Lee H, et al. Integrin alpha(5) interacts with EGFR, is necessary for FcvarepsilonRI signaling and is necessary for allergic inflammation in relation with angiogenesis. Mol Immunol. 2011;48:1035–45.

  48. 48.

    Hirota N, Risse PA, Novali M, McGovern T, Al-Alwan L, McCuaig S, et al. Histamine may induce airway remodeling through release of epidermal growth factor receptor ligands from bronchial epithelial cells. FASEB J. 2012;26:1704–16.

  49. 49.

    McGovern T, Risse PA, Tsuchiya K, Hassan M, Frigola G, Martin JG. LTD(4) induces HB-EGF-dependent CXCL8 release through EGFR activation in human bronchial epithelial cells. Am J Physiol Lung Cell Mol Physiol. 2010;299:L808–815.

  50. 50.

    Holowka D, Wilkes M, Stefan C, Baird B. Roles for Ca2+ mobilization and its regulation in mast cell functions: recent progress. Biochem Soc Trans. 2016;44:505–9.

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This work was supported by grants co-funded by the European Regional Development Fund (ERDF), from the Carlos III National Health Institute (ARADyAL network RD16/0006/0001, RD16/0006/004, RD16/0006/0007, RD16/0006/0019, PI15/00303, and PI17/01593), and the Health Government of Andalusia (PI-0463-2013), and Junta de Extremadura (IB16170). JA Cornejo-García is a researcher from the Miguel Servet Program (Ref CP14/00034), JR Perkins from the Sara Borrell Program (Ref CD14/00242), and I Doña from the Juan Rodés Program (Ref JR15/0036both from the Carlos III National Health Institute, Spanish Ministry of Economy and Competitiveness). M Acosta-Herrera is recipient of a Juan de la Cierva fellowship (FJCI-2015-24028) from the Spanish Ministry of Economy, Industry and Competitiveness. We thank the Malaga Hospital-IBIMA Biobank, belonging to the Andalusian Public Health System Biobank and the National Biobank Platform (project PT13/ 0010/0006, PT13/0010/0033), for sample management, and Dr. Juan Miguel Gómez Zumaquero from the Genomic Unit of IBIMA for his help with genotyping.

Author information


  1. Research Laboratory, IBIMA, Regional University Hospital of Malaga, UMA, Malaga, Spain

    • James R. Perkins
    • , María C. Plaza-Serón
    • , Raquel Jurado-Escobar
    • , Cristobalina Mayorga
    •  & José A. Cornejo-García
  2. ARADyAL Network. Instituto de Salud Carlos III, Madrid, Spain

    • James R. Perkins
    • , Inmaculada Doña
    • , Elena García-Martín
    • , María Isidoro-García
    • , Joan Bartra
    • , Cristobalina Mayorga
    • , María J. Torres
    •  & José A. Cornejo-García
  3. Instituto de Parasitología y Biomedicina López-Neyra, IPBLN-CSIC, P.T.S., Granada, Spain

    • Marialbert Acosta-Herrera
  4. Allergy Unit, IBIMA, Regional University Hospital of Malaga, UMA, Malaga, Spain

    • Inmaculada Doña
    •  & María J. Torres
  5. Department of Pharmacology, University of Extremadura, Caceres, Spain

    • Elena García-Martín
  6. Department of Clinical Biochemistry, Pharmacogenetics Unit, University Hospital of Salamanca, Salamanca, Spain

    • María Isidoro-García
  7. Allergy Department, Institute for Biomedical Research of Salamanca (IBSAL), Salamanca, Spain

    • María Isidoro-García
  8. Department of Medicine, Faculty of Medicine, University of Salamanca, Salamanca, Spain

    • María Isidoro-García
  9. Unitat d´Allergia, Servei de Pneumologia, Hospital Clinic, Universitat de Barcelona, Barcelona, Spain

    • Joan Bartra
  10. Institut d´Investigacions Biomediques August Pi I Sunyer (IDIBAPS), Barcelona, Spain

    • Joan Bartra
  11. Allergy Unit and Faculty of Dentistry, Virgen Macarena Hospital and University of Seville, Seville, Spain

    • David Ribas-Perez
  12. CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain

    • Carlos Flores
  13. Research Unit, Hospital Universitario Nuestra Señora de Candelaria, Santa Cruz de Tenerife, Spain

    • Carlos Flores
  14. Genomics Division, Instituto Tecnológico y de Energías Renovables (ITER), Tenerife, Spain

    • Carlos Flores


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The authors declare that they have no conflict of interest.

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Correspondence to José A. Cornejo-García.

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