title: Variants of CEP68 gene are associated with acute urticaria/angioedema induced by multiple non-steroidal anti-inflammatory drugs.
abstract: Non-steroidal anti-inflammatory drugs (NSAIDs) are the most consumed drugs worldwide because of their efficacy and utility in the treatment of pain and inflammatory diseases. However, they are also responsible for an important number of adverse effects including hypersensitivity reactions. The most important group of these reactions is triggered by non-immunological, pharmacological mechanisms catalogued under the denomination of cross-intolerance (CRI), with acute urticaria/angioedema induced by multiple NSAIDs (MNSAID-UA) the most frequently associated clinical entity. A recent genome-wide association study identified the gene encoding the centrosomal protein of 68 KDa (CEP68) as the major locus associated with aspirin intolerance susceptibility in asthmatics. In this study, we aimed to assess the role of this locus in susceptibility to CRI to NSAIDs by examining 53 common gene variants in a total of 635 patients that were classified as MNSAID-UA (n = 399), airway exacerbations (n = 110) or blended pattern (n = 126), and 425 controls. We found in the MNSAID-UA group a number of variants (17) associated (lowest p-value = 1.13 × 10(-6)), including the non-synonymous Gly74Ser variant (rs7572857) previously associated with aspirin intolerance susceptibility in asthmatics. Although not being significant in the context of multiple testing, eight of these variants were also associated with exacerbated respiratory disease or blended reactions. Our results suggest that CEP68 gene variants may play an important role in MNSAID-UA susceptibility and, despite the different regulatory mechanisms involved depending on the specific affected organ, in the development of hypersensitivity reactions to NSAIDs.
authors.affiliation: Research Laboratory, IBIMA-Málaga University General Hospital, Málaga, Spain.
authors.forename: José Antonio
authors.initials: JA
authors.lastname: Cornejo-García
authors.affiliation: Centro de Investigación Biomédica en Red (CIBER) de Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain; Research Unit, Hospital Universitario N.S. de Candelaria, Tenerife, Spain; Applied Genomics Group (G2A), Genetics Laboratory, Instituto Universitario de Enfermedades Tropicales y Salud Pública de Canarias, Universidad de La Laguna, Tenerife, Spain.
authors.forename: Carlos
authors.initials: C
authors.lastname: Flores
authors.affiliation: Research Laboratory, IBIMA-Málaga University General Hospital, Málaga, Spain.
authors.forename: María C
authors.initials: MC
authors.lastname: Plaza-Serón
authors.affiliation: Centro de Investigación Biomédica en Red (CIBER) de Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain; Research Unit, Hospital Universitario N.S. de Candelaria, Tenerife, Spain; Research Unit, Hospital Universitario Dr. Negrín, Las Palmas de Gran Canaria, Spain.
authors.forename: Marialbert
authors.initials: M
authors.lastname: Acosta-Herrera
authors.affiliation: Allergy Service, Infanta Leonor Hospital, Madrid, Spain.
authors.forename: Natalia
authors.initials: N
authors.lastname: Blanca-López
authors.affiliation: Unidad de Gestión Clinica (UGC) Allergy-Instituto de Investigación Biomédica (IBIMA), Málaga University General Hospital, Málaga, Spain.
authors.forename: Inmaculada
authors.initials: I
authors.lastname: Doña
authors.affiliation: Unidad de Gestión Clinica (UGC) Allergy-Instituto de Investigación Biomédica (IBIMA), Málaga University General Hospital, Málaga, Spain.
authors.forename: María J
authors.initials: MJ
authors.lastname: Torres
authors.affiliation: Research Laboratory, IBIMA-Málaga University General Hospital, Málaga, Spain; Unidad de Gestión Clinica (UGC) Allergy-Instituto de Investigación Biomédica (IBIMA), Málaga University General Hospital, Málaga, Spain.
authors.forename: Cristobalina
authors.initials: C
authors.lastname: Mayorga
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM) U-954, Nutrition-Génétique et exposition aux risques environmentaux, Faculty of Medicine, University of Nancy, Vandoeuvre-les-Nancy, France; University Hospital Center (CHU) of Nancy, Vandoeuvre-les-Nancy, France.
authors.forename: Rosa M
authors.initials: RM
authors.lastname: Guéant-Rodríguez
authors.affiliation: Research Laboratory, IBIMA-Málaga University General Hospital, Málaga, Spain.
authors.forename: Pedro
authors.initials: P
authors.lastname: Ayuso
authors.affiliation: Allergy Service, Alicante Hospital, Alicante, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Fernández
authors.affiliation: Allergy Service, Cruz Roja Central Hospital, Madrid, Spain.
authors.forename: José J
authors.initials: JJ
authors.lastname: Laguna
authors.affiliation: Pharmacology Department, University of Extremadura, Cáceres, Spain.
authors.forename: José A G
authors.initials: JA
authors.lastname: Agúndez
authors.affiliation: Biochemistry, Molecular Biology and Genetics Department, University of Extremadura, Cáceres, Spain.
authors.forename: Elena
authors.initials: E
authors.lastname: García-Martín
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM) U-954, Nutrition-Génétique et exposition aux risques environmentaux, Faculty of Medicine, University of Nancy, Vandoeuvre-les-Nancy, France; University Hospital Center (CHU) of Nancy, Vandoeuvre-les-Nancy, France.
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Guéant
authors.affiliation: Unidad de Gestión Clinica (UGC) Allergy-Instituto de Investigación Biomédica (IBIMA), Málaga University General Hospital, Málaga, Spain.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Canto
authors.affiliation: Research Unit, Hospital Universitario Dr. Negrín, Las Palmas de Gran Canaria, Spain.
authors.forename: Miguel
authors.initials: M
authors.lastname: Blanca
mesh_terms: D000328:Adult; D000483:Alleles; D000799:Angioedema / Q000139:chemically induced* / Q000235:genetics*; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects*; D016022:Case-Control Studies; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006801:Humans; D008869:Microtubule-Associated Proteins / Q000235:genetics*; D008875:Middle Aged; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; C527270:CEP68 protein, human; D008869:Microtubule-Associated Proteins