title: FCERI and Histamine Metabolism Gene Variability in Selective Responders to NSAIDS.
abstract: The high-affinity IgE receptor (Fcε RI) is a heterotetramer of three subunits: Fcε RIα, Fcε RIβ, and Fcε RIγ (αβγ2) encoded by three genes designated asFCER1A, FCER1B(MS4A2), andFCER1G, respectively. Recent evidence points to FCERI gene variability as a relevant factor in the risk of developing allergic diseases. Because Fcε RI plays a key role in the events downstream of the triggering factors in immunological response, we hypothesized that FCERI gene variants might be related with the risk of, or with the clinical response to, selective (IgE mediated) non-steroidal anti-inflammatory (NSAID) hypersensitivity. From a cohort of 314 patients suffering from selective hypersensitivity to metamizole, ibuprofen, diclofenac, paracetamol, acetylsalicylic acid (ASA), propifenazone, naproxen, ketoprofen, dexketoprofen, etofenamate, aceclofenac, etoricoxib, dexibuprofen, indomethacin, oxyphenylbutazone, or piroxicam, and 585 unrelated healthy controls that tolerated these NSAIDs, we analyzed the putative effects of the FCERI SNPsFCER1Ars2494262, rs2427837, and rs2251746;FCER1Brs1441586, rs569108, and rs512555;FCER1Grs11587213, rs2070901, and rs11421. Furthermore, in order to identify additional genetic markers which might be associated with the risk of developing selective NSAID hypersensitivity, or which may modify the putative association of FCERI gene variations with risk, we analyzed polymorphisms known to affect histamine synthesis or metabolism, such as rs17740607, rs2073440, rs1801105, rs2052129, rs10156191, rs1049742, and rs1049793 in theHDC, HNMT, andDAOgenes. No major genetic associations with risk or with clinical presentation, and no gene-gene interactions, or gene-phenotype interactions (including age, gender, IgE concentration, antecedents of atopy, culprit drug, or clinical presentation) were identified in patients. However, logistic regression analyses indicated that the presence of antecedents of atopy and the DAO SNP rs2052129 (GG) were strongly related (P< 0.001 andP= 0.005, respectively) with selective hypersensitivity to ibuprofen. With regard to patients with selective hypersensitivity to ASA, men were more prone to develop such a reaction than women (P= 0.011), and the detrimentalDAOSNP rs10156191 in homozygosity increased the risk of developing such hypersensitivity (P= 0.039).
authors.affiliation: Departamento de Farmacología, Universidad de Extremadura Cáceres, Spain.
authors.forename: Gemma
authors.initials: G
authors.lastname: Amo
authors.affiliation: Laboratorio de Investigación, Instituto de Investigación Biomédica de Málaga, Hospital Regional Universitario de Málaga, Universidad de Málaga Málaga, Spain.
authors.forename: José A
authors.initials: JA
authors.lastname: Cornejo-García
authors.affiliation: Servicio de Alergologia, Hospital Infanta Cristina Badajoz, Spain.
authors.forename: Jesus M
authors.initials: JM
authors.lastname: García-Menaya
authors.affiliation: Servicio de Alergologia, Hospital Infanta Cristina Badajoz, Spain.
authors.forename: Concepcion
authors.initials: C
authors.lastname: Cordobes
authors.affiliation: UGC de Alergia, Instituto de Investigación Biomédica de Málaga, Hospital Regional Universitario de Málaga, Universidad de Málaga Málaga, Spain.
authors.forename: M J
authors.initials: MJ
authors.lastname: Torres
authors.affiliation: Departamento de Farmacología, Universidad de Extremadura Cáceres, Spain.
authors.forename: Gara
authors.initials: G
authors.lastname: Esguevillas
authors.affiliation: Laboratorio de Investigación, Instituto de Investigación Biomédica de Málaga, Hospital Regional Universitario de Málaga, Universidad de Málaga Málaga, Spain.
authors.forename: Cristobalina
authors.initials: C
authors.lastname: Mayorga
authors.affiliation: Departamento de Farmacología, Universidad de Extremadura Cáceres, Spain.
authors.forename: Carmen
authors.initials: C
authors.lastname: Martinez
authors.affiliation: Servicio de Alergologia, Hospital Infanta Leonor Madrid, Spain.
authors.forename: Natalia
authors.initials: N
authors.lastname: Blanca-Lopez
authors.affiliation: Servicio de Alergologia, Hospital Infanta Leonor Madrid, Spain.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Canto
authors.affiliation: Departamento de Matemáticas, Universidad de Extremadura Cáceres, Spain.
authors.forename: Alfonso
authors.initials: A
authors.lastname: Ramos
authors.affiliation: Servicio de Alergologia, Hospital Infanta Leonor Madrid, Spain.
authors.forename: Miguel
authors.initials: M
authors.lastname: Blanca
authors.affiliation: Departamento de Farmacología, Universidad de Extremadura Cáceres, Spain.
authors.forename: José A G
authors.initials: JA
authors.lastname: Agúndez
authors.affiliation: Departamento de Farmacología, Universidad de Extremadura Cáceres, Spain.
authors.forename: Elena
authors.initials: E
authors.lastname: García-Martín
keywords: Fcε RI; biomarkers; histamine; hypersensitivity drug reactions; non-steroidal anti-inflammatory drugs (NSAIDS)