Variants of CEP68 Gene Are Associated with Acute Urticaria/Angioedema Induced by Multiple Non-Steroidal Anti-Inflammatory Drugs

Cornejo-García, José Antonio; Flores, Carlos; Plaza-Serón, María del Carmen; Acosta‐Herrera, Marialbert; Blanca‐López, Natalia; Doña, Inmaculada; Torres, Marı́a José; Mayorga, Cristobalina; Guéant-Rodríguez, Rosa María; Ayuso, Pedro; Fernández, J.; Laguna, José Julio; Agúndez, José A. G.; García‐Martín, Elena; Guéant, Jean‐Louis; Cantó, Gabriela; Blanca, Miguel

doi:10.1371/journal.pone.0090966

Cited by 20 publications

(18 citation statements)

References 53 publications

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“…Seventeen variants showed evidence of association with NIUA, including the SNP rs7572857. Moreover, 8 of these polymorphisms were also marginally associated with NERD and blended reactions [126]. Although our findings suggest a role for CEP68 in crosshypersensitivity to NSAIDs, the molecular basis for these associations requires further elucidation.…”

Section: Beyond the Candidate Gene Approachmentioning

confidence: 66%

“…The authors found an intriguing association between the decline in FEV 1 and a nonsynonymous polymorphism (rs7572857, Gly74Ser) in centrosomal protein of 68 Kd (CEP68) [123], a gene involved in centrosomal cohesion and epidermal growth factor signaling [124,125]. Our group evaluated 53 common SNPs in this gene in a population of Spanish patients presenting NIUA, NERD, and blended reactions [126]. Seventeen variants showed evidence of association with NIUA, including the SNP rs7572857.…”

Section: Beyond the Candidate Gene Approachmentioning

confidence: 99%

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Update on the Genetic Basis of Drug Hypersensitivity Reactions

Jurado‐Escobar¹,

Perkins²,

García‐Martín³

et al. 2017

J Investig Allergol Clin Immunol

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Drug hypersensitivity reactions (DHRs) are unpredictable, complex responses to medicines in predisposed individuals. They represent a major health problem owing to the number of patients affected and the severity of the clinical conditions they can induce. In addition to environmental factors, the underlying mechanisms of DHRs are also influenced by genetic factors, although considerable gaps remain in our knowledge. Therefore, further study of the genetics of DHRs is necessary to shed light on their underlying mechanisms. In this manuscript, we provide an update on the genetic basis of the most frequent types of DHRs, including those mediated by immunological and nonimmunological mechanisms. For the first group, we will focus on immediate reactions to β-lactam antibiotics, which are associated mainly with the IgE pathway (IL13, IL4R, LGALS3, and NOD2) and antigen presentation (HLA-DRA), and nonimmediate reactions to allopurinol, anticonvulsants, antibiotics, and antiretrovirals, which are often associated with polymorphisms in the HLA system. For the second group, we will focus on nonsteroidal anti-inflammatory drugs, which are mostly associated with genetic variants in enzymes and receptors from the arachidonic acid pathway (eg, ALOX5, ALOX5AP, PTGDR, and CYSLTR1). The information provided here will be of interest for medical practitioners from a range of disciplines who come across these reactions in their clinical practice, as well as for allergologists. Key words: Drug hypersensitivity. Immunologically-mediated reactions. Cross-hypersensitivity. Single-nucleotide polymorphisms. Genomewide association study. ResumenLas reacciones de hipersensibilidad a fármacos (RHFs) son respuestas no predecibles que se producen en algunos sujetos y que representan un serio problema de salud pública debido al número de pacientes implicados y a su potencial gravedad. Además de factores ambientales, en estas reacciones también participan factores genéticos, cuya influencia está, en la mayoría de los casos, aún por dilucidar. En este manuscrito describiremos la información disponible sobre la base genética de los tipos más frecuentes de RHFs, tanto de las mediadas inmunológicamente como de aquellas en las que no se requiere reconocimiento antigénico. En el primer grupo nos ocuparemos de las reacciones inmediatas a antibióticos β-lactámicos, que han sido asociadas con variantes relacionadas con la IgE (IL13, IL4R, LGALS3 y NOD2) y la presentación antigénica (HLA-DRA), y de las reacciones no inmediatas a diferentes grupos de medicamentos (alopurinol, anticonvulsivos, antibióticos y antiretrovirales), relacionadas fundamentalmente con polimorfismos en el sistema HLA. En el segundo grupo nos centraremos en las reacciones inducidas por antiinflamatorios no esteroideos (AINE), que han sido asociadas básicamente con variantes en enzimas y receptores de la vía del ácido araquidónico (ALOX5, ALOX5AP, PTGDR y CYSLTR1, entre otros). Esta revisión puede ser de interés no sólo para alergólogos, sino para los profesionales de otras ...

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Section: Beyond the Candidate Gene Approachmentioning

confidence: 66%

Section: Beyond the Candidate Gene Approachmentioning

confidence: 99%

Update on the Genetic Basis of Drug Hypersensitivity Reactions

Jurado‐Escobar¹,

Perkins²,

García‐Martín³

et al. 2017

J Investig Allergol Clin Immunol

View full text Add to dashboard Cite

show abstract

“…Seventeen SNPs, including the Gly74Ser variant, were associated with NIUA. Although not remaining significant after multiple testing corrections, 8 of these variants were also associated with NERD and blended reactions [83]. These results suggest that CEP68 variants may play a key role in the development of various manifestations of NSAIDinduced hypersensitivity.…”

Section: Gwas Approachmentioning

confidence: 79%

“…The most significant associations were found for SNPs in a 68-kDa centrosomal protein (CEP68), and the nonsynonymous polymorphism rs7572857 (Gly74Ser) was associated with the decline in FEV 1 [100]. We recently analyzed 53 common CEP68 variants in a Spanish population of patients with NSAID-induced DHRs including NIUA, NERD, and blended reactions [83]. Seventeen SNPs, including the Gly74Ser variant, were associated with NIUA.…”

Section: Gwas Approachmentioning

confidence: 99%

The Genetics of Drug Hypersensitivity Reactions

Cornejo-García

Jurado‐Escobar

Doña

et al. 2016

J Investig Allergol Clin Immunol

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Drug hypersensitivity reactions (DHRs) are a major problem for healthcare systems, regulatory agencies, and the pharmaceutical industry. DHRs are induced by various mechanisms and encompass a heterogeneous set of potentially life-threatening clinical entities. In addition to environmental effects, individual factors play a key role in this intricate puzzle. However, despite commendable efforts in recent years to identify individual predisposing factors, our knowledge of the genetic basis of these reactions remains incomplete. In this manuscript, we summarize current research on the genetics of DHRs, focusing on specific immune-mediated reactions (immediate and nonimmediate) and on pharmacologically mediated reactions (cross-intolerance to nonsteroidal anti-inflammatory drugs). We also provide some thoughts on potential technological approaches that would help us to decipher the molecular mechanisms underlying DHRs. We believe this manuscript will be of interest not only for allergists and basic researchers in the field, but also for clinicians from various areas of expertise who manage these reactions in their clinical practice. Key words: Drug hypersensitivity. Immediate and nonimmediate reactions. Cross-intolerance. Single-nucleotide polymorphisms. Genome-wide association study. ResumenLas reacciones de hipersensibilidad a fármacos (RHFs) son un problema preocupante para los sistemas de salud, las agencias reguladoras y la industria. Además de la diversidad de mecanismos implicados, las RHFs incluyen un conjunto heterogéneo de entidades clínicas que pueden amenazar la vida del paciente. A esta complejidad se añade el hecho de que, además de factores ambientales, en ellas participan factores individuales. A pesar del considerable esfuerzo desarrollado en los últimos años en la identificación de los factores individuales que predisponen a la aparición de estas reacciones, nuestro conocimiento sobre la base genética de las RHFs es todavía limitado. En esta revisión se presentan los datos disponibles sobre la genética de las RHFs, tomando como modelo las reacciones mediadas por mecanismos inmunológicos específicos (anticuerpos IgE y células T, reacciones inmediatas y no inmediatas) así como las mediadas por mecanismos farmacológicos (intolerancia cruzada a anti-inflamatorios no esteroideos). También se destacan las aproximaciones tecnológicas que pueden proporcionar información fundamental sobre los mecanismos moleculares que subyacen en estas reacciones. Creemos que este manuscrito será útil no solo para alergólogos e investigadores básicos en éste área, sino también para otros profesionales de la medicina que pueden encontrarse con este tipo de reacciones en su práctica clínica. Palabras clave: Hipersensibilidad a fármacos. Reacciones inmediatas y no inmediatas. Intolerancia cruzada. Polimorfismos de un único nucleótido. Estudios de asociación de genoma completo.

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“…The MHC-encoded susceptibility genes Between 1999 and 2014, eight studies, mainly from Spain, evaluated potential genetic predictors in association with NAR to NSAIDs (43)(44)(45)(46)(47)(48)(49)(50). The first report by Quiralte et al evaluated .…”

Section: Genetic Predictors Of Nar: the Examples Of Nonspecific Reactmentioning

confidence: 99%

Genetic variants associated with drugs-induced immediate hypersensitivity reactions: a PRISMA-compliant systematic review

Oussalah

Mayorga

Blanca

et al. 2016

Allergy

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Drug hypersensitivity includes allergic (AR) and nonallergic reactions (NARs) influenced by genetic predisposition. We performed a systematic review of genetic predictors of IgE-mediated AR and NAR with MEDLINE and PubMed search engine between January 1966 and December 2014. Among 3110 citations, the search selected 53 studies, 42 of which remained eligible. These eligible studies have evaluated genetic determinants of immediate reactions (IR) to beta-lactams (n = 19), NAR against aspirin (n = 12) and other nonsteroidal anti-inflammatory drugs (NSAIDs) (n = 8), and IR to biologics (n = 3). We reported two genomewide association studies and four case-control studies on candidate genes validated by replication. Genes involved in IR to beta-lactams belonged to HLA type 2 antigen processing, IgE production, atopy, and inflammation, including 4 genes validated by replications, HLA-DRA, ILR4, NOD2, and LGALS3. Genes involved in NAR to aspirin belonged to arachidonic acid pathway, membranespanning 4A gene family, histamine production pathway, and pro-inflammatory cytokines, while those involved in NAR to all NSAIDs belonged to arachidonic acid pathway and HLA antigen processing pathway. ALOX5 was a common predictor of studies on NAR to both aspirin and NSAIDs. Although these first conclusions could be drawn, this review highlights also the lack of reliable data and the need for replicating studies in contrasted populations, taking into account worldwide allele frequencies, gene-gene interactions, and contrasted situations of environmental exposure.Allergy 71 (2016) 443-462

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Variants of CEP68 Gene Are Associated with Acute Urticaria/Angioedema Induced by Multiple Non-Steroidal Anti-Inflammatory Drugs

Cited by 20 publications

References 53 publications

Update on the Genetic Basis of Drug Hypersensitivity Reactions

Update on the Genetic Basis of Drug Hypersensitivity Reactions

The Genetics of Drug Hypersensitivity Reactions

Genetic variants associated with drugs-induced immediate hypersensitivity reactions: a PRISMA-compliant systematic review

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