HLA-DRA variants predict penicillin allergy in genome-wide fine-mapping genotyping

Guéant, Jean Louis; Romano, Antonino; Cornejo-García, J.A.; Oussalah, Abderrahim; Chéry, Céline; Blanca‐López, Natalia; Guéant-Rodríguez, Rosa María; Gaeta, Francesco; Rouyer, Pierre; Josse, Thomas; Canto, Gabriella; Carmona, F. David; Bossini‐Castillo, Lara; Martín, Javier; Laguna, José Julio; Fernández, J.; Brito, Francisco Feo; Ostrov, David A.; Plasencia, Pablo C.; Mayorga, Cristobalina; Torres, Marı́a José; Blanca, Miguel

doi:10.1016/j.jaci.2014.07.047

Cited by 84 publications

(72 citation statements)

References 35 publications

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“…We found that the rs7192 and rs8084 variants in the HLA-DRA gene were associated with a positive skin test response to amoxicillin and penicillin but not to cephalosporins. We hypothesize that these SNPs could have a role in the presentation of BL-derived antigenic motifs through changes in the 3-dimensional structure of the MHC α/β chains [24]. In addition, an association was found between BL allergy and 2 variants in the HLA-DRA/HLA-DRB5 region (rs7754768 and rs9268832) [24].…”

Section: Immediate Reactions To Bl Antibioticsmentioning

confidence: 92%

“…All the aforementioned studies were performed according to a candidate gene approach on the basis of biological plausibility criteria. We recently published the only available genomewide fine-mapping genotyping study, which was based on 2 independent populations from Spain and Italy [24]. We found that the rs7192 and rs8084 variants in the HLA-DRA gene were associated with a positive skin test response to amoxicillin and penicillin but not to cephalosporins.…”

Section: Immediate Reactions To Bl Antibioticsmentioning

confidence: 99%

“…We hypothesize that these SNPs could have a role in the presentation of BL-derived antigenic motifs through changes in the 3-dimensional structure of the MHC α/β chains [24]. In addition, an association was found between BL allergy and 2 variants in the HLA-DRA/HLA-DRB5 region (rs7754768 and rs9268832) [24]. Our results agree with those of various studies showing a link between increased IgE levels and HLA alleles [30,31] and a potential effect of NOD2 polymorphisms on HLA-DRA expression [32,33].…”

Section: Immediate Reactions To Bl Antibioticsmentioning

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: Immediate Reactions To Bl Antibioticsmentioning

confidence: 92%

Section: Immediate Reactions To Bl Antibioticsmentioning

confidence: 99%

Section: Immediate Reactions To Bl Antibioticsmentioning

confidence: 99%

See 1 more Smart Citation

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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“…The case group had to have a history compatible with an immediate reaction to β-lactam and with a positive result of skin tests. Skin tests were made with major and minor determinants of benzyl penicillin (penicilloyl-polylysine and minor determinant mixture (MDM) containing benzyl-penicillin, sodium benzyl-penicilloate, and benzyl-penicilloic acid at a final concentration of 1.5 mmol/L) (Torres et al, 2003;Guéant et al, 2015). The control group included the patients who presented negative skin test to β-lactam and had no history of allergic, dermatologic, or respiratory diseases, or autoimmune diseases such as asthma, eczema, allergic rhinitis, and urticaria.…”

Section: Subjectsmentioning

confidence: 99%

Correlation analysis of gene polymorphisms and β-lactam allergy

Liu

et al. 2015

J. Zhejiang Univ. Sci. B

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A total of 64 patients with β-lactam allergy and 30 control subjects were enrolled in a case-control study.This study is aimed to analyze the relationship between β-lactam allergy and 10 single nucleotide polymorphisms (SNPs) in interleukin-10 (IL-10), IL-13, IL-4Rα, high-affinity immunoglobulin E-receptor β chain (FcεRIβ), interferon γ receptor 2 (IFNGR2), and CYP3A4, and within the Han Chinese population of Northwest China. Genotyping for the SNPs was conducted using the Sequenom MassARRAY ® platform. SPSS 17.0 was employed to analyze the statistical data and SHEsis was used to perform the haplotype reconstruction and analyze linkage disequilibrium of SNPs of IL-10 and IL-13. The results showed that the genotype distribution of CYP3A4 rs2242480/CT differed significantly between case and control groups of males (P=0.022; odds ratio (OR)=0.167, 95% confidence interval (CI): 0.032-0.867). Further analysis showed that CCA, CCG, and TAA haplotypes of IL-10 had no significant correlation in patients with β-lactam allergy. The correlation between CCT and CAC haplotypes of IL-13 and β-lactam allergy needs to be further studied. The analysis did not reveal any differences in the distribution of others gene polymorphisms between cases and controls.

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“…12 This review focuses on the purely T-cell mediated drug hypersensitivity reactions, although the same principles and models likely apply to B-cell mediated reactions as well. [12][13][14] Here, we provide an overview of the data supporting current models of T-cell mediated DHR, propose a new model of drug hypersensitivity that expands upon the existing models to include the role of microbial pathogen exposure in the generation of drug-specific T-cell responses, and discuss the implications for clinical practice and drug safety, design and development..…”

Section: Introductionmentioning

confidence: 99%

Evolving models of the immunopathogenesis of T cell–mediated drug allergy: The role of host, pathogens, and drug response

2015

Journal of Allergy and Clinical Immunology

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Immune-mediated adverse drug reactions (IM-ADRs) are an underrecognized source of preventable morbidity, mortality, and cost. Increasingly, genetic variation in the HLA loci is associated with risk of severe reactions, highlighting the importance of T-cell immune responses in the mechanisms of both B-cell mediated and primary T-cell mediated IM-ADRs. In this review, we summarize the role of host genetics, microbes and drugs in the development of IM-ADRs, expand upon the existing models of IM-ADR pathogenesis to address multiple unexplained observations, discuss the implications of this work in clinical practice today, and describe future applications for pre-clinical drug toxicity screening, drug design, and development.

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HLA-DRA variants predict penicillin allergy in genome-wide fine-mapping genotyping

Cited by 84 publications

References 35 publications

Update on the Genetic Basis of Drug Hypersensitivity Reactions

Update on the Genetic Basis of Drug Hypersensitivity Reactions

Correlation analysis of gene polymorphisms and β-lactam allergy

Evolving models of the immunopathogenesis of T cell–mediated drug allergy: The role of host, pathogens, and drug response

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