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Next-Generation Sequencing and Genotype Association Studies Reveal the Association of HLA-DRB3*02:02 With Delayed Hypersensitivity to Penicillins
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  • Antonino Romano,
  • Abderrahim OUSSALAH,
  • Céline Chery,
  • Rosa Maria Rodriguez-Gueant,
  • Francesco Gaeta,
  • José Antonio Cornejo-García,
  • Pierre ROUYER,
  • Thomas Josse,
  • Cristobalina Mayorga,
  • María José Torres,
  • Jean Louis Gueant
Antonino Romano
University of Lorraine, INSERM UMR_S 1256, Nutrition, Genetics, and Environmental Risk Exposure (NGERE), Faculty of Medicine of Nancy
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Abderrahim OUSSALAH
Faculty of Medicine of Nancy, University of Lorraine
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Céline Chery
Inserm U 954
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Rosa Maria Rodriguez-Gueant
University of Nancy
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Francesco Gaeta
Allergy Unit, Columbus Hospital, Fondazione Policlinico A. Gemelli
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José Antonio Cornejo-García
Malaga Regional University Hospital-IBIMA, UMA
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Pierre ROUYER
Inserm U 954
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Thomas Josse
Department of Molecular Medicine, Division of Biochemistry, Molecular Biology, and Nutrition, University Hospital of Nancy
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Cristobalina Mayorga
IBIMA-Regional University Hospital of Malaga
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María José Torres
Universidad de Málaga Facultad de Medicina
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Jean Louis Gueant
University of Nancy
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Abstract

Background: Nonimmediate (delayed) allergic reactions to penicillins are common and some of them can be life-threatening. The genetic factors influencing these reactions are unknown/poorly known/poorly understood. We assessed the genetic predictors of a delayed penicillin allergy that cover the HLA loci. Methods: Using next-generation sequencing (NGS), we genotyped the MHC region in 24 patients with delayed hypersensitivity compared with 20 patients with documented immediate hypersensitivity to penicillins recruited in Italy. Subsequently, we analyzed in silico Illumina Immunochip genotyping data that covered the HLA loci in 98 Spanish patients with delayed hypersensitivity and 315 with immediate hypersensitivity compared to 1,308 controls. Results: The two alleles DRB3*02:02:01:02 and DRB3*02:02:01:01 were reported in twenty cases with delayed reactions (83%) and ten cases with immediate reactions (50%), but not in the Allele Frequency Net Database. Bearing at least one of the two alleles increased the risk of delayed reactions compared to immediate reactions, with an OR of 8.88 (95% CI, 3.37–23.32; P <0.0001). The haplotype (ACAA) from rs9268835, rs6923504, rs6903608, and rs9268838 genetic variants of the HLA-DRB3 genomic region was significantly associated with an increased risk of delayed hypersensitivity to penicillins (OR, 1.7; 95% CI: 1.06–1.92; P=0.001), but not immediate hypersensitivity. Conclusion: We showed that the HLA-DRB3 locus is strongly associated with an increased risk of delayed penicillin hypersensitivity, at least in Southwestern Europe. The determination of HLA-DRB3*02:02 alleles in the risk management of severe delayed hypersensitivity to penicillins should be evaluated further in larger population samples of different origins.

Peer review status:IN REVISION

12 Apr 2021Submitted to Allergy
13 Apr 2021Assigned to Editor
13 Apr 2021Submission Checks Completed
16 Apr 2021Reviewer(s) Assigned
09 May 2021Review(s) Completed, Editorial Evaluation Pending
11 May 2021Editorial Decision: Revise Minor