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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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  • Jean Louis Gueant,
  • A Romano,
  • Abderrahim OUSSALAH,
  • Celine Chery,
  • Rosa Maria Rodriguez-Gueant,
  • Francesco Gaeta,
  • José Antonio Cornejo-García,
  • Pierre ROUYER,
  • Thomas Josse,
  • Cristobalina Mayorga,
  • María José Torres
Jean Louis Gueant
Universite de Lorraine Faculte de Medecine
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A Romano
Universite de Lorraine Faculte de Medecine
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Abderrahim OUSSALAH
Universite de Lorraine Faculte de Medecine
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Celine Chery
Universite de Lorraine Faculte de Medecine
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Rosa Maria Rodriguez-Gueant
Universite de Lorraine Faculte de Medecine
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Francesco Gaeta
Fondazione Policlinico Universitario Agostino Gemelli IRCCS
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José Antonio Cornejo-García
Hospital Regional Universitario de Malaga
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Pierre ROUYER
Universite de Lorraine Faculte de Medecine
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Thomas Josse
Universite de Lorraine Faculte de Medecine
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Cristobalina Mayorga
Hospital Regional Universitario de Malaga
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María José Torres
Hospital Regional Universitario de Malaga
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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:UNDER REVIEW

15 Jul 2021Submitted to Allergy
19 Jul 2021Assigned to Editor
19 Jul 2021Submission Checks Completed
21 Jul 2021Reviewer(s) Assigned