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

Jean Louis Guéant, Antonino Romano, Jose Antonio Cornejo-Garcia, Abderrahim Oussalah, Celine Chery, Natalia Blanca-López, Rosa Maria Guéant-Rodriguez, Francesco Gaeta, Pierre Rouyer, Thomas Josse, Gabriella Canto, F. David Carmona, Lara Bossini-Castillo, Javier Martin, Jose Julio Laguna, Javier Fernandez, Francisco Feo, David A. Ostrov, Pablo C. Plasencia, Cristobalina MayorgaMaria Jose Torres, Miguel Blanca

Research output: Contribution to journalArticlepeer-review


Background Immediate reactions to β-lactams are the most common causes of anaphylactic reactions and can be life-threatening. The few known genetic factors influencing these reactions suggest a link with atopy and inflammation.

Objective We performed a fine-mapping genome-wide association study of the genetic predictors of β-lactam allergy to better understand the underlying mechanisms.

Methods We studied 387 patients with immediate allergic reactions to β-lactams and 1124 paired control subjects from Spain. We replicated the results in 299 patients and 362 paired control subjects from Italy.

Results We found significant associations with the single nucleotide polymorphisms rs4958427 of ZNF300 (c.64-471G>A, P = 9.9 × 10-9), rs17612 of C5 (c.4311A>C [p.Glu1437Asp], P = 7.5 × 10-7), rs7754768 and rs9268832 of the HLA-DRA | HLA-DRB5 interregion (P = 1.6 × 10-6 and 4.9 × 10-6), and rs7192 of HLA-DRA (c.724T>G [p.Leu242Val], P = 7.4 × 10-6) in an allelic model, with similar results in an additive model. Single nucleotide polymorphisms of HLA-DRA and ZNF300 predicted skin test positivity to amoxicillin and other penicillins but not to cephalosporins. A haplotype block in HLA-DRA and the HLA-DRA | HLA-DRB5 interregion encompassed a motif involved in balanced expression of the α- and β-chains of MHC class II, whereas rs7192 was predicted to influence α-chain conformation. HLA-DRA rs7192 and rs8084 were significantly associated with allergy to penicillins and amoxicillin (P = 6.0 × 10-4 and P = 4.0 × 10-4, respectively) but not to cephalosporins in the replication study.

Conclusions Gene variants of HLA-DRA and the HLA-DRA | HLA-DRB5 interregion were significant predictors of allergy to penicillins but not to cephalosporins. These data suggest complex gene-environment interactions in which genetic susceptibility of HLA type 2 antigen presentation plays a central role.

Original languageEnglish
Pages (from-to)253-259
Number of pages7
JournalJournal of Allergy and Clinical Immunology
Issue number1
Publication statusPublished - Jan 1 2015


  • amoxicillin
  • anaphylaxis
  • Drug allergy
  • genome-wide association
  • immediate-type reactions
  • penicillins
  • β-lactams

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Medicine(all)


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