HLA-DRAvariants predict penicillin allergy in genome-wide fine-mapping genotyping

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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.


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


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.


We found significant associations with the single nucleotide polymorphisms rs4958427 ofZNF300(c.64-471G>A,P= 9.9 × 10−9), rs17612 ofC5(c.4311A>C [p.Glu1437Asp],P= 7.5 × 10−7), rs7754768 and rs9268832 of theHLA-DRA | HLA-DRB5interregion (P= 1.6 × 10−6 and 4.9 × 10−6), and rs7192 ofHLA-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 ofHLA-DRAandZNF300predicted skin test positivity to amoxicillin and other penicillins but not to cephalosporins. A haplotype block inHLA-DRAand theHLA-DRA | HLA-DRB5interregion 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-DRArs7192 and rs8084 were significantly associated with allergy to penicillins and amoxicillin (P= 6.0 × 10−4 andP= 4.0 × 10−4, respectively) but not to cephalosporins in the replication study.


Gene variants ofHLA-DRAand theHLA-DRA | HLA-DRB5interregion 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.

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