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

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Abstract

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 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.

Conclusions:

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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