TY - JOUR
T1 - HLA-DRA variants predict penicillin allergy in genome-wide fine-mapping genotyping
AU - Romano, Antonino
AU - Guéant, Jean-Louis
AU - Cornejo-Garcia, Jose-Antonio
AU - Oussalah, Abderrahim
AU - Chery, Celine
AU - Blanca-López, Natalia
AU - Guéant-Rodriguez, Rosa-Maria
AU - Rouyer, Pierre
AU - Josse, Thomas
AU - Canto, Gabriella
AU - Carmona, F. David
AU - Bossini-Castillo, Lara
AU - Martin, Javier
AU - Laguna, Jose-Julio
AU - Fernandez, Javier
AU - Feo, Francisco
AU - Ostrov, David A.
AU - Plasencia, Pablo C.
AU - Mayorga, Cristobalina
AU - Torres, Maria-Jose
AU - Blanca, Miguel
PY - 2015
Y1 - 2015
N2 - 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.
Copyright © 2014 American Academy of Allergy, Asthma & Immunology. All rights reserved.
KEYWORDS:
Drug allergy; HLA-DRA; amoxicillin; anaphylaxis; genome-wide association; immediate-type reactions; penicillins; β-lactams
AB - 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.
Copyright © 2014 American Academy of Allergy, Asthma & Immunology. All rights reserved.
KEYWORDS:
Drug allergy; HLA-DRA; amoxicillin; anaphylaxis; genome-wide association; immediate-type reactions; penicillins; β-lactams
KW - genetic predictors
KW - genetic predictors
UR - http://hdl.handle.net/10807/72429
U2 - 10.1016/j.jaci.2014.07.047
DO - 10.1016/j.jaci.2014.07.047
M3 - Article
VL - 135
SP - 253
EP - 259
JO - JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY
JF - JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY
SN - 0091-6749
ER -