title: HLA-DRA variants predict penicillin allergy in genome-wide fine-mapping genotyping.
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 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.
authors.affiliation: Inserm U-954, Faculté de Médecine, University of Lorraine and University Hospital Center (CHU) of Nancy, Nancy, France. Electronic address: jean-louis.gueant@univ-lorraine.fr.
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Guéant
authors.affiliation: Department of Internal Medicine and Geriatrics, UCSC-Allergy Unit, Complesso Integrato Columbus, Rome, Italy; IRCCS of Mental Retardation and Brain Aging, Oasi Maria S.S., Troina, Italy.
authors.forename: Antonino
authors.initials: A
authors.lastname: Romano
authors.affiliation: Inserm U-954, Faculté de Médecine, University of Lorraine and University Hospital Center (CHU) of Nancy, Nancy, France; Allergy Service, Carlos Haya Hospital (IBIMA-Hospital Regional Universitario de Malaga), Malaga, Spain.
authors.forename: Jose-Antonio
authors.initials: JA
authors.lastname: Cornejo-Garcia
authors.affiliation: Inserm U-954, Faculté de Médecine, University of Lorraine and University Hospital Center (CHU) of Nancy, Nancy, France.
authors.forename: Abderrahim
authors.initials: A
authors.lastname: Oussalah
authors.affiliation: Inserm U-954, Faculté de Médecine, University of Lorraine and University Hospital Center (CHU) of Nancy, Nancy, France.
authors.forename: Celine
authors.initials: C
authors.lastname: Chery
authors.affiliation: Allergy Service, Infanta Leonor Hospital, Madrid, Spain.
authors.forename: Natalia
authors.initials: N
authors.lastname: Blanca-López
authors.affiliation: Inserm U-954, Faculté de Médecine, University of Lorraine and University Hospital Center (CHU) of Nancy, Nancy, France.
authors.forename: Rosa-Maria
authors.initials: RM
authors.lastname: Guéant-Rodriguez
authors.affiliation: Department of Internal Medicine and Geriatrics, UCSC-Allergy Unit, Complesso Integrato Columbus, Rome, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Gaeta
authors.affiliation: Inserm U-954, Faculté de Médecine, University of Lorraine and University Hospital Center (CHU) of Nancy, Nancy, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Rouyer
authors.affiliation: Inserm U-954, Faculté de Médecine, University of Lorraine and University Hospital Center (CHU) of Nancy, Nancy, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Josse
authors.affiliation: Allergy Service, Infanta Leonor Hospital, Madrid, Spain.
authors.forename: Gabriella
authors.initials: G
authors.lastname: Canto
authors.affiliation: Instituto de Parasitología y Biomedicina López Neyra, Armilla, Granada, Spain.
authors.forename: F David
authors.initials: FD
authors.lastname: Carmona
authors.affiliation: Instituto de Parasitología y Biomedicina López Neyra, Armilla, Granada, Spain.
authors.forename: Lara
authors.initials: L
authors.lastname: Bossini-Castillo
authors.affiliation: Instituto de Parasitología y Biomedicina López Neyra, Armilla, Granada, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Martin
authors.affiliation: Allergy Unit, Hospital de la Cruz Roja, Madrid, Spain.
authors.forename: Jose-Julio
authors.initials: JJ
authors.lastname: Laguna
authors.affiliation: Allergy Service, Hospital de Alicante, Alicante, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Fernandez
authors.affiliation: Allergy Service, Hospital Ciudad Real, Ciudad Real, Spain.
authors.forename: Francisco
authors.initials: F
authors.lastname: Feo
authors.affiliation: College of Medicine, University of Florida, Gainesville, Fla.
authors.forename: David A
authors.initials: DA
authors.lastname: Ostrov
authors.affiliation: College of Medicine, University of Florida, Gainesville, Fla.
authors.forename: Pablo C
authors.initials: PC
authors.lastname: Plasencia
authors.affiliation: Allergy Service, Carlos Haya Hospital (IBIMA-Hospital Regional Universitario de Malaga), Malaga, Spain.
authors.forename: Cristobalina
authors.initials: C
authors.lastname: Mayorga
authors.affiliation: Allergy Service, Carlos Haya Hospital (IBIMA-Hospital Regional Universitario de Malaga), Malaga, Spain.
authors.forename: Maria-Jose
authors.initials: MJ
authors.lastname: Torres
authors.affiliation: Inserm U-954, Faculté de Médecine, University of Lorraine and University Hospital Center (CHU) of Nancy, Nancy, France; Allergy Service, Carlos Haya Hospital (IBIMA-Hospital Regional Universitario de Malaga), Malaga, Spain.
authors.forename: Miguel
authors.initials: M
authors.lastname: Blanca
mesh_terms: D004342:Drug Hypersensitivity / Q000453:epidemiology / Q000209:etiology / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D059805:HLA-DR alpha-Chains / Q000235:genetics*; D006801:Humans; D007558:Italy / Q000453:epidemiology; D008297:Male; D010406:Penicillins / Q000009:adverse effects*; D020641:Polymorphism, Single Nucleotide; D013030:Spain / Q000453:epidemiology
chemical_list: D059805:HLA-DR alpha-Chains; D010406:Penicillins
keywords: Drug allergy; HLA-DRA; amoxicillin; anaphylaxis; genome-wide association; immediate-type reactions; penicillins; β-lactams