Jean-Louis Guéant1, Antonino Romano2, Jose-Antonio Cornejo-Garcia3, Abderrahim Oussalah4, Celine Chery4, Natalia Blanca-López5, Rosa-Maria Guéant-Rodriguez4, Francesco Gaeta6, Pierre Rouyer4, Thomas Josse4, Gabriella Canto5, F David Carmona7, Lara Bossini-Castillo7, Javier Martin7, Jose-Julio Laguna8, Javier Fernandez9, Francisco Feo10, David A Ostrov11, Pablo C Plasencia11, Cristobalina Mayorga12, Maria-Jose Torres12, Miguel Blanca3. 1. 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. 2. 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. 3. 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. 4. Inserm U-954, Faculté de Médecine, University of Lorraine and University Hospital Center (CHU) of Nancy, Nancy, France. 5. Allergy Service, Infanta Leonor Hospital, Madrid, Spain. 6. Department of Internal Medicine and Geriatrics, UCSC-Allergy Unit, Complesso Integrato Columbus, Rome, Italy. 7. Instituto de Parasitología y Biomedicina López Neyra, Armilla, Granada, Spain. 8. Allergy Unit, Hospital de la Cruz Roja, Madrid, Spain. 9. Allergy Service, Hospital de Alicante, Alicante, Spain. 10. Allergy Service, Hospital Ciudad Real, Ciudad Real, Spain. 11. College of Medicine, University of Florida, Gainesville, Fla. 12. Allergy Service, Carlos Haya Hospital (IBIMA-Hospital Regional Universitario de Malaga), Malaga, Spain.
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.
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.
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