title: HLA-A*3101 and carbamazepine-induced hypersensitivity reactions in Europeans.
abstract: BACKGROUND
  Carbamazepine causes various forms of hypersensitivity reactions, ranging from maculopapular exanthema to severe blistering reactions. The HLA-B*1502 allele has been shown to be strongly correlated with carbamazepine-induced Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS-TEN) in the Han Chinese and other Asian populations but not in European populations.
  
  
  METHODS
  We performed a genomewide association study of samples obtained from 22 subjects with carbamazepine-induced hypersensitivity syndrome, 43 subjects with carbamazepine-induced maculopapular exanthema, and 3987 control subjects, all of European descent. We tested for an association between disease and HLA alleles through proxy single-nucleotide polymorphisms and imputation, confirming associations by high-resolution sequence-based HLA typing. We replicated the associations in samples from 145 subjects with carbamazepine-induced hypersensitivity reactions.
  
  
  RESULTS
  The HLA-A*3101 allele, which has a prevalence of 2 to 5% in Northern European populations, was significantly associated with the hypersensitivity syndrome (P=3.5×10(-8)). An independent genomewide association study of samples from subjects with maculopapular exanthema also showed an association with the HLA-A*3101 allele (P=1.1×10(-6)). Follow-up genotyping confirmed the variant as a risk factor for the hypersensitivity syndrome (odds ratio, 12.41; 95% confidence interval [CI], 1.27 to 121.03), maculopapular exanthema (odds ratio, 8.33; 95% CI, 3.59 to 19.36), and SJS-TEN (odds ratio, 25.93; 95% CI, 4.93 to 116.18).
  
  
  CONCLUSIONS
  The presence of the HLA-A*3101 allele was associated with carbamazepine-induced hypersensitivity reactions among subjects of Northern European ancestry. The presence of the allele increased the risk from 5.0% to 26.0%, whereas its absence reduced the risk from 5.0% to 3.8%. (Funded by the U.K. Department of Health and others.).
authors.affiliation: Molecular and Cellular Therapeutics, the Royal College of Surgeons in Ireland, Dublin, Ireland.
authors.forename: Mark
authors.initials: M
authors.lastname: McCormack
authors.forename: Ana
authors.initials: A
authors.lastname: Alfirevic
authors.forename: Stephane
authors.initials: S
authors.lastname: Bourgeois
authors.forename: John J
authors.initials: JJ
authors.lastname: Farrell
authors.forename: Dalia
authors.initials: D
authors.lastname: Kasperavičiūtė
authors.forename: Mary
authors.initials: M
authors.lastname: Carrington
authors.forename: Graeme J
authors.initials: GJ
authors.lastname: Sills
authors.forename: Tony
authors.initials: T
authors.lastname: Marson
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Jia
authors.forename: Paul I W
authors.initials: PI
authors.lastname: de Bakker
authors.forename: Krishna
authors.initials: K
authors.lastname: Chinthapalli
authors.forename: Mariam
authors.initials: M
authors.lastname: Molokhia
authors.forename: Michael R
authors.initials: MR
authors.lastname: Johnson
authors.forename: Gerard D
authors.initials: GD
authors.lastname: O'Connor
authors.forename: Elijah
authors.initials: E
authors.lastname: Chaila
authors.forename: Saud
authors.initials: S
authors.lastname: Alhusaini
authors.forename: Kevin V
authors.initials: KV
authors.lastname: Shianna
authors.forename: Rodney A
authors.initials: RA
authors.lastname: Radtke
authors.forename: Erin L
authors.initials: EL
authors.lastname: Heinzen
authors.forename: Nicole
authors.initials: N
authors.lastname: Walley
authors.forename: Massimo
authors.initials: M
authors.lastname: Pandolfo
authors.forename: Werner
authors.initials: W
authors.lastname: Pichler
authors.forename: B Kevin
authors.initials: BK
authors.lastname: Park
authors.forename: Chantal
authors.initials: C
authors.lastname: Depondt
authors.forename: Sanjay M
authors.initials: SM
authors.lastname: Sisodiya
authors.forename: David B
authors.initials: DB
authors.lastname: Goldstein
authors.forename: Panos
authors.initials: P
authors.lastname: Deloukas
authors.forename: Norman
authors.initials: N
authors.lastname: Delanty
authors.forename: Gianpiero L
authors.initials: GL
authors.lastname: Cavalleri
authors.forename: Munir
authors.initials: M
authors.lastname: Pirmohamed
mesh_terms: D000927:Anticonvulsants / Q000009:adverse effects* / Q000627:therapeutic use; D002220:Carbamazepine / Q000009:adverse effects* / Q000627:therapeutic use; D004342:Drug Hypersensitivity / Q000235:genetics*; D005076:Exanthema / Q000139:chemically induced / Q000235:genetics; D055106:Genome-Wide Association Study; D005838:Genotype; D015234:HLA-A Antigens / Q000235:genetics*; D006650:Histocompatibility Testing; D006801:Humans; D020641:Polymorphism, Single Nucleotide; D013262:Stevens-Johnson Syndrome / Q000139:chemically induced / Q000235:genetics; D044465:White People / Q000235:genetics*
chemical_list: D000927:Anticonvulsants; D015234:HLA-A Antigens; C506273:HLA-A*31:01 antigen; D002220:Carbamazepine