Genetic variation in CFH predicts phenytoin-induced maculopapular exanthema in European-descent patients

Neurology. 2018 Jan 23;90(4):e332-e341. doi: 10.1212/WNL.0000000000004853. Epub 2017 Dec 29.


Objective: To characterize, among European and Han Chinese populations, the genetic predictors of maculopapular exanthema (MPE), a cutaneous adverse drug reaction common to antiepileptic drugs.

Methods: We conducted a case-control genome-wide association study of autosomal genotypes, including Class I and II human leukocyte antigen (HLA) alleles, in 323 cases and 1,321 drug-tolerant controls from epilepsy cohorts of northern European and Han Chinese descent. Results from each cohort were meta-analyzed.

Results: We report an association between a rare variant in the complement factor H-related 4 (CFHR4) gene and phenytoin-induced MPE in Europeans (p = 4.5 × 10-11; odds ratio [95% confidence interval] 7 [3.2-16]). This variant is in complete linkage disequilibrium with a missense variant (N1050Y) in the complement factor H (CFH) gene. In addition, our results reinforce the association between HLA-A*31:01 and carbamazepine hypersensitivity. We did not identify significant genetic associations with MPE among Han Chinese patients.

Conclusions: The identification of genetic predictors of MPE in CFHR4 and CFH, members of the complement factor H-related protein family, suggest a new link between regulation of the complement system alternative pathway and phenytoin-induced hypersensitivity in European-ancestral patients.

Publication types

  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anticonvulsants* / adverse effects
  • Anticonvulsants* / therapeutic use
  • Apolipoproteins* / genetics
  • Asian People / genetics
  • Carbamazepine / adverse effects
  • Carbamazepine / therapeutic use
  • Case-Control Studies
  • Complement Factor H / genetics
  • Drug Eruptions* / ethnology
  • Drug Eruptions* / etiology
  • Drug Eruptions* / genetics
  • Epilepsy / drug therapy
  • Epilepsy / genetics
  • Genetic Variation*
  • Genome-Wide Association Study
  • HLA-A Antigens / genetics
  • Humans
  • Linkage Disequilibrium
  • Mutation, Missense
  • Pharmacogenomic Variants
  • Phenytoin* / adverse effects
  • Phenytoin* / therapeutic use
  • Retrospective Studies
  • White People / genetics


  • Anticonvulsants
  • Apolipoproteins
  • Carbamazepine
  • CFH protein, human
  • CFHR4 protein, human
  • Complement Factor H
  • HLA-A Antigens
  • HLA-A*31:01 antigen
  • Phenytoin