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


Mark McCormack, Hongsheng Gui, Andrés Ingason, Doug Speed, Galen E.B. Wright, Eunice J. Zhang, Rodrigo Secolin, Clarissa Yasuda, Maxwell Kwok, Stefan Wolking, Felicitas Becker, Sarah Rau, Andreja Avbersek, Kristin Heggeli, Costin Leu, Chantal Depondt, Graeme J. Sills, Anthony G. Marson, Pauls Auce, Martin J. Brodie, Ben Francis, Michael R. Johnson, Bobby P.C. Koeleman, Pasquale Striano, Antonietta Coppola, Federico Zara, Wolfram S. Kunz, Josemir W. Sander, Holger Lerche, Karl Martin Klein, Sarah Weckhuysen, Martin Krenn, Lárus J. Gudmundsson, Kári Stefánsson, Roland Krause, Neil Shear, Colin J.D. Ross, Norman Delanty, for the EPIGEN Consortium;, Munir Pirmohamed, Bruce C. Carleton, for the Canadian Pharmacogenomics Network for Drug Safety;, Fernando Cendes, Iscia Lopes-Cendes, Wei-ping Liao, Terence J. O’Brien, Sanjay M. Sisodiya, for the EpiPGX Consortium;, Stacey Cherny, Patrick Kwan, Larry Baum, for the International League Against Epilepsy Consortium on Complex Epilepsies;, Gianpiero L. Cavalleri 

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.


Posted on