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

McCormack, M. et al. (2018) Genetic variation in CFH predicts phenytoin-induced maculopapular exanthema in European-descent patients. Neurology, 90(4), e332-e341. (doi: 10.1212/WNL.0000000000004853) (PMID:29288229) (PMCID:PMC5798660)

Abstract

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.

• Item Type: Articles
• Additional Information: Authors, for the EPIGEN Consortium;, for the Canadian Pharmacogenomics Network for Drug Safety;, for the EpiPGX Consortium;, for the International League Against Epilepsy Consortium on Complex Epilepsies. This article has a correction. Please see: Genetic variation in CFH predicts phenytoin-induced maculopapular exanthema in European-descent patients - October 16, 2018 : https://doi.org/10.1212/WNL.0000000000006483
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Sills, Dr Graeme
• Authors: McCormack, M., Gui, H., Ingason, A., Speed, D., Wright, G. E.B., Zhang, E. J., Secolin, R., Yasuda, C., Kwok, M., Wolking, S., Becker, F., Rau, S., Avbersek, A., Heggeli, K., Leu, C., Depondt, C., Sills, G. J., Marson, A. G., Auce, P., Brodie, M. J., Francis, B., Johnson, M. R., Koeleman, B. P.C., Striano, P., Coppola, A., Zara, F., Kunz, W. S., Sander, J. W., Lerche, H., Klein, K. M., Weckhuysen, S., Krenn, M., Gudmundsson, L. J., Stefánsson, K., Krause, R., Shear, N., Ross, C. J.D., Delanty, N., Pirmohamed, M., Carleton, B. C., Cendes, F., Lopes-Cendes, I., Liao, W.-p., O'Brien, T. J., Sisodiya, S. M., Cherny, S., Kwan, P., Baum, L., and Cavalleri, G. L.
• College/School: College of Medical Veterinary and Life Sciences > School of Life Sciences
• Journal Name: Neurology
• Publisher: Wolters Kluwer Health Inc. on behalf of the American Academy of Neurology
• ISSN: 0028-3878
• ISSN (Online): 1526-632X
• Published Online: 29 December 2017
• Copyright Holders: Copyright © 2017 The Authors
• First Published: First published in Neurology 90(4):e332-e341
• Publisher Policy: Reproduced under a Creative Commons License