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Variants ID'd in Phenytoin-Related Adverse Skin Reactions

TUESDAY, Aug. 5, 2014 (HealthDay News) -- CYP2C variants have been identified as being involved in phenytoin-related severe cutaneous adverse reactions, according to a study published in the Aug. 6 issue of the Journal of the American Medical Association.

Wen-Hung Chung, M.D., Ph.D., from Chang Gung Memorial Hospital in Taoyuan, Taiwan, and colleagues conducted a case-control study to examine the genetic factors associated with phenytoin-related severe cutaneous adverse reactions. Data were included for 105 cases with phenytoin-related severe cutaneous adverse reactions, 78 cases with maculopapular exanthema, 130 phenytoin-tolerant control participants, and 3,655 population controls from Taiwan, Japan, and Malaysia. The samples were used for a genome-wide association study, direct sequencing of associated loci, and replication analysis, and were validated in different case-control populations.

The researchers identified a cluster of 16 single-nucleotide polymorphisms in CYP2C genes at 10q23.33 that reached genome-wide significance. A missense variant rs1057910 (CYP2C9*3) was identified on direct sequencing of CYP2C, which showed significant association with phenytoin-related severe cutaneous adverse reactions (odds ratio, 12). The association was seen in additional samples from Taiwan, Japan, and Malaysia. In a meta-analysis there was an overall odds ratio of 11 for CYP2C9*3 with phenytoin-related severe cutaneous adverse reactions. Patients with phenytoin-related severe cutaneous adverse reactions, especially CYP2C9*3 carriers, had delayed clearance of plasma phenytoin.

"This study identified CYP2C variants, including CYP2C9*3, known to reduce drug clearance, as important genetic factors associated with phenytoin-related severe cutaneous adverse reactions," the authors write.

Two authors disclosed a patent application pending for risk assessment for phenytoin-induced adverse drug reactions.

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