Editors' ChoiceDrug Reactions

Actionable Pharmacogenetics for Epilepsy

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Science Translational Medicine  20 Apr 2011:
Vol. 3, Issue 79, pp. 79ec57
DOI: 10.1126/scitranslmed.3002509

Size isn’t everything, even when considering sample size in genetic studies. In a recent study, McCormack et al. studied a small but well-defined population of individuals to identify a strong genetic risk factor for a rare severe adverse skin reaction to the anti-epileptic drug carbamazepine. This drug is a commonly used medication for epilepsy, and like all medications, its use is not without risk. These rare but severe hypersensitivity reactions can result in mortality in up to 10% of subjects.

The authors performed a genome-wide association study of just 22 individuals of European ancestry who had severe hypersensitivity reactions to carbamazepine. The authors unexpectedly found a signal with genome-wide statistical significance originating from the HLA-A*3101 allele, when cases were compared with data from 2691 control subjects in the Wellcome Trust Case-Control Consortium. They followed up this association in 106 subjects who had a less severe carbamazepine-induced skin eruption and found similar evidence for association with the HLA-A*3101 allele. In a separate study of 12 subjects who had a serious reaction called Stevens-Johnson syndrome in response to carbamazepine, the authors demonstrated a striking enrichment of the HLA-A*3101 allele—an odds ratio greater than 25! Stevens-Johnson syndrome is a rare severe adverse drug reaction in which skin blisters and literally sloughs off large areas of the body, frequently resulting in death. Carbamazepine is one of many drugs for which this syndrome has been reported.

With a genetic effect this strong, clinical applicability is likely. The authors calculate that only 83 patients would have to be screened for HLA-A*3101 to prevent one case of carbamazepine-induced hypersensitivity. This study demonstrates the power of using carefully defined and extreme cases in genetic studies, and the success of this study should encourage similar work. There may be many more big fish to catch in the genetics of rare severe drug reactions, even when an initial statistical power calculation may appear daunting.

M. McCormack et al., HLA-A*3101 and carbamazepine-induced hypersensitivity reactions in Europeans. N. Engl. J. Med. 364, 1134–1143 (2011). [PubMed]

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